PROMISE& PROGRESS T H E S I D N E Y K I M M E L C O M P R E H E N S I V E C A N C E R C E N T E R AT J O H N S H O P K I N S

SPECIAL COMMEMORATIVE ISSUE of PROMISE & PROGRESS THE LUDWIG CENTER at JOHNS HOPKINS “The elimination of cancer will surely rank as one of man’s greatest and uncontroversial achievements.That day may be long delayed. How long we cannot tell. But I do not doubt that it will surely come.” —Daniel K. Lud wig

2013/2014 TABLE OF CONTENTS

1 Director’s Letter 2Daniel K. Ludwig 4The Gene Team 14 A Cancer Revolution 17 Headline Makers 28 Global Scientists 32 Honors and Awards 34 Q&A with Dr. Bert Vogelstein 36 Q&A with Dr. Ken Kinzler

VID E O O N T H E W E B— get inside the Ludwig Center at Johns Hopkins www.hopkinskimmelcancercenter.org THE LUDWIG CENTER at JOHNS HOPKINS 1

D ir e c t or’s L e t t e r A Ludwig-Johns Hopkins Partnership

TODAY, WE HEAR FREQUENTLY about the promise changes discourages investigators from pursuing novel and of personalized cancer medicine. However, what many do challenging ideas. Mr. Ludwig understood the relationship not realize is that the reason we can talk about it, the reason between risk and reward. The Ludwig funding allowed the it exists, is primarily due to the pioneer- Vogelstein/Kinzler team, some of the best scientists in the ing work of Drs. Bert Vogelstein and world, to take risks and swing for the fences. The payoff has Kenneth Kinzler and their team. When been huge. It is the model for how a partnership between it comes to cancer genetics, their work private philanthropy and science can and should work. is on the cutting edge of the cutting edge. They led the world to understand that In that regard, Daniel K. Ludwig accomplished exactly what he cancer is a disease of genetic defects and set out to do in bringing the best minds and resources to bear in then became the first laboratory in the the fight to conquer cancer. Mr. Ludwig said, “The true value world to reveal what those defects are. But they didn’t do it will not be measured until the clinical potential of discoveries alone. Of equal importance to their accomplishments is are realized and they are impacting human suffering.” the funding that made these discoveries possible. The Ludwig Center at Johns Hopkins is home to the laboratory It has already begun to happen. In the Ludwig Center, the of Drs. Vogelstein and Kinzler and the site of these revolu- Vogelstein/Kinzler team’s cancer gene research is poised to tionary cancer discoveries. It is not an exaggeration to say change cancer medicine. They are developing tests that find that their research—the most commonly cited in all of cancer DNA in a small sample of blood or bodily fluids and medical science—would not have been possible without can be used to detect cancer, personalize therapies to combat the support of Ludwig Cancer Research. the unique genetic alterations within a tumor, and to monitor cancers’ response to treatment. Perhaps the greatest promise The genius of Drs. Vogelstein and Kinzler led them to prove will be realized through prevention and the ability to intervene more than two decades ago that cancer resulted from errors and change the fate of cancer cells before they can cause harm. in cells’ genetic instructions. In the last decade, with Ludwig funding that allowed them to purchase and take We at this great institution have a common goal. Cancer is advantage of automated gene sequencing technology, they among the most complex of diseases, and the discoveries of could begin to envision ways this new understanding of the Vogelstein/Kinzler team are nothing short of amazing. cancer could be used to benefit cancer patients. They now This example of ingenuity and progress in the face of what had the capacity to look at all genes in the cancer genome often seemed like insurmountable odds is why Ludwig Cancer simultaneously, and for the first time in the history of Research and other donors invest in Johns Hopkins. The medicine, could reveal the genetic mistakes driving a Ludwig commitment and our leadership’s willingness and cancer. Research that once took years could now be desire to apply what we have learned here to improve the health completed in months. Ludwig support truly represented and well-being of humans has brought us to this historical a critical turning point in cancer discovery and the moment in time, where we can begin to alter the course of opportunity to bring about unprecedented changes in cancer in ways we could only imagine before. how cancer treatment could be imagined and delivered.

Cancer research funding is limited and highly competitive, William G. Nelson, M.D., Ph.D. and we are fortunate at the Kimmel Cancer Center to have Marion I. Knott Professor and Director talented faculty who do well in this process. However, lim- The Sidney Kimmel Comprehensive ited funding that is affected by economic and governmental Cancer Center at Johns Hopkins 2 SPECIAL COMMEMORATIVE ISSUE of PROMISE & PROGRESS THE LUDWIG CENTER at JOHNS HOPKINS 3

Daniel K. Ludwig

Shipping magnate DANIEL K. LUDWIG was a self-made Mr. Ludwig died in 1992 at 95, but his legacy continues through billionaire. He built his shipping empire from the ground up, the pioneering cancer research he has funded. Through a trust working as a machinist, marine engineer, and ship handler created under his will, two professorial chairs in cancer research to learn all elements of the business. His understanding of were endowed at six prominent United States academic institu- how the industry worked allowed him to grow his business, tions designated by Mr. Ludwig. In 2006, the trust established and he became one of the most successful and wealthiest Ludwig Centers at each of the six institutions and funded them businessmen in the world with operations spanning 23 coun- with an initial $120 million split evenly among the centers. In tries. Yet he remained private and humble, devoting much the winter of 2013, an additional $540 million was divided among of his wealth to cancer research through the Ludwig Institute, the centers. To date, Ludwig Cancer Research has provided a global research enterprise, and a trust that established $900 million in funding to the six institutions for the Ludwig Ludwig Centers and professorships at six research institu- Centers and endowed chairs. tions in the United States. Ludwig Cancer Research, on behalf of Daniel K. Ludwig, has committed $2.5 billion to Cancer genetics pioneers Bert Vogelstein, M.D., and Kenneth research to alter the course of cancer. The most recent gift of Kinzler, Ph.D., are directors of the Ludwig Center at Johns $540 million, is reported to be the largest cancer research Hopkins. Mr. Ludwig’s vision of bringing together the best contribution worldwide from a single private source. minds and best resources to tackle cancer has been realized through their work and the work of the talented young In 1971, Mr. Ludwig began applying the same prin- investigators who have trained with them. It was in ciples that made him successful in business this laboratory that cancer was defined as a genetic to cancer research. In shipping, he gained $540M disease. Like Mr. Ludwig, their influence far and used his knowledge of the industry to T H E M O ST R E C E N T GIF T O F exceeds their name recognition. Drs. Vogelstein $540 MILLIO N , IS R E P O RT E D succeed. In the same way, he understood that T O B E T H E L A R G E ST C A N C E R and Kinzler are not household names, but their to make progress against cancer, the extraor- R E S E A R C H C O N TRIB U TI O N research in deciphering the genetic causes of W O RL D W ID E F R O M A dinarily complex disease must first be under- SIN G L E PRIVAT E cancer is considered among the most relevant in stood. Through the Ludwig Institute and Ludwig S O U R C E . the field of cancer research, having set the paradigm Centers, known collectively as Ludwig Cancer for how modern cancer research is conducted. With Research, he assembled the greatest scientific minds in the support of Ludwig funding, their team has cracked the the world and provided them with the resources and genetic codes of more forms of cancer than any other research freedom to do their jobs. In doing so, he created a global team in the world. “The Ludwig Fund gave us the tools to com- enterprise focused on cancer discovery and, ultimately, plete these comprehensive genetic studies,” says Dr. Vogelstein. ways to prevent and cure it. “It takes more than good ideas to drive discoveries, and the Ludwig bequests have revolutionized what we’ve been able to “Success in any complex enterprise consists in bringing the accomplish. Because of this funding, we have pursued some of best minds to bear on each problem, in providing the best the most important questions in cancer research.” resources possible, and in putting each concept into practice whenever and wherever the opportunities are most favor- Displaying humility similar to that of his benefactor, when asked able,” said Mr. Ludwig in 1974. “I believe firmly in the value how he would like to be remembered in 100 years, Dr. Vogelstein of applying these principles in grappling with tasks as responded, “I hope I’m not remembered because that will mean momentous as finding ways to relieve the human suffering cancer is no longer a threat.” We suspect Daniel K. Ludwig caused by cancer.” would concur. • 4 SPECIAL COMMEMORATIVE ISSUE of PROMISE & PROGRESS

The Gene Team A Look Inside the Ludwig Center Lab That Defined Cancer

Feel a sneeze coming on? Reach for a Kleenex. Need to wrap a package? Scotch tape is a must-have. Looking for answers on the Internet? “Google” it, of course. There are certain go-to brands that are so equated with excellence that their trademark has become synony- mous with the product itself. Cancer science and medicine are no different. Though they are not household names, the best of the best are Bert Vogelstein and Kenneth Kinzler when cancer genes are at issue.

DRS. VOGELSTEIN and Kinzler are are a shining example of high-impact An unprecedented and all-encompassing the quintessential cancer gene finders. philanthropy,” says Dr. William Nelson, view of precisely what was happening With more than 200,000 scientific jour- director of the Sidney Kimmel Compre- inside the cancer cell was at last possible. nal references and counting, the pair’s hensive Cancer Center at Johns work in deciphering the genetic causes Hopkins. “Clearly, they are brilliant This first comprehensive view inside of cancer is universally regarded as scientists, but funding is as critical to the immortal cell revealed an intricate the most relevant in the study of the making scientific advances as great convolution of genetic errors. If not for disease. They developed the model for ideas, and Ludwig Cancer Research has the cell’s menacing purpose, its ability cancer initiation and progression, first provided that essential component.” to hijack and exploit normal cellular with colon cancer, and then applied functions to its benefit would be some- their methods to other cancers and Drs. Vogelstein and Kinzler, directors thing to marvel. The phenomenon of this cracked the genetic codes of more of the Ludwig Center at Johns Hopkins, corrupted cell was, however, outdone— forms of the disease than any had already firmly established their and more importantly, undone—by other research team in the world. reputation as leaders in cancer research. the virtuosity of the Ludwig Center Their work is now considered The important discoveries that scientific sleuths who amazingly classic, the paradigm for unfolded one by one in the their deciphered its game plan. much of modern cancer laboratory led the world to research. 200,000 understand that cancer is a W IT H M O R E T H A N 200,000 A Genetic Tutorial S CIE N TIFIC J O U R N A L RE F ERE N C E S genetic disease. However, To truly appreciate the scale and com- A N D C O U N TIN G , V O G E LST EIN A N D In 2006, this cancer KIN ZL E R’S W O RK IN D E CIP H E RIN G until this point, their find- plexity of the accomplishments of the research powerhouse T H E G E N E TIC C A U S E S O F C A N C E R ings came by painstakingly Vogelstein/Kinzler team, it is important IS U NIV E RS A LLY R E G A R D E D A S drew the attention of T H E M O ST R E L E VA N T IN T H E looking at just a few suspect to understand the series of genetic ST U D Y O F T H E DIS E A S E Ludwig Cancer Research genes at a time. The Ludwig events involved in cancer formation. and earned a transforma- gift brought automated gene- Dr. Vogelstein compares it to an ency- tional $20 million gift and the dis- sequencing equipment to their labora- clopedia. “Each of us has an encyclope- tinction of being named one of only six tory, which allowed the scientists to dia in our cells, and each page of that Ludwig Centers in the United States. simultaneously sequence millions of encyclopedia represents one gene,” genes. Research that once took years he says. A set of genetic encyclopedias “The long list of accomplishments could now be done in months and for a comprises 46 books, and each of these made by Drs. Vogelstein and Kinzler fraction of the cost of earlier studies. books represents chromosomes— D RS. V O G E LST EIN (T O P) A N D KIN ZL E R, DIR E C T O RS O F T H E L U D W IG C E N T E R AT J O H N S H O PKIN S, H A D A LR E A D Y FIR M LY E STA B LIS H E D T H EIR R E P U TATI O N A S L E A D E RS IN C A N C E R R E S E A R C H . 6 SPECIAL COMMEMORATIVE ISSUE of PROMISE & PROGRESS

23 books are inherited from our mother Save for about 50 of these errors among immune system and treatable with and 23 are inherited from our father. the millions of characters that make up drugs known as antibiotics. The rea- Each “chromosome” book has about the genes, cancer cells are nearly identi- son, Dr. Kinzler says, is that bacterial 1,000 pages—one for each gene on that cal to normal cells, and that is what genomes are so different from the chromosome. Every page is filled with makes cancer such a complex disease. human genome. Bacteria have 1,000 about 1,500 letters. However, the letters Teasing out these errors from a sea to 2,000 genes all of which are vastly on the “gene” pages are not the 26 A of normal cells has confounded both different from the 20,000 or so genes in through Z alphabet characters. Rather, scientists and the human body’s own the human genome. These differences just four characters represent the checks and balances. make it possible to develop drugs “gene” alphabet: A, C, G and T, an that target gene products made by abbreviation for the chemicals that “ Cancer is a very difficult bacteria and impact infections without make up genes. disease to treat because affecting human cells. “In cancer, 19,950 basically the enemy here genes are the same in most cases, and Mistakes that occur in this genetic the other 50 have just slight changes encyclopedia are like misspelled words. is our own cells. Cancer that distinguish them from normal For example, if a book contains letters cells are very similar to cells,” says Dr. Vogelstein. To further to form the word “feet,” it means one us. There may be only a complicate matters, “Two cancers thing to the reader. If two letters are hundred specific genetic can be from the same organ, and look transposed, and the word appears as changes in coding genes similar under the microscope, but “feat,” it means something completely that distinguish a normal genetically they are distinct.” That is different. The same is true of the char- why therapies that work in one patient acters that make up the genetic alpha- cell from a cancer cell, and may not work in another. bet. The cancer cell genome may have w e need to figure out how an “A” instead of a “C,” or a “G” instead to use that to specifically Despite this complexity, in the last six of a “T.” This, he says, is a mutation, kill cancer cells.” years, they have accomplished some- and when they occur, they change the thing that would have been impossible way a cell interprets its instructions “Cancer is a very difficult disease to just a decade ago. Using the most and, as a result, how it behaves. treat because basically the enemy here advanced technology, the team has is our own cells,” says Dr. Kinzler. analyzed all of the genes in a cancer A few other types of errors can occur. “Cancer cells are very similar to us. cell—more than 30 million base pairs Sometimes a page is repeated, in a There may be only a hundred specific of DNA—and provided the first-ever process known as gene amplification. genetic changes in coding genes that comprehensive blueprint of cancer: In other cases, the page is missing. distinguish a normal cell from a cancer what goes wrong in the cellular in- This is a genetic deletion. Dr. Vogelstein cell, and we need to figure out how to struction manual to cause cancer. This says that of these possible errors, by far use that to specifically kill cancer cells.” task of superhuman scope has taken the most common is the typographical the cancer world by storm, opened new character substitutions known as, Compare the cancer genome to the vistas of research and, for the first time, point mutations. bacterial genome. Bacterial infections presented a full genetic understanding are easily recognized by the body’s of one of humankind’s greatest threats. • THE LUDWIG CENTER at JOHNS HOPKINS 7

The Beginning As complex and transforming as these firsts are, they started humbly and quietly in 1983 in a converted supermarket on the Johns Hopkins East Baltimore medical campus.

sequencing technology, the researchers accomplished the near impossible.

They were among the first scientists to apply molecular biology to the study of cancer. They developed tools to look inside the submicroscopic molecules of the cell and found rare, uncorrected errors to DNA that set the cancer process in motion.

One by one, they uncovered a series of genetic mistakes that revealed how colorectal cancer started and progressively became more and more AT THE TIME, little was understood an advantage to cell growth. In essence, dangerous as these genetic alterations about cancer. There were lots of theo- cancer is nothing more than a normal accumulated. They identified the genes ries, but no real answers. All that was cell that does not die. As this immortal responsible for the major forms of really known was that it was an unsta- cell divides, it eventually reveals itself inherited colorectal cancer as well as ble disease that got worse with time. in the form of a tumor. While many genes that initiated the more common Inspired by the National Cancer Act’s focused on the tumor, Dr. Vogelstein noninherited form of the disease. “War on Cancer” initiative that prom- realized very early on that it was what ised a cure for cancer, most scientists precipitated the tumor that mattered. The mystery was solved. Cancer was were searching for a magic bullet— He compared it to an iceberg. The a genetic disease. Drs. Vogelstein and a unilateral approach that would con- tumor was the tip of the iceberg that Kinzler’s breakthrough discoveries sent quer cancer. Many were looking for could be seen, and the genetic alter- reverberations throughout the world of quick fixes—drug treatments they ations were the layers that began form- science as research teams at institutions hoped would rein in this vicious killer. ing beneath the water decades earlier. throughout the country scrambled to Drs. Vogelstein and Kinzler took a The hidden layers, what happened look for similar genetic alterations in different approach. Successfully treating inside the cell before the tumor devel- other cancers. cancer, they believed, would require oped, was what he was interested in an understanding of what it was. learning about, and he was certain it Having identified the gene alterations Their research was revealing a much was the key to controlling cancer. that caused inherited colon cancers, more complicated, multifarious genetic such as familial colon cancer and famil- disease than most scientists of the Dr. Benjamin Baker, a Johns Hopkins ial adenomatous polyposis, they devel- time—or the public—had appreciated. internist, was intrigued by Dr. Vogel- oped tests to detect the alterations and They were uncovering a genetic infra- stein’s revolutionary concept that radically changed how these patients structure unlike anything that had cancer was caused by genes gone awry. were managed in the clinic. For the first ever been described in human disease. He helped Dr. Vogelstein form the time, clinicians could know which fam- It centered on a delicate balance Bowel Tumor Working Group, which ily members had inherited colorectal- between cell-growth accelerators proved to be a turning point, bringing cancer-causing mutations, so that those known as oncogenes and the cancer- together seasoned clinicians and inves- at risk could be monitored closely for controlling genes called tumor tigators and bright, young scientists to cancer. As important, the tests also suppressor genes that kept them explore this visionary gene-centered revealed family members who did not in check. hypothesis in colorectal cancer. have the gene mutations so they could be spared unnecessary screening meas- Alterations to these genes, either Dr. Vogelstein and team were about to ures. It was the first example of person- inherited or acquired throughout life, break open Pandora’s box. Without alized, genome-based medicine for disrupted the delicate balance, giving the benefit of today’s automated gene- patients with typical forms of cancers. • 8 SPECIAL COMMEMORATIVE ISSUE of PROMISE & PROGRESS

RESEARCH AND DISCOVERIES

PATIENTS

PERSONALIZED CANCER MEDICINE The Ludwig Difference Harnessing the power of these cancer gene discoveries and applying them to the general population was a much greater challenge. The $20 million-plus gift from Ludwig Cancer Research would prove to be another turning point for the Vogel- stein/Kinzler team. The donation established the Ludwig Center at Johns Hopkins and provided a steady stream of income to fund the laboratory and its scientists.

“In many ways, the establishment of the Ludwig Center was the beginning of our work,” says Dr. Vogelstein. Although they had already made unprecedented discov- eries, the Ludwig funding allowed the team to pursue gene sequencing on a massive scale and, once again, to lead the world in making pioneering cancer discoveries.

The Vogelstein/Kinzler team had already revealed to the world that cancer was a genetic disease, and uncovered some of the genes involved. Now, cancer type by cancer type, they would study every gene in the cancer genome and lay out a spe- cific blueprint of the alterations that caused each cancer to start, grow and spread. “For the first time in the history of medicine, we had the technology to define the mistakes in that genetic code that occur in human cancers,” explains Dr. Kinzler. • THE LUDWIG CENTER at JOHNS HOPKINS 9

The Team With this new support from Ludwig Cancer Research, these investigators, arguably the most brilliant in cancer research, have revealed to the world answers that had remained elusive for decades.

DR. BERT VOGELSTEIN is even- heading in a certain direction scientifi- eries. He pioneered the discovery of tempered, soft-spoken and deliberate. cally, you can be sure that it’s the right cancer genes in their group and became He is as humble as he is smart. He listens one, and that’s usually the direction I go.” the world’s foremost expert on the intently when his laboratory scientists, APC gene, the most frequently mutated students and trainees discuss their Dr. Vogelstein’s brilliance goes beyond tumor suppressor gene in colon cancer. research, present problems and ask his scientific prowess. As the architect Energetic, fast-talking and equally questions. Likewise, they listen intently of the laboratory that led the world to reflective, Dr. Kinzler is the perfect when he responds. They seem to recog- understand the origins of cancer, his complement to Dr. Vogelstein. A solu- nize and appreciate that they are among brilliance also is reflected in the investi- tion finder, he is able to overcome defi- the few who have earned an opportunity gators he has hand-picked to join his ciencies in technology to move research to study with the master. One of his for- team and mission. forward, inventing methods like SAGE, mer trainees, who now co-directs the a predecessor to today’s automated gastrointestinal cancer program at the The first of them was DR. KEN KIN- gene-sequencing technology. SAGE Kimmel Cancer Center, once said of him, ZLER, a pharmacology and molecular reads DNA much like a grocery store “Bert Vogelstein is the smartest person sciences expert, who has worked with scanner reads and monitors product I have ever met.” He describes him as a Dr. Vogelstein since 1983 and played a quantities. It provided some of the first scientific compass of sorts. “If Bert is central role in the cancer gene discov- high-tech analysis of gene expression,

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K E N KIN ZL E R showing which genes were over- and joined the faculty in 2005. He ful, and Johns Hopkins has now expressed or under-expressed in makes sure the team’s research is on licensed his technology to industry cancer. Dr. Vogelstein says that Kinzler course to benefit patients. Dr. Diaz, so that patient clinical studies can is “an out-and-out genius, with intu- who specializes in gastrointestinal be conducted around the world. itions and talents that continue to cancers, primarily colon cancer and amaze me, even after working so pancreas cancer, quips, “You never The team also includes students, closely with him for two decades.” want to see me because that means trainees and technicians from a wide you have a bad cancer.” In truth, he is variety of backgrounds. Each person DR. NICKOLAS PAPADOPOULOS precisely who these patients want and contributes a necessary expertise and is calm with a comforting smile and an need to see. Backed by some of the most a unique perspective. Just as a good engaging Greek accent. His expertise is significant cancer discoveries ever made, recipe requires the finest ingredients, in cancer genetics. He trained with Drs. he is the essential connection between the Ludwig Center team has just the Vogelstein and Kinzler and then left to cancer research and cancer medicine. right mix of people and ideas. It is work in industry where he developed immediately recognizable that this lab- gene-based diagnostics. He rejoined the DR. SHIBIN ZHOU has a big smile, oratory is different. The drive of super- research team in 2006 with the opening quiet voice, and a completely different focused scientists who have made some of the Ludwig Center. His aim is to scientific background than that of his of the most significant cancer discover- translate what he and his colleagues Ludwig Center colleagues. He came to ies is tempered by a feeling of comfort have learned about cancer genetics into the Vogelstein/Kinzler laboratory and collegiality. A row of tabletop better diagnostics for cancer. His top nearly 20 years ago as a postdoctoral candy dispensers, comic strip cutouts, priority is sketched out on his office fellow. He is the member of the Ludwig a pool table, and random toys are oddly wall, a formula that he hopes will im- Center team focused on novel thera- conspicuous in this world of top-notch prove next generation sequencing. peutics. Like a landscape artist, he sees science. They provide silent testimony The technology works well for basic beauty in how all aspects of a cell’s that these researchers with seemingly research, but the error rate currently biology function together. He has an superhuman intellectual capacities are, makes it unreliable for patient care. Dr. image of how the rogue cancer cell in fact, real people. Like the intricate Papadopoulos’ combined cancer genet- develops and begins breaking all of the and complex cancer cell they study, ics expertise and industry experience rules that govern normal cell behavior they do not fit a mold. It is this willing- position the Ludwig Center team to and has devised innovative ways to ness to walk outside of the lines and make the critical bridge between genetic beat it. In one such inventive approach, to think in ways no one has thought discoveries and personalized cancer Dr. Zhou genetically engineered before that has given rise to their prevention, diagnostics and treatment. bacteria that grows only in the oxygen- unprecedented success. starved core of malignant tumors. Key to that transition is DR. LUIS The bacteria safely colonizes inside the “We’re not interested in hammering the DIAZ, the only practicing oncologist tumor, developing an abscess that eats nail into the weakest part of the wood. on the Ludwig Center team. He is away at the tumor from inside out. We’re interested in hammering the nail driven, compassionate, and always When it reaches the outside rim of the into the foundation of the wood—the moving, dividing his time between the tumor, the area connected to oxygen- hardest part,” says Dr. Vogelstein. laboratory and the clinic. Dr. Diaz rich blood supply, it no longer works. completed his residency and fellowship Dr. Zhou then uses other agents to fin- Hammer they did, providing insights at Johns Hopkins, came to the Vogel- ish off the crippled tumor. Laboratory into cancer that had never been under- stein/Kinzler lab as a trainee in 2002 and animal models have been success- stood, never even imagined. Collaborat- THE LUDWIG CENTER at JOHNS HOPKINS 11

ing with the Hopkins’ internationally roadblocks to effective treatment can complete. Today, to sequence a cancer recognized pancreatic cancer program, potentially be exploited to improve genome, he says, it takes about a week this cancer was one of the first cancer treatment. “I call this genome-based and costs only a few thousand dollars. genomes the Ludwig Center team deci- medicine,” says Dr. Vogelstein. “Even Right now, the gene-alteration-targeted phered. For this study, the scientists though each patient’s cancer genome is treatments do not provide cures. examined 24 pancreas cancers and different, these differences can some- Tumors that initially respond tend to determined the sequence of all of the times be targeted with drugs.” recur. Ongoing research focused on genes in these cancers. On average, they combining these targeted therapies found just 50 mutations (genetic mistakes For decades, the world searched des- with other drugs may lead to better that are present only in cancer cells) perately for a picture of what cancer and longer-lasting responses. among the 20,000 genes in each cell. Other really was. What was driving this than these 50 differences, the genes in disease that appeared to come out of “The history of medicine the cancer cell were identical to those in nowhere, for a time seemed submissive shows that when a disease normal cells. It is no wonder then that to treatment and then mounted a is understood, it eventually progress has come slower than the pub- second, often-lethal, vengeful attack? lic would like and that general curative Drs. Vogelstein, Kinzler and team becomes manageable.” treatments have been elusive. These painted that picture. —Bert Vogelstein studies also revealed a staggering com- plexity. While every cancer had a similar Dr. Vogelstein says there are probably As promising is the potential to engage number of alterations, not every cancer not many surprises left in cancer genet- the immune system. “Every one of had the same 50 alterations. They varied ics. “It is unlikely that there are many these mutations that alters a gene from patient to patient. “No two cancers more genes frequently mutated in can- should make it foreign to the immune were genetically the same, even though cer. These types of common mutations system. The body has never seen these they may look the same under the most would likely have been found by now,” particular genes. In this way, it is powerful microscope,” says Dr. Kinzler. he says. “It’s time to take what we’ve similar to a bacterial or viral infection,” learned and put it into action.” says Dr. Vogelstein. Cancer genome sequencing has revealed genetic muta- Personal, Genome- The real beauty of the Ludwig Center tions that should be susceptible to an Based M edicine team’s research is its potential for immune attack. Cancer immunologists If ever a disease required a personal- broad applications. With the cost of can now find and exploit these mutant ized approach to treatment, it would be genome sequencing plummeting, soon proteins within cancer cells to the bene- cancer. Cancer is not a one-size-fits-all every patient of the Kimmel Cancer fit of patients. “This is a cancer immu- disease. If each patient’s cancer is Center will have his or her cancer’s nologist’s dream,” says Dr. Vogelstein. genetically unique, then diagnostic and genome sequenced to reveal its unique clinical methods need to take that fact genetic signature and determine the “Knowing the roadmap of a cancer is into consideration for screening, best course of treatment, he predicts. the key to attacking it. Now that we detection and treatment plans. These When Dr. Vogelstein and team deci- have identified the key gene mutations, differences from cancer to cancer pose phered the pancreas cancer genome in we can focus on determining at what significant obstacles. However, now 2006, the research cost about $200,000 point in the cancer process they occur, that they are better understood, the per patient and took several months to whether they guide prognosis and if

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L UIS DIA Z they might be good targets for preven- they have acquired so many gene The First True tion or treatment,” adds Dr. Kinzler. alterations that they are often resistant to treatment. Tests for Cancer Prevention Is Cure As tumor cells divide, they develop their own blood supply to get the What the Ludwig Center team pro- This revelation that cancer is in place nutrients they need to survive and vided was the detailed schematic for for decades before it enters its final, grow. As a result, cancer cell DNA gets how a tumor starts and how it becomes lethal stage led the Ludwig team to carried into the bloodstream, providing progressively more dangerous. As the focus their efforts on prevention. Their evidence of the cancer’s existence. result of heredity or outside cell-dam- goal is not necessarily to prevent a Similarly, cancer cells also may shed aging exposures, like cigarette smoke cancer from occurring, but to use what this DNA in other body fluids and or high-fat diets, cell DNA is changed. they have learned about the cancer secretions. For example, a colorectal Over the course of up to 30 years, ge- genome to keep it from killing people. cancer would shed DNA into stool, a netic alterations amass until the cancer They are creating safe, simple and bladder cancer into urine, a lung cancer makes a lethal transformation in which inexpensive tests that detect early into sputum or an endometrial cancer cancer cells can travel from the original genetic changes that precipitate cancer in cervical excretions. Sensitive tests tumor site and invade other vital or- development. Such tests would allow that could easily, safely and inexpen- gans and tissue. This process is known doctors to find, diagnose and eradicate sively detect these early changes would as metastasis, and in cancer, it repre- cancers in their very earliest stages. permit early interventions and could sents the point of no return, often the potentially make many cancers curable. line between curable and incurable. This is easier said than done, Dr. Vogel- stein admits, but he and his team are Bladder cancer is a prime example. Take colon cancer, for example. Accord- now focused on developing such cancer Nearly 75,000 people in the United ing to Dr. Vogelstein, of the 55,000 screening tests. If past accomplish- States are diagnosed with bladder people who die each year, nearly all of ments are any indicator, it is likely they cancer each year. Although the majority the deaths occur because the cancers will be successful. of patients initially respond to cancer were not detected until this final stage. treatment, at least half will have their He believes that if the cancers are The tests they are developing are differ- cancers come back. As a result, patients detected before cancer cells spread, ent than the cancer screening tests with bladder cancer require lifelong most patients can be cured with sur- currently being used, such as PSA for monitoring. Currently, there is no gery and drug treatment or potentially prostate cancer and fecal occult blood screening test for bladder cancer, and even surgery alone. for colon cancer. These tests are undeni- costs to treat and monitor patients ably useful, but they are not specific. exceed $3 billion a year. Per person, “It takes about 30 years for a cancer to Many noncancer conditions can cause a experts say, it is the most expensive go from its submicroscopic stage to a positive result. The tests the Ludwig cancer to treat. Dr. Papadopoulos says full-blown metastatic cancer capable of team has invented are definitive indica- a test that detects cancer DNA in urine killing a patient,” says Dr. Vogelstein. tors of cancer, as they detect the genetic could be used to discover cancers “The last stage of metastasis, where alterations that actually cause the can- very early and also to monitor existing the cancer spreads, the stage that cer. The challenge is determining the patients for recurrence. Such a test, he actually kills people, occurs only in the blood and body fluids from which this says, would greatly reduce the need for last few years of this 30-year process.” cancer DNA could be easily extracted invasive and quality-of-life-altering Unfortunately, this is when many and ensuring the test is sensitive enough treatments and dramatically slash cancers are diagnosed. By this time, so it does not miss genetic alterations. health care costs. THE LUDWIG CENTER at JOHNS HOPKINS 13

Another example is a new test being to reach the uterus and cervix and, cancer screening tests that will make developed by Ludwig Center scientists therefore, are diminished in numbers possible the detection of many cancers Dr. Diaz and Isaac Kinde, M.D., Ph.D. and quality. The Ludwig Center investi- in an early and highly treatable stage. It uses Pap tests, routinely performed gators are working to improve Pap- since the 1950s in gynecologists’ offices Gene’s sensitivity to ovarian cancer, but If he is right, the coming decades will throughout the country to detect and even at 40 percent, it could help many see dramatic decreases in cancer deaths. prevent cervical cancer. Drs. Diaz, Kinde, women. Currently, there is no test for the Some of the change will come through and their colleagues have been able to early detection of ovarian cancer, a lethal improved gene and immune-targeted develop a test that detects not just cervi- disease often referred to as the silent therapies, but the biggest differences will cal cancers, but also uterine and ovarian killer because it does not cause symp- be made, Dr. Kinzler predicts, through cancers. The test, called PapGene, cap- toms and frequently goes undiagnosed early detection and prevention. “The tures DNA that is shed from cancer cells until it is well-advanced. Similarly, there history of medicine shows that when a and contains genetic alterations that is no screening test for uterine cancers. disease is understood, it eventually be- the Ludwig team determined lead to comes manageable,” says Dr. Vogelstein. endometrial and ovarian cancer develop- “ We still can’t cure polio. ment. It extracts the endometrial and We can’t cure a massive In public health, he points out, preventive ovarian cancer-specific DNA from the heart attack or stroke, but techniques, not cures, have been most same cervical fluid collected during con- w e can prevent them, effective at reducing deaths. “We still can’t ventional Pap tests to warn of developing and that has led to their cure polio. We can’t cure a massive heart cervical cancers. This new test could attack or stroke, but we can prevent them, one day make it possible to test for three decreased incidence. I and that has led to their decreased inci- female cancers at a woman’s annual well- think the same will happen dence,” says Dr. Vogelstein. “I think the ness exam. “This discovery is an example with cancer.”—Bert Vogelstein same will happen with cancer.” That is of the innovation the Ludwig support has the next revolution—the most important produced,” says Dr. Diaz. “This type of If the team finds similar results in larger one—to take this knowledge we have funding sparks ideas that save lives.” studies, the $100 test could begin to be gathered and help patients in ways that introduced in doctors’ offices in three could only be imagined before. In early small-scale studies of PapGene, to five years. the test detected 100 percent of endome- He and Dr. Kinzler believe that their trial cancers and 40 percent of ovarian Dr. Kinzler envisions tests like these be- Ludwig Center team is poised to make cancers. The difference in test sensitivity coming a regular part of annual physical that leap. “The Ludwig gift enabled our is really a matter of geography, specifi- exams. “People normally give blood, generation to decipher cancer, to become cally the proximity of each organ to stool, urine when they visit their doctors. the first generation in the history of the cervix. The endometrium is in the Women have Pap smears, and smokers mankind to know what cancer is. It uterus and closer to the cervix, so it may provide sputum samples. All of enabled us to make this progress, and sheds a greater number of cells into the these could be examined for mutations,” it inspires us and charges us to go cervical fluid collected during a Pap test. says Dr. Kinzler. He is hopeful that the farther, to conquer cancer,” says On the other hand, cells from the ovaries ongoing work in the Ludwig Center Dr. Vogelstein. “It’s a commitment we must travel through the fallopian tubes laboratory will result in gene-based intend to make good on.”•

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A Cancer Revolution Tracking and Attacking the Malignant Cell The discoveries that led the world to understand that cancer is a genetic disease unfolded one by one in the molecular genetics laboratory of Bert Vogelstein, Kenneth Kinzler, Nickolas Papadopoulos, Luis Diaz, and Shibin Zhou—since 2006 known as the Ludwig Center at Johns Hopkins. 1987 1991 1993-1999 Bert Vogelstein and his then-student Ken Their studies of inherited colon cancer With these discoveries, cancer gene testing Kinzler discovered the GLI gene through syndromes led Drs. Vogelstein and was catapulted into mainstream medicine. its amplification in advanced forms of Kinzler to identify the cause of an inher- The Vogelstein/Kinzler lab developed brain tumors. The GLI gene and related ited colon cancer syndrome called novel tests that could accurately detect the genes later found by Drs. Kinzler and Vogel- Familial Adenomatous Polyposis (FAP). hereditary mutations in a cost-effective and stein are now known to be the central com- They found that this syndrome is the result sensitive fashion. This testing is now part ponents of a signaling transduction pathway of hereditary mutations of the APC gene. of the routine management of patients that contributes to the development of many They soon showed that noninherited with strong family histories of colon different forms of tumors. (somatic) mutations of this gene initiated cancer and has dramatically altered how colorectal tumors in the general population these patients are diagnosed and treated. 1988 and caused normal cells to form the In a now classic paper published in the precancerous growths known as polyps. 1995-2005 New England Journal of Medicine, Dr. Vogel- ScienceWatch names Dr. Vogelstein as the stein presented a model for the develop- 1992-2000 most frequently cited scientist in the world, ment of colorectal cancer. The model The Vogelstein/Kinzler lab discovered the in all fields of science. His work has become posited that cancer was a genetic disease genes that mediate the effects of the tumor the benchmark not only for cancer research driven by sequential mutations in oncogenes suppressor genes p53, APC, and others. but for biomedical research in general. and tumor suppressor genes. It has since These include genes involved in controlling become the standard icon for understanding cell growth, such as p21, 14-3-3 sigma, and 1999-2004 human tumors in general. ß-catenin, as well as genes controlling cell The Vogelstein/Kinzler lab initiated death, such as PUMA. These studies another field of cancer research when 1989 proved enormously valuable for under- they described chromosomal instability Dr. Vogelstein identified mutations of p53 standing how genetic alterations are (CIN) as a major underlying feature of most in colon cancers and showed that it is a translated into tumor development. human tumors. In addition to outlining the tumor suppressor gene. He later demon- concept, they discovered several genes that strated that p53 is a common denominator 1993-1994 promote it in various tumor types. underlying many forms of human tumors. The Vogelstein/Kinzler lab, working with These discoveries initiated a revolution in that of Albert de la Chapelle in Finland, 2000-2006 cancer research that continues today, with discovered that the other major form of The Vogelstein/Kinzler lab developed new ramifications for epidemiology, biochemistry, hereditary colorectal cancer, hereditary tests to detect presymptomatic colorectal molecular biology and clinical medicine in non-polyposis colon cancer (HNPCC), is tumors on the basis of mutant genes that addition to genetics. There have been more caused by a gene on chromosome 3 that escape into the stool or blood. They devel- than 30,000 mutations of p53 discovered disrupts normal DNA repair processes. oped highly sophisticated technologies since the first one reported by Dr. Vogelstein. This seminal finding lead Dr. Vogelstein’s that can detect one mutant DNA molecule The p53 gene is the most commonly mutated team and other researchers to clone among 10,000 normal copies derived from of all genes ever found in human tumors, and identify what are now known as the noncancer cells. These tests have the capac- including both suppressor genes and human mismatch repair genes. ity to revolutionize noninvasive testing oncogenes. for colon and other cancers and prevent hundreds of thousands of needless deaths. THE LUDWIG CENTER at JOHNS HOPKINS 15

2004 2009 2011 The Vogelstein/Kinzler lab discovered The Ludwig Center team used genome The Ludwig Center team developed a mutations in PIK3CA, a gene whose sequencing of an individual with a heredi- gene-based test to distinguish harmless product modifies lipids. They showed that tary form of pancreatic cancer to locate from precancerous pancreatic cysts. mutations in this gene occur not only in the mutation that was responsible for The test may eventually help some patients colorectal cancers but also in breast, stomach, initiating the disease. The discovery avoid needless surgery to remove the brain and other tumors. The PIK3CA is now marked their first use of a genome-wide harmless variety. recognized to be the most highly mutated scanning system to uncover the basis for oncogene yet identified in human cancers. an inherited syndrome. 2012 In a study of 28 advanced colon cancer With Dr. Papadopoulos and other col- patients treated with a targeted therapy 2006 leagues in the Ludwig Center laboratory, called panitumumab, Ludwig Center The Ludwig Center published a landmark Drs. Kinzler and Vogelstein discovered researchers found that drug resistance study that provided the first draft of the how two cancer-promoting genes enhance mutations appear in the blood of patients genetic code for any cancer. This paper laid a tumor’s capacity to grow and survive about five to seven months after treatment, the foundation for future genetic discoveries under conditions where normal cells die. and low levels of these mutations exist that have the capacity to improve prevention, The knowledge, they say, may offer new before the therapy begins, making the detection and treatment of cancer. treatments that starve cancer cells of a cancers predestined to recur. key nutrient—sugar. 2008 2013 Drs. Vogelstein, Kinzler and their Ludwig 2010 Using cervical fluid obtained during routine Center team decoded the genomes for Ludwig Center researchers revealed that Pap tests, scientists in the Ludwig Center pancreatic cancer and glioblastoma pancreatic cancer develops and spreads developed a test to detect early ovarian and multiforme, a brain cancer. The findings much more slowly than scientists have uterine cancers. pointed to a group of key pathways in both thought. The finding indicated that there cancers that are targets for future therapies. is a potentially broad window for diagnosis In 2011, the scientists also cracked the ge- and prevention of the disease. nomic code for a rare form of pancreatic cancer, called neuroendocrine or islet cell tumors, and pancreatic cysts, which can be precursors to pancreatic cancer. Investigators working with Drs. Vogelstein and Kinzler in the Ludwig Center have also mapped the genomes of ovarian cancer, oligoden- drogliomas (a common form of brain cancer), liver cancer, and ovarian clear cell cancer. 16 SPECIAL COMMEMORATIVE ISSUE of PROMISE & PROGRESS THE LUDWIG CENTER at JOHNS HOPKINS 17

Headline Makers The Ludwig Center at Johns Hopkins

late Lloyd J. Old, M.D., Chairman of the with chemotherapy. Anticancer drugs 2006 Ludwig Fund’s Trustees when the cannot reach places where blood Centers were founded. “Their work does not circulate, so this is where Ludwig Center at Johns on the genetics of human cancer forms Clostridium novyi-NT goes to work. Hopkins Established much of the basis for our current The investigators use a nanoparticle A research team at the Sidney Kimmel understanding and has identified a that packages doxorubicin, a well-known Comprehensive Cancer Center was plethora of potential new therapeutic chemotherapy agent, to attack dividing one of six in the nation to share in a targets for cancer. The trustees are de- cells by damaging their DNA strands $120 million gift from the Ludwig lighted that Drs. Vogelstein and Kinzler beyond repair. Fund, named for the late shipping and their outstanding colleagues at In animal studies, this combined tycoon Daniel K. Ludwig. An intial Johns Hopkins will become an integral germ/chemo approach temporarily $20 million established the Ludwig part of the collaborative Ludwig Cancer wiped out certain tumor types in the Center at Johns Hopkins in 2006, Research network of Ludwig Centers great majority of mice and permanently and the total giving ensures a lifetime and the Ludwig Institute for Cancer cured more than two-thirds of them. annual commitment of over $3 million Research.” The Ludwig Center at Johns The reined-in bacteria selectively to cancer research at Johns Hopkins. Hopkins collaborates with Ludwig scientists around the world. targeted cancer cells and showed no interest in normal cells. Clinical trials “We recognize that it takes more than a in a limited number of patients are good idea to drive future discoveries in Cancer-Eating Bacteria ongoing. However, in human studies, cancer research,” says Bert Vogelstein, Science the use of live bacteria calls for extreme M.D., co-director of the Hopkins center. Nature Biotechnology caution, and so our clinicians and “It takes resources, and we’re grateful Tough cases require innovative medicine, investigators are moving ahead slowly. to Ludwig Cancer Research for this and for colon cancer patients whose Patients who develop fevers following unique investment in the future of cancers have not relented to other treatment must be given antibiotics, cancer research.” Dr. Vogelstein and treatments, a new therapy called which, of course, eliminate the bacteria co-director Kenneth Kinzler, Ph.D., COBALT (combined bacteriolytic and prevent it from doing its job. As were among the pioneers in uncovering therapy) has shown promise. At the the team demonstrates control over the genetic mutations responsible for the center of the therapy is the bacteria bacteria, they look forward to include onset and development of cancer. Clostridium novyi-NT, a germ that scaling back use of antibiotics to allow “Ludwig Cancer Research has given causes gas gangrene when it gets the bacteria to finish its job against us the resources for comprehensive into wounds. the cancer. studies so that we can collectively impact morbidity and mortality from A research team led by Shibin Zhou, M.D., Rampant Oncogene Is this disease,” said Dr. Kinzler. Ph.D. genetically modified the bacteria creating a strain without a lethal toxin. Treatment Target for With Ludwig Fund support, their Colon Cancer team completed the first genetic map Delivered via injection, the bacteria American Association for Cancer Research of colon and breast cancers. “Johns work within the oxygen-starved core The oncogene PIK3CA gene is not only Hopkins is revered as one of the of tumors. Researchers use the bacteri- mutated in 32 percent of colon cancers, outstanding institutions for cancer olytic therapy in combination with but now Ludwig Center researchers say research in the world, and Drs. Vogel- chemotherapy with the goal of selec- it plays an active role in the progression stein and Kinzler have been mighty tively attacking tumors from the inside and spread of this and other cancers. contributors to this renown,” said the with bacteria and from the outside 18 SPECIAL COMMEMORATIVE ISSUE of PROMISE & PROGRESS

PIK3CA is part of a family of genes cell to transform it into a cancer cell? alterations driving each individual encoding lipid kinases, enzymes that Now, the Johns Hopkins Ludwig colon or breast cancer. This helps modify fatty molecules and direct cells Center group that helped define cancer explain why cancers of the same organ to grow, change shape, and move. as a genetic disease has uncovered and often respond so differently to therapies, PIK3CA alterations selectively alter mapped the bulk of the culprit genes they say. “Each cancer has a different other genes in its pathway, hampering for colon and breast cancer. It is the blueprint,” says Dr. Vogelstein. “No two cell death and aiding tumor spread. first comprehensive examination of patients are identical.” gene mutations in cancers. “It is now clear that PIK3CA is one of Tumors that appear to be the same the two most highly mutated oncogenes This is a different approach from past under the microscope are genetically discovered in human tumors,” says discoveries that revealed mutations in very different, say the researchers. Kenneth W. Kinzler, Ph.D. “Cancer cells individual genes, mostly in colon can- “It’s like a city. From far away, all of the appear to be addicted to this pathway. cer and linked primarily to inherited buildings look the same, but as you get If we can inhibit the gene, we can po- forms of cancers and cancer progres- closer and closer, you see how many tentially kill the cancer.” Treating cells sion. Though important in terms of differences there really are,” says Dr. with a PIK3CA inhibitor blocked the screening and early detection in high- Kinzler. He expects investigators from gene’s ability to signal other genes and risk populations, they were only a part the Kimmel Cancer Center and other shut down the growth of cells contain- of the picture. What the investigators cancer centers around the country to ing mutant PIK3CA, opening the door have now revealed is the actual blue- begin taking a closer look at the newly to potential new therapies. print—a schematic of what is wrong in identified genes. He also expects that the colon and breast cancers’ control the approaches and concepts pioneered centers. “Cancer is the enemy, and now in this study will be used to create we know its game plan,” says Kenneth blueprints for other types of cancer. 2007 Kinzler, Ph.D., co-director of the The Blueprints Ludwig Center at Johns Hopkins and The method was built upon computer- for Cancer a lead investigator of the study. ized and other technologies developed Investigators Reveal Cancer by the researchers over the last two Genome for Colon and Breast The research reveals about 100 broken decades. The team started with 11 Cancers genes overall for each type of cancer. samples from each tumor type and Science It includes the genes they previously examined all the well-characterized It’s hard to fix something if you don’t discovered, but also some new genes human genes—13,023 to be exact. This know what’s broken. This has been the that, until now, were not known to play represents about two-thirds of all the problem tormenting cancer researchers a role in tumors. The mutations vary genes that are thought to be present in and clinicians for decades. What ex- from tumor to tumor, with a combina- the human genome. The researchers actly is it that goes wrong in the normal tion of three to eight critically important sifted through more than 500 million letters (ATCG) that make up the coding sequences of these genes to identify those rare transposed letters that trans- late into alterations in the genetic code. After validating their findings in two dozen more breast and colon tumors, the team whittled down the field to a relatively small number of genes that appeared to be important in the process. THE LUDWIG CENTER at JOHNS HOPKINS 19

Despite the genetic differences among DNA damage control, cell maturation, the tumors, the researchers suspect and tumor invasion, were altered in that further research will reveal simi- 67 percent to 100 percent of tumors. larities among the pathways through “This perspective changes the way we which these genes operate. This new think about solid tumors and their information should enable novel can see the whole picture, it is clear management because drugs or other strategies for detection or treatment. that these mountains are the defining agents that target the physiologic features of the cancers, though other effects of these pathways, rather than The researchers say the promising less frequently mutated genes clearly individual gene components, are likely effects of new gene-specific drugs like play a role.” to be the most useful approach for Gleevec and Herceptin prove that developing new therapies,” says Dr. targeting genetic alterations is a viable Vogelstein. treatment option. Dr. Vogelstein says researchers can now begin to search 2008 In addition to the pathway discoveries, for how these mutations occur, looking Blueprints for Pancreas a number of individual mutated genes for both environmental and cellular and Brain Cancers that play central roles in pancreatic processes that drive these changes. cancer and the most lethal form of Revealed brain cancer, glioblastoma multiforme Mountains and Molehills: Science Express (GBM) were identified. Additionally, The complete genetic blueprint for 70 genes that were dramatically over- Mapping the Genetic lethal pancreatic cancer and brain expressed in either cancer encoded Landscape of Cancer cancer was deciphered by the same proteins that are on the surface of cells Science Express Ludwig Center team who completed or secreted, making them potential In cancer, it may be wise to make maps of the breast cancer and colorec- diagnostic and screening targets. mountains out of molehills. In their tal cancer genomes in 2007. latest research, the Ludwig Center The researchers found one gene, team that just over one year ago began Believed to be the most comprehensive isocitrate dehydrogenase 1 (IDH1), that mapping the colon and breast cancer result to date for any tumor type, the was frequently mutated in a subset of genome, has completed the job by new map evaluated mutations in GBM brain cancers and had never been analyzing every single gene that is virtually all known human protein- suspected to be involved in any tumor translated into proteins, a monumental encoding genes, composed of more type. The mutations were significantly and unprecedented task. At the molec- than 20,000 genes, in 24 pancreatic more common in young GBM patients ular level, each tumor is genetically cancers and 22 brain cancers. A core and were associated with improved different. set of regulatory gene processes and survival. IDH1 mutations were also pathways, about a dozen for each found in nearly all cases of secondary Everest-like genes such as APC and p53 tumor type, were found to be altered GBMs (cancers that progress from pre- have stood out in the past because they in the majority of tumors studied existing lower grade tumors), raising were discovered through serendipity by the researchers. the possibility that this mutation may combined with insightful hunches. By be a useful marker for identifying analyzing every gene, in a completely The Ludwig Brain Tumor Initiative which low-grade brain tumors are most unbiased way, the full spectrum of represents the first formal collabora- likely to develop into the lethal GBMs. mutations has become clear. These tion of Ludwig Centers since the six Patients with IDH1 mutations may genes, and others like them, have been Ludwig Centers were established by ultimately benefit from different treat- the focus of cancer research for years the Ludwig Fund in 2006. ments targeting IDH1. because they were the only genes known to contribute to cancer, says In pancreatic cancer, each of these “The landscape of human cancers is Bert Vogelstein, M.D. “Now that we 12 pathways, including those linked to clearly more complex than has been 20 SPECIAL COMMEMORATIVE ISSUE of PROMISE & PROGRESS

previously appreciated. Fighting it is not only detected the mutant genes in researchers found that colon cancer going to be more of a guerilla war than all 18 cases but also measured the level cells hijack a gene called GLUT1 to a conventional one because there are of circulating tumor DNA. Higher improve their ability to soak up glucose, many mutated genes in each tumor, ” levels of circulating tumor DNA allowing them to grow and thrive in says Kenneth W. Kinzler, Ph.D., Ludwig translated to more disease. The new sugar-depleted environments that Center co-director. “Individually, these approach monitors tumor burden in a would otherwise be inhospitable to mutations don't seem formidable. But completely non-invasive way based on cell growth. working together, they form an enemy the mutations that actually cause the that will require us to develop novel disease. Moreover, it has the sensitivity “We think increased GLUT1 is a survival strategies to combat them, and the to measure minimal residual tumor adaptation that makes cancer cells very best long-term strategy may be early cells undetectable in X-rays and efficient at gathering what little circulat- detection of tumors, when the number CT scans. ing sugar exists in the nutrient-scarce of guerilla warriors is still small and inner environment of tumor cells,” says more easily handled.” Patients in the study underwent poten- Nickolas Papadopoulos, Ph.D. tially curative surgery for colorectal Test Finds, M easures, cancer and were followed for up to two In laboratory studies, cancer cells with years. After surgery, the test detected KRAS and BRAF gene mutations were and Monitors Cancer circulating tumor DNA in all patients Nature Medicine found to survive in sugar-depleted whose disease later recurred, often Virtually all cancers arise through environments while cells without these as soon as one day after surgery and mutation of genes that control cell mutations died. As a result, mutant months before it was visible in X-rays growth. As the cancers grow, they shed cells become the predominant cells. and CT scans. Patients whose mutant fragments of DNA, biological evidence “These gene mutations clearly give DNA levels fell to undetectable levels of these mutant genes, into the blood- colon cancer cells the ability to grow after surgery remained disease-free. stream. Ludwig Center researchers under conditions in which normal cells developed a novel test to measure this would not,” says Dr. Papadopoulos. “We know that not all patients need biological DNA. The blood test is based intensive adjuvant chemotherapy, and on the unique genetic signature of In mice, the researchers used an this test could help us decide who every cancer. It detects the presence of experimental drug that blocks glucose would benefit,” said Dr. Diaz. He says cancer and also tracks its progress. metabolism to stop cancer growth the test could be applied to any cancer, “Just as DNA has been used to detect, without any toxic side effects. They because all cancers have mutations. measure, and manage chronic viral are working to further develop thera- infections, like HIV, measuring circu- pies based on this discovery. lating tumor DNA could similarly enhance the management of cancer,” Personalized Genome- says Ludwig Center clinician-scientist 2009 Luis Diaz, M.D. Colon Cancer’s Based Therapy Heals Sugar Fix Patient with Advanced Every cancer has a set of mutated genes Science Express Pancreas Cancer that are present in cancer cells but not Starving colon cancer cells of sugar Science Express in normal cells. Using tumor tissue may make them die. It is not the kind Culling together the results of several from 18 patients with colorectal cancer, of sugar bought in the grocery store, genetic research projects, Ludwig Dr. Diaz and team identified the muta- but the nutrient glucose, a critical Center researchers and clinicians were tions in each patient’s cancer and component, or fuel, of normal cellular able to develop a personalized treat- used a technology developed in the function. (The scientists caution that ment for one pancreas cancer patient. Ludwig Center laboratory to search for limiting the consumption of dietary corresponding mutant tumor DNA in sugar will not impact cancer develop- This dramatic outcome stemmed from plasma from these patients. Their test ment and growth.) Ludwig Center new research that used personalized THE LUDWIG CENTER at JOHNS HOPKINS 21

genome sequencing on an individual the Duke University School of Medicine with a hereditary form of pancreatic linked mutations in two genes, IDH1 cancer to locate the gene mutation and IDH2, to nearly three-quarters of responsible for initiating the disease. gliomas, one of the most common types The discovery marked the first use of of brain cancer. The researchers found a genome scanning system to uncover that patients that carry these mutations genes controlling chromatin may play suspect mutations in inherited genes. survive at least twice as long as those a significant role in ovarian clear cell who do not have the mutations. Addi- cancer and provide opportunities for It revealed the culprit as a gene called tional research on the genes could lead developing new biomarkers and PALB2, which stands for “partner and to more precise diagnosis and treat- targeted therapies. co-localizer of BRCA2.” PALB2 seems ment of these deadly cancers. to disrupt BRCA2 interactions that are First Pediatric Cancer critical to DNA repair. Alterations to the BRCA2 gene were linked in research Genome Mapped 2010 Science Express done years earlier to 10 percent or more Major Discovery in Ludwig Center scientists were the first of pancreas cancers and were found to to decipher the genetic code of a pedi- make these cancers more responsive Ovarian Cancer Science Express atric cancer. Using sophisticated new to treatment with the FDA-approved Investigators linked mutations in two gene sequencing technologies, the re- drugs mitomycin C and cisplatin. genes to ovarian clear cell carcinoma, searchers mapped the genetic sequence one of the most aggressive and treat- of medulloblastoma, the most common Investigators observed that a personal- ment-resistant forms of ovarian cancer. type of pediatric brain cancer. As ized xenograft (a mouse implanted with Ludwig Center researchers, including suspected, this analysis showed that a human tumor sample) was having a Nickolas Papadopoulos, Ph.D., and genetic changes in pediatric cancers remarkable response to the drugs Siân Jones, Ph.D., reported that they are remarkably different from adult mitomycin C and cisplatin. The tumor found an average of 20 mutated genes tumors. The work revealed fewer genetic sample used in the xenograft came per each ovarian clear cell cancer alterations than are typically found from a patient who had advanced studied. Two genes not previously in adult tumors, and the researchers pancreatic cancer that was unstoppable linked to any cancer—ARID1A, which believe this may make it easier to use with standard therapies. Genetic analy- normally suppresses tumors, and the findings to develop new therapies. sis of the patient’s tumor revealed an PPP2R1A, an oncogene that, when The research also uncovered epigenetic inactive PALB2 gene. Based on these altered, helps turn normal cells into alterations, biochemical variations that findings, the patient was treated with tumor cells—were commonly mutated occur to the environment of genes and several cycles of the two drugs and among the samples. ARID1A muta- have the ability to turn genes on and went from having just three months tions were identified in more than half off without mutating them, as a more to live to symptom-free. of the tumors studied. In addition, significant culprit in pediatric cancer the mutations in ARID1A provide an than commonly thought. Using drugs This work illustrates the potential of important new link between genetic to block the abnormal biochemical ac- personalized cancer medicine to im- and epigenetic (gene regulatory) mech- tivity can return normal gene function prove cancer therapy and the value of anisms in human cancer. An epigenetic and stop the development of cancer knowing the genes that, when altered, component, known as chromatin, cells. “Information like this, gained predispose individuals to cancer. compresses DNA to make it fit inside from gene sequencing technology, cells and provides a means for control- could potentially help our team change Two Mutant Genes ling how and when the DNA is read. the course of some relentless childhood Linked to Brain Cancer With ARID1A mutations, the chro- cancers. As a result, we hope to con- The New England Journal of Medicine matin is altered, allowing genes to be tinue this work in other pediatric can- In a collaborative study, scientists at the incorrectly switched on or off. The cers,” said Ludwig Center co-director Ludwig Center at Johns Hopkins and researchers believe alterations in the Kenneth W. Kinzler, Ph.D..

THE LUDWIG CENTER at JOHNS HOPKINS 23 24 SPECIAL COMMEMORATIVE ISSUE of PROMISE & PROGRESS

studies but had not been implicated 2011 in brain tumors. Oligodendroglioma Cancer Gene brain cancer patients are typically young, often in their thirties or forties, Discoveries in Head and those with PIK3CA mutation in and Neck Cancer their tumors may benefit from these Science cancers and no mutations of the com- clinical trials now being carried out on Ludwig Center researchers sequenced mon cancer-related p53 gene. On the patients with other types of tumors. the cancer genome of head and neck other hand, cigarette smoking was cancer. Little was known about the associated with markedly increased Pancreas Cancer cause of head and neck cancers, and numbers of mutations. Head and neck this research revealed mutations in two tumors from smokers had twice as Timeline Reveals Ample genes, NOTCH1 and FBXW7, never many mutations as tumors from Time for Intervention before associated with the cancer. In a nonsmokers. Nature surprising twist, the researchers found For the first time, investigators quanti- that NOTCH1, identified as a cancer The researchers’ next step is to decipher fied the development of pancreas cell growth-promoting oncogene in the function of the mutated genes cancer and disproved popular scientific blood and bone marrow cancers, is a they discovered and their potential as thought that the disease progressed to malfunctioning tumor suppressor gene targets for treatment. a deadly stage very early in its develop- in head and neck cancers. This key ment. To the contrary, the research finding demonstrated that genes are team calculated that it takes an average not preset to be either oncogene or sup- Brain Cancer Genome of 11 years before a cancer cell arises pressor gene, but, instead, their roles Sequenced from a precancerous pancreas lesion, can vary among tumor types, depend- Science and another seven years may pass as ing upon mutations. “The mutational Researchers have long known that that cancer grows to form a tumor and analysis of NOTCH clearly indicates up to 70 percent of a type of brain cancer gives at least one cell the potential to the power of genetics to determine the known as oligodendroglioma are break away and spread the cancer function of these genes,” said Nickolas characterized by a fusion of two chro- outside of the pancreas. The spread, or Papadopoulos, Ph.D. mosomes that result in the loss of metastasis, represents a lethal turning many genes. Ludwig team researchers point in the progression of the cancer. The team’s mutational analysis also revealed what had eluded scientists for confirmed earlier findings from years—the specific mutated genes that To make their calculations, the team Kimmel Cancer Center investigators allowed the cancer to develop. In their studied tissue collected at autopsy from that linked the human papillomavirus analysis, they found that two-thirds seven patients who died of metastatic (HPV) to a biologically unique subset of of the tumor samples they studied con- pancreas cancer. Ludwig Center inves- head and neck cancers associated with tained mutations in two genes, CIC and tigators Bert Vogelstein, M.D., Kenneth improved prognosis. The HPV-related FUBP1. “Whenever we find genes mu- W. Kinzler, Ph.D., and team identified head and neck cancers had four times tated in a majority of tumors, it is likely and classified the genetic alterations in fewer mutations than the non-HPV that the pathway regulated by that gene each patient’s pancreas cancer and the is critical for cancer development and sites to which the cancer spread. In the biology of the tumor,” said Ludwig all patients studied, the investigators Center co-director Kenneth Kinzler, found similar mutations in both the Ph.D. The researchers also found mu- original tumor and the body sites to tations in the PIK3CA gene, which had which it spread, genetically linking been discovered to be important in the metastatic lesions to the original cancer by the Ludwig team in previous pancreas tumor. They classified muta- THE LUDWIG CENTER at JOHNS HOPKINS 25

cancers. Some of these tumors produce “There has long been a need for accu- hormones that leave telltale biological rate, quantitative ways to identify cysts signs of their existence, including that are more worrisome and to help changes in blood sugar levels, weight patients avoid unnecessary surgeries gain, and rashes. Hormone-free tumors for harmless cysts,” said Ludwig do not produce these signs, making Center co-director Bert Vogelstein, M.D. tions that occurred prior to metastasis them difficult to detect and to distin- He believes genetic analysis offers a and those that happened after the guish from other types of pancreas new way to sort them out. cancer spread. Working with Martin cancers. Nowak, Ph.D., and his colleagues at Dr. Vogelstein and his team analyzed Harvard University, they applied this The research team studied 63 nonhor- 132 precancerous cysts for mutations in information to mathematical models monal pancreas neuroendocrine 169 known cancer-causing genes. They to create a timeline of progression. tumors and revealed several common found that the GNAS and KRAS genes gene mutations, including two in genes were commonly mutated in cysts of Although their findings reveal a large that had not previously been linked the type that develop into pancreas window of time before a pancreas to cancer. Mutations in three genes, cancers. Neither mutation was found cancer turns deadly, most patients MEN-1, DAXX, and ATRX, seemed in benign cysts. Dr. Vogelstein believes are diagnosed after that window has to translate to a survival advantage. that developing a test to identify these closed. The researchers hope to de- Patients whose tumors had these muta- mutations should be relatively straight- velop a screening method, analogous tions survived at least 10 years after forward, as mutations predominantly to those used to screen for colorectal diagnosis, while more than 60 percent occur at one spot in both of the genes. or cervical cancers, to detect early of people whose tumors did not have However, he said, further studies on a pancreas cancers before they cause the mutations died within five years larger number of patients are required symptoms and become incurable. of diagnosis. The team also found before a gene-based test can be widely mutations in a family of genes called offered. Genetic Cause of a mTOR in about 14 percent of patients. Pancreas Cancer These patients would be candidates for treatment with agents that inhibit the Uncovered pathways through which these genetic Science Express alterations increase cell growth. Ludwig Center investigators pieced together the genetic puzzle and deci- phered the genetic causes of a type Gene Test IDs Bad of pancreas cancer known as neuroen- Pancreas Cysts docrine or islet cell tumors. The Science Translational Medicine researchers uncovered a genetic Ludwig Center scientists developed a signature that predicted how aggres- gene-based test to distinguish precan- sive the disease was and how well it cerous pancreas cysts from harmless would respond to treatments. “This cysts. The researchers estimate that tells us that it may be more useful to these fluid-filled cysts are identified in classify cancers by gene alteration type more than a million patients each year, rather than by organ or cell type,” and their test may eventually help says Nickolas Papadopoulos, Ph.D. some of these patients avoid needless surgery. Most cysts are benign, but Pancreas neuroendocrine tumors make differentiating the harmless ones from up about five percent of all pancreas the dangerous ones is challenging. 26 SPECIAL COMMEMORATIVE ISSUE of PROMISE & PROGRESS

2012 2013 Resistance Mutations PapGene Test Cause Treatments to Fail Science Translational Medicine Ludwig Center scientists Isaac Kinde, Nature M.D., Ph.D., and Dr. Luis Diaz, M.D., Researchers found that the origins developed a method to detect early of cancer treatment resistance are Genes Point to uterine and ovarian cancers. It is based contained within the cancer cell popu- Aggressive Form of on Pap tests, routinely performed since lation even before treatment is started. Children’s Cancer the 1950s in gynecologists’ offices The Ludwig Center team of Bert Vogel- Nature Genetics throughout the country to detect and stein, M.D., Kenneth Kinzler, Ph.D., In a genome sequencing study of 74 prevent cervical cancer. The test, called and Luis Diaz, M.D., found that resist- neuroblastoma tumors in children, PapGene, captures DNA that is shed ance mutations are often the cause Ludwig Center investigators and their from cancer cells, and specifically alter- when cancer treatments fail. Cancer collaborators at the Children’s Hospital ations that Drs. Kinde, Diaz, and their cells have acquired genetic alterations of Philadelphia (CHOP) found that colleagues have determined lead to that allow them to grow immortally alterations to two genes were linked to endometrial and ovarian cancer devel- and uncontrollably. Gene alterations poor prognosis. Patients with changes opment. The PapGene test extracts that coincidentally occur during this to the ARID1A or ARID1B genes sur- the endometrial and ovarian cancer- growth are hard-wired into the cancer vived only a quarter as long as patients specific DNA from the same cervical genome. Though these mutations do without the changes. The discovery fluid collected during a Pap test to not affect cancer cell growth before could eventually lead to early identifi- warn of developing cancers. There are therapy, the mutations can make tumor cation of patients with aggressive currently no early screening tests for cells resistant to such therapy. The neuroblastomas who may benefit from endometrial and ovarian cancers, and researchers found that a typical tumor additional or alternative treatments. the new test could one day make it contains thousands of cells that are possible to test for three female cancers resistant to single therapeutic agents. Neuroblastoma is a pediatric cancer at a woman’s annual wellness exam. The more advanced a cancer is, the of the nerve tissue, and it is the most more resistance alterations it acquires, common nonblood cancer in children. In early small-scale studies of Pap- giving the cells that contain them a Sometimes the cancer is highly Gene, the test detected 100 percent of greater chance to survive treatment. curable while other times it is lethal. endometrial cancers and 40 percent This latest research adds to the build- Researchers believe part of the expla- of ovarian cancers. The difference ing body of evidence that metastatic nation of the most aggressive form in test sensitivity is a matter of each cancers are extremely difficult to is these alterations inARID1A and organ’s proximity to the cervix. The control. The ideal opportunity to cure ARID1B. endometrium is in the uterus and cancer lies in detecting it early when sheds a greater number of cells into tumors are small and have fewer resist- the cervical fluid collected during a ance genes and can be removed with Pap test. On the other hand, cells surgery. When possible, multi-drug from the ovaries must travel through and method combinations that simulta- the fallopian tubes to reach the uterus neously attack a variety of mutant and cervix and, therefore, are dimin- gene products or reactivate silenced ished in numbers and quality. tumor suppressor genes are a better option than single-drug approaches. THE LUDWIG CENTER at JOHNS HOPKINS 27

The research team, led by Kenneth to set a global record for total cancer Kinzler, Ph.D., used whole-exome research funding from a single private sequencing on 19 Taiwanese upper source, according to foundation experts. urinary tract cancer patients exposed to aristolochic acid and seven patients Bert Vogelstein, M.D., and Kenneth with no suspected exposure to the Kinzler, Ph.D., co-directors of the Ludwig Though the Ludwig Center team is toxin. The technique scours the exome, Center at Johns Hopkins, used an initial working to improve PapGene’s sensitiv- part of the human genome that contains $20 million Ludwig gift in 2006 to ity to ovarian cancer, Dr. Diaz says, codes for functional proteins and can establish the center and create the first even at 40 percent, it could help many reveal particular mutations, in this genomic maps of cancer. “The Ludwig women. Currently, there is no test for case, those associated with cancer. bequests have revolutionized what early detection of ovarian cancer, a we’ve been able to do,” says Dr. Vogel- lethal disease often referred to as the “The technology gives us a recognizable stein. “We’ve pursued some of the most silent killer because it does not cause mutational signature to say with cer- important questions in cancer, but not symptoms and frequently goes undiag- tainty that a specific toxin is responsi- necessarily the most fundable.” nosed until it is well advanced. ble for causing a specific cancer. Our hope is that using this more targeted The current focus of the Ludwig Center Large-scale clinical trials are being whole-exome sequencing process will at Johns Hopkins is diagnostics for early developed. If the team finds similar provide additional data to guide public detection and prevention of cancer. results in these larger studies, the $100 health decisions related to the preven- “Compared with treatment research, test could begin to be introduced in tion of other types of cancer,” said early detection and prevention research doctors’ office in three to five years. Dr. Kinzler. is underfunded, but it can potentially make a greater impact on reducing DNA Mutation Signature Ludwig Center at cancer deaths,” says Dr. Kinzler. “This type of research takes a long Links Cancers to an Johns Hopkins Shares time and a sustained effort, and it has Herbal Toxin in Half-Billion Dollar Gift been possible largely because of the Science Translational Medicine for Cancer Research Ludwig support.” Genomic sequencing experts at the Scientists at the Kimmel Cancer Center Ludwig Center at Johns Hopkins part- received approximately $90 million in Drs. Kinzler and Vogelstein are consis- nered with pharmacologists at Stony new funding as part of a $540 million tently ranked as two of the world’s most Brook University to reveal a striking gift from Ludwig Cancer Research to six highly cited scientists because of the mutational signature of upper urinary U.S. institutions. The award is believed global impact their research has had. tract cancers. The research used molec- ular biology to prove that the cancers were caused by aristolochic acid, a plant compound, also known as birthwort herb, contained in herbal remedies used for thousands of years to treat a variety of ailments, including arthritis, gout, and inflammation. 28 SPECIAL COMMEMORATIVE ISSUE of PROMISE & PROGRESS

Training Scientists Who Lead Cancer Discovery Around the Globe Ludwig Center scientists are among the most sought after in the world. Each year, Drs. Vogelstein and Kinzler receive more than 1,000 applications from talented young researchers who want to train in the world-renowned laboratory. The best and the brightest are selected. Some like Shibin Zhou, Nickolas Papadopoulos, and Luis Diaz remain members of the Ludwig Center laboratory. Others go on to studies and faculty positions at other prestigious institutions and leadership roles in biomedical industry to help guide the world in the research and application of cancer medicine. THE LUDWIG CENTER at JOHNS HOPKINS 29

N. Agrawal, M.D.: H.-J. Hwang, Ph.D.: J. Sager, M.D.: Faculty, Otolaryngology, Inostics, Baltimore Medical Director, Sanofi-Aventis Head and Neck Surgery, JHU P. Jallepalli, M.D., Ph.D.: S. Saha, Ph.D.: P. Angenendt, Ph.D.: Faculty, Global Director of Research, Scientific Officer, Inostics, Germany Memorial Sloan Kettering Cancer Institute BioMed Valley Discoveries, Inc.

K. Bachman, Ph.D.: S. Jones, Ph.D.: Y. Samuels-Lev, Ph.D.: GlaxoSmithKline Personal Genome Diagnostics Faculty, National Institutes of Health

T. Barber, Ph.D.: A. Kim, B.A.: M. Sausen, Ph.D.: Eli Lilly & Company Graduate student, Personal Genome Diagnostics Cellular and Molecular Medicine Program, JHU C. Bettegowda, M.D., Ph.D.: K. Schmidt, M.D.: Resident, Neurological Surgery, I. Kinde, B.S.: Resident, Vanderbilt University Johns Hopkins Hospital Graduate student, Cellular and Molecular Medicine Program, JHU O. Schmidt-Kittler, Ph.D.: E. Brower, Ph.D.: Scientist, Sanofi-Aventis Researcher, Paragon Bioservices M. Kohli, Ph.D.: Functional Genetics D. Shen, M.D., Ph.D.: I. Cheong, Ph.D.: Faculty, Scientist, Temasek Life Sciences, R. Leary, Ph.D.: Genome Institute at Washington University Singapore Novartis T. Sjoblom, Ph.D.: J. Cummins, Ph.D.: C. Lengauer, Ph.D., M.B.A.: Faculty, Uppsala University, Sweden Resident, Director, Blueprint Medicines Memorial Sloan Kettering Cancer Center S. Springer, B.S.: M. Li, Ph.D.: Human Genetics graduate student, JHU L. Dang, M.D., Ph.D.: Pathology, JHU Faculty, G. Traverso, Ph.D.: University of Michigan Medical Center J. Lin, B.S.: Faculty, Trinity College, Cambridge, UK Washington University, St. Louis F. Diehl, Ph.D.: V. Velculescu, M.D., Ph.D.: CEO, Inostics, Germany D. Mandelker, M.S., M.D., Ph.D.: Faculty, Director, Resident, Brigham and Women’s Hospital, Cancer Genetics & Therapeutics Lab, J. Douglass, M.S., M.D., Ph.D.,: Harvard Medical School Kimmel Cancer Center graduate student, Cellular and Molecular Medicine Program A. Nanda, Ph.D.: Q. Wang, M.S.: at JHU Resident, Brigham and Women’s Hospital, Pharmacology Program student, JHU Harvard Medical School D. Dressman, Ph.D.: T.-L. Wang, Ph.D.: Life Technologies R. Pagliarini, Ph.D.: Faculty, Johns Hopkins University Research Investigator, Novartis K. Ericson, Ph.D.: Y. Wa n g, B . S . : Lund University Clinical Sciences, Sweden D. W. Parsons, M.D., Ph.D.: Cellular and Molecular Medicine student, JHU Faculty, Baylor College of Medicine J. He, M.D., Ph.D.: Z. Wang, Ph.D.: Resident, B. Peter, B.S.: Faculty, Case Western Reserve University Scott & White Hospital, Genentech Texas A&M University C. White-Gan, Ph.D.: C. Rago, Ph.D.: Staff Scientist, Novum Y. He, Ph.D.: OpenOnward Co. Faculty, Duke University H. Yan, Ph.D.: H. Rajagopalan, Ph.D.: Faculty, Duke University Medical Center W. Hendricks, Ph.D.: Resident, Brigham and Women’s Hospital, Staff Scientist, Harvard Medical School J. Yun, Ph.D.: Translational Genomics Research Institute Faculty, University of Wisconsin M. Reis, M.D., Ph.D.: M. Holdhoff, M.D., Ph.D.: Universidade Federal de Santa Maria, Brazil X. Zhang, M.D.: Faculty, Kimmel Cancer Center Resident, Massachusetts General Hospital S. Rey, M.D., Ph.D.: X. Huang, M.D., Ph.D.: Sr. Postdoctoral Fellow, Ontario Cancer Institute J. Zhu, Ph.D.: Consultant, the Boston Consulting Group., Ltd., Chempartner, Shanghai China I. Rhee, Ph.D.: Resident, Massachusetts General Hospital 30 SPECIAL COMMEMORATIVE ISSUE of PROMISE & PROGRESS

Laboratory Directors Post Doctoral Fellows

Kenneth W. Kinzler Bert Vogelstein Margaret Hoang Yuchen Jiao

Lead Investigators

Christine Joseph Yuan Qiao

Luis Diaz Nickolas Papadopoulos Shibin Zhou

Investigators

Nick Roberts Andrew Skora

Nishant Agrawal Chetan Bettegowda

Surojit Sur Fay Wong Teamwork Cancer research requires many talented individuals to do their part. It is fundamental to the Ludwig Center at Johns Hopkins.

People are its most valuable resource. Zhao-Bo Li Ming Zhang Behind the discoveries are men and women who share the same goal—to do their part to end deaths due to cancer.

WATC H A VI D E O O R R E AD MO R E A B O UT TH E LU DWIG C E NTE R TE AM

WWW.HOPKINS KIM M ELCANCERCENTER.ORG Jian Yang THE LUDWIG CENTER at JOHNS HOPKINS 31

Students Research Technicians Administration

Jackie Douglass Bjarne Bartlett Natalie Silliman Kathy Helwig

Antonio Kim Lisa Dobbyn Joy Schaefer Mark Kelman

Security

Qiang Liu Maria Popoli Latice Watson

Officer Robinson

Simeon Springer Janine Ptak

Clinical Research Team

Quing Wang

Cherie Blair Kathy Roman Judge Eden Stotsky-Himelfarb

Yuxuan Wang 32 SPECIAL COMMEMORATIVE ISSUE of PROMISE & PROGRESS

Honors and Awards Cancer Research Powerhouse Scientific journals are researchers’ way of disseminating key findings throughout the scientific and medical community. Rather than starting from scratch, investigators build upon published discoveries of others. In cancer research, the “others” are Bert Vogelstein, M.D., and Kenneth Kinzler, Ph.D., who, according to Thomson Reuters ScienceWatch were the most frequently cited in cancer research from 1995-2005. With more than 50,000 citations, Drs. Vogelstein and Kinzler, were called “doctors of the decade” and earned the Kimmel Cancer Center the distinction of being dubbed a cancer research powerhouse. “The impressive number of citations these exceptional researchers have received is evidence of their profound influence on modern scientific thought,” reported ScienceWatch editor Christopher King. “The Kimmel Cancer Center solidifies its stance as a research powerhouse in the field of oncology.” THE LUDWIG CENTER at JOHNS HOPKINS 33

The Big Prize AACR Honors In February 2013, Bert Vogelstein, M.D., Dr. Vogelstein is among the most hon- The American Association of Cancer was awarded the inaugural Breakthrough ored of cancer researchers. In 2003, he Research (AACR) is the oldest and Prize in Life Sciences. He was selected was ranked by the Institute for Scien- largest scientific organization in the for his landmark work in cancer ge- tific Information in Philadelphia as the world focused on preventing and cur- nomics and tumor suppressor genes. most highly-cited scientist in the world ing cancer through research, education, during the previous 20 years. Other communication, and collaboration. Its Vogelstein was among inaugural win- awards include the American Cancer goal is to foster the exchange of knowl- ners who received $3 million each for Society Medal of Honor, the Karnofsky edge and new ideas among scientists their groundbreaking research in the Memorial Award from the American dedicated to cancer research, provide life sciences. The Breakthrough Prize Society for Clinical Oncology, the training opportunities for the next was established by technology entre- Richard Lounsbery Award from the generation of cancer researchers, and preneur Yuri Milner, Google founder National Academy of Sciences, the increase public understanding of cancer. Sergey Brin, 23andMe co-founder Louisa Gross Horwitz Prize from In 2013, the Ludwig Center team has re- Anne Wojcicki, Facebook founder and Columbia University, the Harvey Prize ceived multiple honors from the AACR. CEO Mark Zuckerberg and his wife in Human Health from the Technion, Kenneth Kinzler, Ph.D., was elected to Priscilla Chan to recognize excellence the Charles S. Mott Prize from the Gen- the Nominating Committee. Bert Vogel- in research aimed at curing intractable eral Motors Cancer Research Founda- stein, M.D., was named an inaugural diseases and extending human life. tion, and the Prince of Asturias Award fellow of the AACR Academy. Drs. The Breakthrough Prize in Life in Technical and Scientific Research, Kinzler and Vogelstein, Luis Diaz, M.D., Sciences Foundation was created to considered the “Spanish Nobel.” and Nickolas Papadopoulos, Ph.D., administer the prize and is chaired were members of a multi-institutional by Art Levinson, chairman of the Dr. Vogelstein was elected to the Amer- group that received the AACR Team Board of Apple and Chairman and ican Academy of Arts and Sciences and Science Award for research decipher- former CEO of Genentech. National Academy of Sciences in 1992 ing the genetic changes that character- and to the American Philosophical ize pancreas cancer. Last year, Dr. “This is a tremendous honor. An honor Society in 1995. His advisory roles have Vogelstein received the eighth annual I share with my fellow investigators included Chairmanship of the National AACR-Irving Weinstein Foundation who have worked with me so tirelessly Research Council Committee on the Distinguished Lectureship, which over the last three decades to pinpoint Biological and Biomedical Applications acknowledges an individual whose molecular genetic causes of cancer,” of Stem Cell Research and the Board of outstanding innovations in science says Dr. Vogelstein. Scientific Counselors of the National and whose position as a thought leader Human Genome Research Institute. have the potential to inspire creative He has also held editorial positions at thinking and new directions in cancer Science, Molecular Cell, Cancer Cell and research. The New England Journal of Medicine. 34 SPECIAL COMMEMORATIVE ISSUE of PROMISE & PROGRESS

Sequencing Our Genes: Is Cancer Written in Our DNA? Dr. Bert Vogelstein Answ ers

There is no one better suited to explain the intricacies of cancer genetics than Dr. Bert Vogelstein. He ranks today, as he has for more than a decade, as the preeminent international scientist. His more than three decades of discoveries, revealing cancer as a genetic disease, are universally regarded as the most relevant in the field of cancer.

He also is one of the world’s leading sequencing can tell us about cancer risk, no hereditary predisposition. For the experts on a new technology called next- and as important, what it does not tell. majority of the population, who were generation sequencing. His laboratory not born with a cancer-promoting has used it to scour the genome of the Q. What is the whole genome and alteration in their DNA, whole genome cancer cell and uncover the collection what does it tell us about cancer? sequencing won’t predict whether they of genetic errors that make cancers A. Our whole genome is the DNA we’re will get cancer. The reason is that our originate, grow, and finally spread. born with. For some of us that DNA inherited DNA is not the final manu- This technology also can be used to contains the code for cancers that occur script of our life and all of the health reveal an individual’s complete and in our families. These cancers are events we will face. Each of us plays an entire DNA (whole genome). Right directly attributable to inherited genetic important part in editing and interpret- now, it costs about $5,000 to sequence alterations. In this scenario, whole ing the script with the foods we eat, an individual’s whole genome, but the genome sequencing can be extremely the air we breathe, and the habits we price tag is decreasing rapidly. With beneficial in identifying the specific acquire. Other things, like random its increasing affordability, many gene and mutation that is causing these mistakes that cells make as they divide, have suggested that it could be used cancers and potentially in determining also play a role but are out of our control. to identify individuals who were likely how best to treat them. to develop cancer in the future as well In fact, heredity accounts for only as those who would be safe from the However, most cancer is not related about one percent of cancers. For most disease. Dr. Vogelstein explains what to an inherited genetic mutation. people, lifestyle behaviors are far more the genome is, what whole genome Most cancers develop in people with damaging. People cannot change the THE LUDWIG CENTER at JOHNS HOPKINS 35

genes they inherit, but they can change It also can be looked at in another way. than the genome people are born with. behaviors. It is estimated that diet, There are 156 million women in the The cancer genome reveals the genetic obesity, and lack of exercise contribute United States today. Based on current alterations specific to each person’s to 35 percent of cancers, and smoking ovarian cancer rates, about 2.2 million cancer, and these alterations can be tar- is a factor in an additional 30 percent of them will develop ovarian cancer geted to detect cancers, monitor them, of cancers. sometime in their lives. Whole genome and treat them. Within a few years, we sequencing could, with much further anticipate that all cancer patients at the Q. Will whole genome sequencing research, identify 100,000 to 500,000 Kimmel Cancer Center will have their predict cancer? of them. Most women—1.7 to 2.1 million tumors sequenced to reveal their cancer A. As the technology that makes it pos- of them—would have no sign of their genomes. It will not only help cancer sible to quickly sequence an individual’s impending cancers. experts determine which treatments whole genome becomes increasingly may work for a particular patient, but more available and affordable, people Q. Where does that leave us then? just as important, which ones may not. have begun to wonder about its ability A. These calculations show that many This is the focus of personalized cancer to predict diseases a person is likely individuals may indeed derive benefit medicine, and we have just begun to to develop. “If I had my whole genome from genetic tests for predisposition to realize its potential. sequenced, could it reveal whether or cancers. If the genetic information from not I will develop cancer in the future?” these tests is provided to patients in a Q. Will cancer genome sequencing highly responsible manner, such test- improve cancer prevention and For this we turned to a database of ing could be useful and save lives. On treatment? 53,666 identical twins. Twins are natu- the other hand, most individuals who A. As tumor cells divide, they develop ral clones, and as such, they share the develop cancers will not be alerted to their own blood supply to get the nutri- same genome. Generally speaking, the fact that they will develop cancers. ents they need to nourish and grow, if one twin is followed over a period In most cases, cancers do not result and as a result, pieces of the cancer’s of time and all of the diseases he or from hereditary factors but rather from DNA get carried into the bloodstream, she develops are cataloged and then environmental influences and bad luck. leaving telltale evidence of its existence. compared to the other twin, measuring The best way to manage cancer risk is In the Ludwig Center, our research how often he or she developed the through prevention and early detection. team has developed a simple blood test same diseases, it is possible to calculate that can detect DNA from cancer cells. inherited genetic risk for these diseases. People are rarely born with a cancer- These tests have the potential to detect causing genetic alteration. Cancer is cancers before they are seen on X-rays, What many overlook in whole genome usually the result of accumulating edits CT scans, or through other types of sequencing, particularly as it relates to made to the DNA of certain cells. It diagnostic methods and long before cancer, is not about what it reveals, but would be a good idea, then, to eliminate they cause symptoms. Universal, pre- rather what it does not. as much as possible from our lives— cise, and specific, this test can pluck those things we know make these one cancer cell from a sea of a half- Ovarian cancer is a perfect example. cancer-starting edits to cell DNA. million normal cells. It can also help Our study predicted that about two According to cancer prevention experts, doctors determine whether a cancer percent of women who would undergo if we do just these things—applying therapy is working by measuring the whole genome sequencing would get the science we understand today to amount of cancer DNA in the blood. a positive result and alert them to an strengthen cancer prevention—we If a treatment is working, the amount inherited genetic risk for ovarian cancer. could decrease cancer incidence by half. of DNA should decline. If it goes up, On the other hand, 98 percent of it’s a sign that the treatment may not be women would get a negative test result. Q. What about the cancer genome? killing the cancer. Rising levels of cancer That doesn’t mean these women won’t A. Just as every person is genetically DNA could also alert doctors that a get cancer—based on ovarian cancer unique, so is every cancer. While cancer cancer has come back. incidence rates, evidence proves that is not usually written in the DNA many of them will. It just means that we are born with, the story of each Such a test, used together with the whole genome sequencing usually individual cancer is contained within prevention strategies already discussed, cannot predict which ones will develop the unique and different DNA of the could eventually make 75 percent of the cancer and which ones will not. cancer cell—the cancer genome rather cancers curable. • 36 SPECIAL COMMEMORATIVE ISSUE of PROMISE & PROGRESS Ken Kinzler on the Ludwig Center Many scientists make a discovery, but few make them by the dozens as the Ludwig Center team co-directed by Kenneth Kinzler, Ph.D., has done. Ludwig Center researchers became the first to define essentially all of the genetic mutations that occur in cancer, and they are consistently on the forefront of cancer medicine and discovery. In this conversation, Dr. Kinzler gives us a glimpse into the laboratory and discusses the challenges the Ludwig Center team has taken on.

Q. With far fewer scientists, your us make sure we’re steered in the right dinated fashion. They do it because laboratory became the first to deci- direction. Our team is not just faculty they have a genetic instruction book to pher the cancer genome and time and members, of course. It’s young people, guide them. Cancer results when this time again, your discoveries have the best and brightest in the world, from instruction book becomes corrupted. outpaced much larger laboratories. a variety of disciplines, including chem- What is the key to this success? istry, physics, yeast genetics, fruitfly In 2004, the entire genetic code of A. Part of the reason we have been so research, veterinary medicine, computer normal cells was read for the first time. successful and beaten huge groups is science, neurosurgery, protein structure, That can be compared to reading 3,000 because of our Ludwig funding. It allows engineering, and even classic Greek. volumes of “War and Peace.” This us to do what’s important. Our focus is These different experiences and per- was important, because now that we not decided by committee. We could do spectives allow us to take on this incred- knew what the normal human genome the most groundbreaking research ibly complex problem with the ability looked like, we could begin to sort out without having to worry about where to see it from many different vantage the differences in the cancer cell. That’s the next level of funding would come points. Individually, I think it’s fair to what our lab did and revealed where from. We had the freedom to think say we are all very good scientists, but the genetic instructions broke down— outside of the box and do things outside collectively, collaboratively we are that specifically what genetic alterations of the box. We try to develop research much more. As a team, we have been were driving cancer. projects that are not in the mainstream able to do extraordinary things. now, but we could put them there a Q. What does this mean for the decade from now. As important is our Q. What makes cancer so complicated? management of cancer? team of scientists. We are fortunate to A. Think about trying to tell identical A. Take the IDH1 gene, for example. have some of the most talented scientists twins apart. There are probably a few No one was interested in it. Then we from around the world, and they all things that make them different, but made a discovery in gliomas linking it share the vision of pushing research to they are very subtle. And that’s the dif- to 70 percent of these brain cancers. the limit to help cancer patients. ficulty with cancer. The enemy is our No one else was interested in IDH1 until own cells. The changes that distinguish our laboratory proved it was important. Q. What is different about the a cancer cell from a normal cell are not Now, there are drugs to target it. Ludwig Center team? easily recognized. At one time in history, A. For one thing, our scientists have it was infections, like the plague, that These discoveries also point to functions widely different backgrounds. I have threatened the most lives, but these in cells that are defective in cancer and a background in toxicology and phar- things are as foreign to our body as are the very basis of individualized macology. Bert Vogelstein trained in they can be, and so the immune system medicine and risk assessment. Already, mathematics and pediatrics and is the recognizes them. Our immune system clinicians are using this information undisputed leader in the basic science doesn’t recognize cancer cells as well as to select drugs for therapy, and more of human cancer. Nick Papadopoulos is infections because the cancer cells are and more drugs are being identified to an expert in genetics and diagnostics so similar to normal cells. target these defects. and their translation to the clinic. Shibin Zhou trained as a physician and With 50 trillion cells in the human body, In our lab, we are most excited about in neuroscience and is now an expert in it is a complex machine that functions the potential to use them to detect cancer biological therapies. Luis Diaz is a board in a coordinated fashion. Each cell con- earlier. As the defects we’ve described certified oncologist who sees lots of tains DNA that is six-billion chemicals occur only in cancer cells, we can use them patients every week and brings a famil- strung together. These cells know to develop tests that find cancers before iarity with clinical issues and with can- when to replicate, when to die, when to they produce symptoms and to monitor cer patients on a personal level that helps reproduce. They must work in a coor- how they respond to treatment. •

38 SPECIAL COMMEMORATIVE ISSUE of PROMISE & PROGRESS

LUDWIG CANCER RESEARCH and JOHNS HOPKINS The Ludwig gift enabled us to decipher cancer, to become the first in the history of mankind to know the human genetic code and to have the technology to define the mistakes in the genetic code that cause cancer. It enabled us to make this progress and it inspires us and charges us to go farther, to conquer cancer. It’s a commitment we intend to make good on. —Kenneth W. Kinzler, Ph.D., and Bert Vogelstein, M.D., the most frequently cited scientists in cancer medicine and Co-Directors of the Ludwig Center at Johns Hopkins Promise & Progress is published by The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Office of Public Affairs 901 South Bond Street Suite 573 Baltimore, Maryland 21231 (410) 955-1287 William G. Nelson, M.D., Ph.D. Director Amy Mone Director of Public Affairs Valerie Matthews Mehl Editor and Sr. Writer [email protected] Michelle Potter Production Manager and Editorial Assistant Vanessa Wasta Associate Director, Media Relations and Web Projects Flynn Larson Feature Photography MSK Partners, Inc. Design and Production

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C O M I N G I N T H E N E X T I S S U E : E PI G E N E T I C S The Other Cancer-causing Gene Alteration