Scientific Royalty Sitting Down with David Lane

LudwigLink July 2013

Scientific royalty

Shortly after joining the Ludwig Institute, I was invited to a board dinner where I had the pleasure of sitting next to our new scientific director, David Lane. I remember being particularly intrigued by the “Sir” on his nametag. When was he knighted? Why? We got to talking, and although I never learned the circumstances of his knighthood, I was captivated by his fascination with the Institute, its approach and the achievements that resulted from its independence and flexibility.

At the time, he was particularly excited about a Ludwig discovery, the 806 antibody, which he felt exemplified Sir David Lane Ludwig’s distinct approach to research. We encourage collaborations of Sitting down with David Lane laboratory and clinical research that not only further our understanding of cancer, An internationally recognized leader in ability to tackle big problems. They have but also translate laboratory discoveries the field of tumor suppressor biology great resources and the infrastructure to into candidates for clinical therapy. and a strong voice in the battle against do their research at the very highest level, cancer, his pioneering research led to the which accounts for the extraordinary When I interviewed David a few weeks discovery of a tumor suppressor gene, contributions Ludwig scientists have ago, this same unbridled enthusiasm p53, which he named the “guardian of made to cancer research. for Ludwig was the first thing he shared the genome.” Knighted for his services when asked why he wanted to join the to cancer research, he served as Cancer What are Ludwig’s greatest strengths? Institute and what makes it stand out Research UK’s first chief scientist. Avrion Independence. We choose exactly how from other cancer research organizations. Mitchinson, with whom he did his PhD we want to spend our resources for the Words like “fleet-footed,” “long-term in immunology, still refers to him as “the best possible outcome. We support really vision,” “whole research spectrum,” “real best student I ever had in University outstanding science and make sure it gets impact for patients” and “outstanding College.” This gifted scientist is David translated—it doesn’t just get stuck in science” rolled easily off his tongue. Lane, the Ludwig Institute’s new scientific a journal, but is further developed and director. We had a chance to sit down evaluated so that it has the potential to Click here (password: Ludwig) to with him and chat about his role. help patients. listen to David talk about his new role at Ludwig and what he hopes to achieve Why did you want to join the Institute? And speed. So often we see an as our scientific director. You’ll also Having worked on the Scientific Advisory opportunity but it takes years of grant learn more about his research and the Committee and the Board of Directors writing before it can happen, whereas opportunities he sees for the future of for a number of years, I got to know the at Ludwig, one of our scientists can cancer research. David’s passion drives Institute very well. And I have to say, it’s come to us and say, “This is a fantastic his talent for world-class achievements. a pretty amazing organization. I’ve been opportunity for a clinical trial,” and we able to see firsthand how its scientists can quickly evaluate whether to pursue Rachel Steinhardt, carry out outstanding research—all it. Similarly, if someone comes and says, Director of Communications the way from basic to clinical research. “This is a piece of equipment we really Ludwig supports its scientists with long- need; it’s really going to transform how term funding, which gives them the Continued on next page

Continued from previous page Much of the best science we’re doing our research,” we’re able to make the decision quickly on whether to comes from unexpected buy it or not. collaboration. Fostering

Where do you think Ludwig has a unique an atmosphere where opportunity with regard to funding and people feel happy and how it can support research? The current funding climate for science comfortable working with worldwide is very challenging. And the one another, and making consequence is that ‘the butter is being spread rather thinly’—so individual sure they know they are scientists are competing harder for going to be supported, Christian de Duve rather limited funds. And because that results in an extreme level of scrutiny, is on my radar. the type of grants that get funded A scientific giant tend to be the more conservative ones. —Sir David Lane, His discoveries brought him great Ludwig needs to continue to counter Ludwig Institute Scientific Director intellectual satisfaction, but that was not those trends. We have great faith and enough for Christian de Duve. His goal trust in our scientists, and give them was to use them to conquer disease. His enough resources to do outstanding motto was “mieux comprendre pour mieux work and sustain that investment so they second nature to me. I was chief guérir,” or “the better we understand, can take risks. No one can predict what scientist at Cancer Research UK while the better we can cure.” de Duve, kind of research will ultimately lead to working with A*STAR—and at one a Belgian biochemist with a special big breakthroughs. The tremendous point simultaneously running a biotech connection to the Ludwig Institute, died progress in immune therapy has come company as well as holding a university in May at his home in Nethen, Belgium. from 30-plus years of basic research on job. His discoveries about the internal the immune system, and nobody could workings of cells helped give birth to the have predicted the impact we are now What are some of the challenges field of modern cell biology and shed seeing. So we have to sustain that sort you face? light on genetic disorders. He shared of long-term investment and go for Institutions like Ludwig have really the 1974 Nobel Prize in Physiology excellence. And when we see excellence, captured the world’s attention by or Medicine with Albert Claude and support it. Really nourish our shoots and showing that cancer can become a George Palade. make sure they flower. treatable disease. We need to continue to do research that deepens our de Duve was a big part of the Ludwig How do you plan to begin at Ludwig understanding of the disease and community. In 1978, he proposed and help advance its cancer research discover and develop new therapies to that the Ludwig Institute base its programs? help patients. Our researchers have been Belgian branch within the walls of the Getting to know everyone well is and will remain a part of the revolution International Institute of Cellular and my number-one priority. There’s no that shifts cancer from a death sentence Molecular Pathology, which he founded substitute for personal contact. I’m a into a manageable disease. and was subsequently renamed in his scientist myself, a very active scientist. I honor. In his very active retirement, he love science and I think that puts me in Final words of wisdom? remained involved in Ludwig research a position where I can understand what We all need to keep the faith. Science and activities. people are doing and why they’re doing is hard and long and what Ludwig it—while helping people interact with has achieved is just tremendous. “I believe Christian’s most important each other and promoting collaboration. Progress over the past 40 years by contribution to Ludwig was recruiting Much of the best science comes from the entire Ludwig community now Thierry Boon,” said Benoît Van den unexpected collaboration. Fostering an provides unprecedented opportunities Eynde, Ludwig Brussels director. “It atmosphere where people feel happy and to translate current discoveries into was Ludwig’s long-term support that comfortable working with one another, improved patient care. We are at a allowed Thierry to pursue his ambitious and making sure they know they are pivotal juncture with the potential for and innovative research, which led going to be supported, is on my radar. significant gains in the near future. And to uncovering the first T cell-defined we’re going to continue to be one of the tumor antigen in human beings, and Will it be tough juggling two roles? leaders in developing new therapies and thereby reinvigorated the field of tumor Over the years, I’ve had to master the new approaches to cancer treatment immunology. We will always be grateful art of using my time efficiently, and while constantly striving to understand to Dr. de Duve for his serendipitous juggling multiple roles has become the disease better. matchmaking.”

2 PEOPLE ON THE MOVE Leading the charge Brazil is gearing up for the “biosimilar” boom, and Andy Simpson, Ludwig’s former scientific director, is leading the charge. Biologic biosimilars are copycat versions of complex biological drugs, such as the lung cancer drug Avastin, the breast cancer drug Herceptin, and Rituxan, which is used to treat cancer of the lymphatic systems as well as rheumatoid arthritis. Brazil is determined to become an important player in this area, joining a select but growing group Andy of nations becoming manufacturing hubs Simpson for biosimilars. they offer the very real possibility of biosimilar and the approved biological The Brazilian government has a key providing patients with quality medicines product in safety, purity and potency. role in supporting the industry by giving and enhanced treatments at better grants and loans to biotechnology start-up prices,” Andy said. “The government Andy, who recently stepped down from companies. Two new entities were created was spending a lot of money importing the Institute’s board of directors to by existing Brazilian pharmaceutical biological drugs, which was affecting the pursue his new responsibilities, brings companies with support from the balance of payments. Now that some the right mix of scientific expertise Brazilian government to serve this market, of these antibodies are about to come and experience in leading complex Orygen Biotecnologia and BioNovis. off patent, it is possible to think about projects. Two products, trastuzumab producing and manufacturing them in and etanercept, have already been Andy is taking the reins of Orygen as Brazil.” produced in Orygen’s pilot plant. Four CEO at a propitious moment. Biologics other projects are under way, as are are expected to account for nearly 15 Since biosimilar drugs are never negotiations with the government for percent of the global pharmaceutical exact copies of the original medicine, plans to build an industrial plant. This is market by 2017. Andy expects that the establishing appropriate standards for not an easy feat in Brazil. first biosimilar monoclonal antibody will clinical development, manufacturing be the breast cancer drug trastuzumab, processes and therapeutic use are the “Every start-up has a life of its own. commonly known as Herceptin. biggest hurdles. Tiny differences in Each project brings unique challenges manufacturing mean biological drugs are and opportunities. At Orygen, everyone “Biosimilar drugs will be a game changer. impossible to replicate exactly. As a result, understands that this is a project of They’ll go a long way in meeting Brazil’s clinical trials are needed before approval, national importance, and there is need for affordable health care for its because there can’t be any clinically the same spirit of collaboration and growing population of 200 million, as meaningful differences between the commitment that embodies Ludwig.”

Did you know ...? common in men than women, and cancers are surgically removed while more prevalent in high-income they are still small and have not spread Nicknamed the silent killer, it spreads countries, where rates are increasing. to the lymph nodes. rapidly and is seldom detected in its early stages. Symptoms may not Actor Patrick Swayze, best known Ludwig scientist Bert Vogelstein is a appear until it’s reached an advanced for his roles in the hit films Ghost and member of the Pancreatic Cancer stage. It has the lowest relative survival Dirty Dancing, was diagnosed with Research Consortium and a scientific rate of all cancers—95 percent stage 4 pancreatic cancer in January advisor of the Lustgarten Foundation, a of patients die within five years of 2008. Rumored to have no more private, nonprofit foundation dedicated diagnosis and 74 percent within the than six months to live, he beat those to funding pancreatic cancer research. first year. odds but died after a valiant 20-month He and his team developed a gene- battle. based test to distinguish harmless Pancreatic cancer is the 13th most pancreatic cysts from precancerous common cancer in the world, with But there’s good news on the horizon— ones. This may eventually help some more than 280,000 new cases the five-year survival rate for pancreatic patients avoid needless surgery to diagnosed every year. It is more cancer approaches 40 percent if the remove the harmless variety.

3 AWARDS A noble tradition

Web Bert Bob Cavenee Vogelstein Weinberg

First class Three Ludwig scientists were named as fellows in the inaugural class of the American Association for Cancer Research (AACR) Academy, the most prestigious honor bestowed by the association. They are Web Cavenee of Ludwig San Diego, Bert Vogelstein of Ludwig Johns Hopkins and Bob Weinberg of Ludwig MIT. The AACR The Nobel Foundation’s new chairman of the board is Ludwig Uppsala’s director Calle Heldin. Academy was created to recognize and honor distinguished scientists whose “I’m pleased and honored by the Nobel Foundation’s major scientific contributions have propelled significant innovation and expression of trust and look forward to this important progress against cancer. and exciting assignment. The Nobel Prize has a unique international status and I will do my utmost to contribute “Each of these researchers has pioneered advancements in cancer research. They to the foundation’s efforts to preserve its position and have helped to transform the landscape further develop its activities.” by enhancing the understanding of the underlying causes of cancer and accelerating the development of new tools to defeat it,” said Ed McDermott, society. Xin joins David Lane, Ludwig’s Brain trust Ludwig’s president and CEO. “We are new scientific director, who is a founding It’s the most common and deadly form grateful for the recognition by AACR of member of the academy. of brain cancer: glioblastoma multiforme the life work of these researchers.” (GBM). Life expectancy after diagnosis The honor recognizes Xin’s outstanding is 15 months. But the National Brain contributions to the innovative Tumor Society is determined to change application of scientific knowledge. She that prognosis. It’s launched the Defeat discovered the ASPP family of proteins, GBM Research Collaborative, an and her group focuses on understanding initiative that aims to double the survival how to selectively kill cancer cells. They rate of deadly brain cancer in just five study the role of ASPP proteins in tumor years. suppression pathways with the aim of identifying therapeutic targets. To achieve this goal, the collaborative will connect leading brain tumor researchers Up to 44 new fellows are elected to the from top cancer institutions across Xin Lu academy each year. They are selected the globe. Projects will be combined from biological and laboratory sciences, and driven by investigator teams with An excellent fellow clinical academic medicine and other proven track records to significantly Molecular biologist and Ludwig Oxford professions affiliated with medical science. improve patient survival. The primary director Xin Lu was elected a fellow of Election to the academy is based on a goal is to share data among projects and the Academy of Medical Sciences in candidate’s outstanding contribution to investigator teams to advance potential April for her exceptional contribution the advancement of medical science, therapies along the drug discovery to science in the UK. With a vision to their application of existing scientific pipeline. improve health through research, the knowledge to innovative health academy’s mission is to promote medical interventions, or their conspicuous service Ludwig scientists Web Cavenee in science and its translation to benefit to medical science and health care. Continued on next page

4 AWARDS NEWS ROUNDUP

Continued from previous page San Diego and George Demetri at Dana-Farber/ Harvard are two of the senior cancer experts on the Strategic Scientific Advisory Council that will George oversee the collaborative. Demetri These advisors will chart the strategic direction of research, review achievements and progress, and hold the project teams accountable for attaining key milestones and annual goals over the next five years

Scientific rock stars Science is cool.

Tech titans want to turn scientists into Joan Heath superheroes, and they’re rewarding them each with a $3 million Breakthrough Prize in Life Sciences. The new, Family ties intestinal epithelial cells under stress international award, similar to the Nobel What is shorter than your little finger, from ribosome failure did not die. Prize, rewards scientists who think big, translucent, and a useful model for Instead, the cells initiated a process take risks and do research aimed at biomedical research? known as autophagy to promote their curing intractable diseases and extending survival. human life. While the prize recognizes The answer: zebrafish. researchers at the top of their fields, it’s Currently, there is great interest in also intended to inspire future scientists. The zebrafish attracts researchers developing therapeutics to block investigating many human diseases and ribosome production as a strategy to Three Ludwig scientists were among the new treatments. Zebrafish share many prevent cancer cells from dividing. The eleven recipients of the first Breakthrough genes with humans. They can develop team’s zebrafish model of disrupted Prize in Life Sciences, which is funded by most of the types of tumors that humans ribosome biogenesis suggests that this several Silicon Valley entrepreneurs. do through the same genetic pathways. approach requires caution.

Titia de Lange, a Ludwig While studying mutant zebrafish “An anticancer treatment that Scientific Advisory embryos, Ludwig researchers in inadvertently promotes the survival of Committee member at Melbourne, Australia, led by Joan cancer cells through the induction of Rockefeller University, Heath discovered a genetic defect that autophagy would not be desirable,” was recognized for her can halt cell growth and allow cells to said Joan. “However, our findings in work on telomeres, the evade death. The discovery, reported in zebrafish have also shown that in cells protective sequences at the PLOS Genetics, has implications for where ribosome assembly is blocked, ends of our chromosomes. Titia the development of new treatments for the inhibition of autophagy causes She continues to explore de Lange diseases including cancer. rapid cell death. Therefore it is possible how the loss of these that a combination of inhibitors that structures leads to cancer and aging. Bert The gene Pwp2h, which harbored the block ribosome function and autophagy Vogelstein of Ludwig Johns Hopkins defect, is required for the proper assembly could provide an effective anticancer discovered many of the genes responsible of ribosomes, the cellular powerhouses treatment.” for human tumorigenesis and devised that support growth and proliferation. a model for the pathogenesis of colon When the gene is mutated, ribosome The group has assembled a collection of cancer that undergirds much of modern assembly is disrupted and rapidly dividing zebrafish mutants harboring mutations cancer research. Bob Weinberg of cells no longer produce the proteins that disrupt the growth and proliferation Ludwig MIT, who studies cancers and required to fuel their growth. of the intestinal epithelium. Now that how they metastasize, discovered the several of these mutants have been first human oncogene, a gene that ‘goes Joan and her collaborators studied the cloned, the underlying mutant genes are rogue’ after a mutation and drives tumor effects of the mutated pwp2h gene in similarly being evaluated as potential growth. zebrafish. To the researchers’ surprise, targets for anticancer treatments.

5 NEWS ROUNDUP

Continued from previous page Checkpoint Charlie It’s alive! It’s ALIVE! The PD-1 pathway shields tumor cells Can you imagine creating something from destruction by the immune system. that has absolutely no chance of It has two components, PD-1, a receptor surviving, but does anyway? expressed on the surface of T cells, and PD-L1, which is expressed on both Ludwig San Diego investigators Chris cancer cells and a variety of normal cells. Campbell and Arshad Desai engineered Together PD-1 and PD-L1 suppress the a mutant yeast cell that they thought function of T cells, the immune system’s had no chance of surviving. But did. attack dogs, so the cells do not recognize Their discovery, published in the April and destroy tumor cells. 25 issue of Nature, upends the prevailing model for how dividing cells monitor In a June 1 study in the equal distribution of their chromosomes. Journal of Immunology, a team led by Ludwig Chromosomes are made up of DNA, researcher Ralph and humans have 23 pairs of them. Weichselbaum at the They carry all the information used to Arshad Desai University of Chicago help a cell grow, thrive and reproduce. explored the effects of Ralph radiation and an antibody Weichselbaum “Getting the right number of to PD-L1 in two different chromosomes into each cell is absolutely mouse models. They treated irradiated essential to sustaining life,” explained tumors in the equilibrium phase, during Arshad, “but it’s also something that which the immune system maintains goes terribly wrong in cancer. The tumor dormancy, with an antibody kinds of mistakes that occur when this to PD-L1. The antibody blocked the process isn’t functioning properly are interaction between PD1 and PD-L1, seen in about 90 percent of cancers, and boosting T cell activity. very frequently in advanced and drug- resistant tumors.” Nearly all of the mice whose tumors were induced into the equilibrium Chris and Arshad studied the enzyme phase by radiation were cured with the Aurora B kinase, which regulates addition of the antibody to PD-L1. The chromosome tension to ensure proper animals who received radiation alone cell division. Its location was thought relapsed 75 percent of the time. “When to be central to its role to monitor exposed to localized radiation with an chromosome tension. But their research Chris Campbell anti-PD-L1 antibody, the tumors moved shows otherwise. Arshad and Chris from the equilibrium phase to complete found that when Aurora B congregates regression,” Ralph said. in a different location, the required How the protein does this remains tension is still achieved on chromosomes unclear, and both scientists are before they are parceled out to daughter conducting experiments to test various When good receptors go bad cells. hypotheses. Cancer cells are wily, well-traveled adversaries that can sidestep the treatments thrown at them to try and stop them from spreading. In the April therapies. Drugs developed to target this drugs that target EGRF signaling by 23 issue of Cancer Discovery, a team led protein work only until the cancer cells hijacking the signaling of a perfectly by Paul Mischel at Ludwig San Diego adapt to evade the therapy. normal cell surface receptor. This reports an important step toward receptor, platelet-derived growth factor thwarting these crafty cancer cells. So far, most research on this drug receptor-b (PDGFR-b), affects vascular They identified a unique mechanism resistance has focused on how development. Targeting both receptors by which glioblastoma cells develop mutations of other proteins in cancer at once, they found, prevents resistance resistance to drugs that target EGFR cells allow them to resist drugs. But and suppresses glioblastoma tumors in signaling. EGFR, a protein frequently Paul and his team have unearthed laboratory models. mutated in lung and colon cancers something unexpected. They found that and glioblastoma, is a major target of glioblastoma cells develop resistance to Continued on next page

6 NEWS ROUNDUP

On-off switch Many complex diseases have their roots in early human development. Susceptibility to disease is, in part, the result of epigenetic regulation of the genetic blueprint. Epigenetics is the study of changes in gene activity that don’t involve alterations to the genetic code but are passed down to at least one successive generation. The great hope for epigenetic research is that with the flip of a biochemical switch, researchers could instruct genes that play a role in many diseases—including cancer—to lie dormant.

A large, multi-institutional research team involved in the US National Institutes of Health Epigenome Roadmap Project Bing Ren published a sweeping analysis in the May 23 issue of Cell. The study details how genes are turned on and off to Modifications that orchestrate later that aberrant DNA methylation plays direct early human development. Led by stages of cellular differentiation, when an important role in various cancers, Ludwig San Diego researcher Bing Ren, cells become increasingly committed these results suggest that changes to the the scientists describe how novel genetic to specific functions, are primarily cell’s DNA methylation machinery itself phenomena probably play a pivotal role silenced by DNA methylation. may be important in the evolution of not only in the genesis of the embryo but DNA methylation stably alters the tumors. also in cancer. expression of genes in cells as cells divide and differentiate from embryonic “These data are going to be very The researchers found that modifications stem cells into specific tissues. useful to the scientific community in to DNA and histone proteins, understanding the logic of early human known as the epigenome, govern DNA methylation and H3K27me3 development,” said Bing. “But I think the regulation of early embryonic are both involved in the establishment our main contribution is the creation development and tend to be switched and maintenance of epigenetic gene of a major information resource for off by H3K27me3 histone methylation. silencing. While it has long been known biomedical research.”

Continued from previous page Rebel with a cause metastatic melanoma, and how it can be “Our findings highlight the remarkable The most common mutation leading revived. In the April 25 issue of Cancer adaptability of cancer cells and how to cancer is in the gene that makes Cell, a team of researchers led by Xin Lu they harness multiple mechanisms to p53, a protein that recognizes and of Ludwig Oxford describes how p53 maintain the growth signals critical to suppresses aberrant cell growth that is silenced in advanced melanomas by their survival. These results could have leads to cancers. A cancer cell starts out the protein iASPP. In over 50 percent implications for our understanding of a as a normal cell, but becomes a ‘rebel,’ of all human carcinomas, p53 is limited wide variety of cancers,” said Paul. dividing recklessly, invading other tissues, in its antitumor activities by mutations usurping resources and in some cases in the protein itself. The researchers The next step is to test in clinical trials eventually killing the body in which it explored whether they could restore how targeting both receptors affects the lives. If the DNA damage is so extensive p53’s function in advanced melanomas treatment of glioblastoma. Paul and his that it cannot be repaired, p53 triggers by checkmating iASPP activation. colleagues also hope to work with other the cell to commit suicide. When p53 Ludwig researchers to explore small is mutated, however, cancers can grow “These results demonstrate that molecule inhibitors of PDGFR-b and unchecked in the body. functional p53 in melanoma is normally examine whether similar drug resistance inhibited by two different factors, instead mechanisms are found in other cancers. New research reveals how the tumor of one, as previously thought. They also suppressor p53 is shut down in Continued on next page

7 NEWS ROUNDUP

Continued from previous page cancer drug resistance. Glioblastoma is They explored the role of promyleocytic provide a proof of principle that both the most common malignant primary leukemia gene, or PML, in causing of those factors need to be blocked if brain tumor of adults and one of resistance to mTOR inhibitor p53 is to be successfully reactivated in the most lethal forms of cancer. It’s treatment. They found that when cancer cells,” said Xin. tough to treat because tumors rapidly glioblastoma patients are treated with become resistant to therapy—and drugs that target the mTOR pathway, The team treated advanced melanomas it’s very resistant to mTOR-targeted PML levels rise dramatically. They also in mouse models with two small therapy. The mTOR signaling pathway showed that an increase in expression molecules and the drug vemurafenib, is hyperactivated in nearly 90 percent of PML made tumor cells resistant to which blocks the action of abnormal of glioblastomas and plays a critical mTOR inhibitors. If they suppressed proteins that signal cancer cells to role in regulating tumor growth and the ability of the tumor cells to multiply and helps slow or stop the survival. Therapies that inhibit mTOR upregulate the PML protein, the tumor spread of cancer cells. With such signaling are under investigation as cells died in response to the mTOR treatment, advanced melanoma tumors drug development targets, but so far inhibitor therapy. shrank by 75 percent after 28 days of results have been disappointing. mTOR treatment. This work has implications inhibitors halt tumor growth but fail to “Current therapy upregulates PML, for the treatment of cancers in which kill tumor cells. turning off the mTOR signaling p53 is not mutated but is instead pathway. The tumor cells hide, waiting functionally silenced; these comprise Ludwig researchers Paul Mischel, for the target signal to return,” said roughly half of all cancer cases. Web Cavenee and Frank Furnari in Paul. “When low-dose arsenic is added, San Diego uncovered a molecular it not only stops the cell from returning, mechanism that causes resistance to but also shuts down the escape route, Tracking a villain mTOR inhibitors and identified a killing the tumor cell. These data mTOR. No, it’s not a comic book novel drug combination that reverses suggest a new approach for potential villain. this resistance using low-dose arsenic treatment of glioblastoma, and we’re in mice. Their study was published in moving forward to test that possibility in It’s a molecular pathway that regulates the March 12 issue of Proceedings of the people.” tumor growth, survival and, potentially, National Academy of Sciences.

Ask a scientist What do you believe are the most important benefits scientific research provides to society?

As human beings we have Scientific research has great Scientific research provides Although the benefits of the extraordinary and intrinsic potential to increase general knowledge and insight scientific research are difficult ability to seek the truth and knowledge and to improve into diseases and disease to evaluate, scientific research try and understand the world the overall well-being of each mechanisms, thus providing is the only approach we that surrounds us. Research individual; it thereby promotes new strategies for treatment. possess that allows us to generates knowledge, which the health of our society. In However, one important factor accurately detect and also not only makes us more history, scientific research has that is often overlooked is that face major challenges, such complete, but also translates repeatedly challenged existing scientific research provides as environmental changes, into new technologies, expertise dogmata and thus constantly hope—hope for new cures, emergence of new diseases or and information that positively inspires society to scrutinize our hope for better treatments and societal problems. affect our everyday quality of perception of the world. hope for surviving whatever the life. future might hold. —Natalia Sacilotto, —Lars Tögel, —Alexandra Karlén, —Christian Pecquet, Ludwig Oxford Ludwig Melbourne Ludwig Stockholm Ludwig Brussels

8 Q&A WITH JEDD WOLCHOK A hero who heals others

Celebrated medical oncologist, outstanding researcher, compassionate clinician, accomplished musician: Ludwig’s Jedd Wolchok, who was also just appointed as the Lloyd J. Old Chair for Clinical Investigation

Your research It broke new ground in the treatment yielded fantastic of metastatic melanoma and produced results on a new durable tumor shrinkage in about half immunotherapy the patients. Ipilimumab is the first in combination— an emerging class of therapies we call ipilimumab and “checkpoint blocking agents,” which nivolumab. Why is enhance the immune system’s ability to this so exciting? identify and kill cancer cells. The approval of ipilimumab to treat advanced metastatic melanoma was a game changer not only for the thousands of people fighting this disease, but also for the entire field of oncology. Now our data indicate that when ipilimumab and nivolumab are given concurrently, they may be more effective against metastatic melanoma than either appears to be alone, as each one impacts the immune system in a distinct but complementary way. So there’s renewed hope for patients whose disease has a person have than to be face to face progressed after ipilimumab. Alternative with someone who desperately needs a immunotherapies can still work for them. better answer? Over the past 17 years, I’ve been able to change the tenor of the conversation I have with patients. It’s Who or what was Summer of 1984. I had the honor gone from “I’m sorry there’s nothing we the catalyst for of meeting with Lloyd Old, who was have that works well” to “We have several pursuing melanoma supervising a dozen different labs at options that will extend your survival but research? Memorial Sloan-Kettering Cancer Center we’re trying to do better than that and (MSKCC) at the time. He handed me that’s why you should consider a clinical a stack of papers to read and told me trial.” The advances accrued over the past to pick the one that resonated, and he’d decade have fundamentally changed the have me work there for the summer. I conversations that doctors can have with had just finished my freshman year at their patients. Princeton and the most accessible paper was on a clinical trial on melanoma written by Alan Houghton. As I learned What is the biggest Balancing how much time and energy more through the 80s and early 90s and obstacle that I have to do the very important job of became an oncology fellow at MSKCC, you have had to taking care of sick patients while paying I grew to appreciate what a significant overcome in your the appropriate amount of attention to and challenging problem melanoma had career? the science. In my world they are both become and how there was a desperate so important and finding that balance is need for better answers. extraordinarily difficult. I see patients one day a week and take care of inpatients two weeks a year. But even though clinic What inspires you The ability to bring new treatments to is just once per week, people can be sick most about your people who need them. We now have a on the other days and I need the temporal research today? spate of new drugs helping more patients space to help them. If I were seeing than ever before—giving them more patients in the clinic every day, I would time and a better quality of life. I have not have enough time or capacity to do the extraordinary privilege of trying to science, whether that’s clinical, basic or help people who are facing a devastating translational science. You need cognitive illness. And what more motivation could Continued on next page

9 Continued from previous page Scientists want to make progress and space. You need creative space. There eliminate the dependence on writing are precious few places like the Ludwig grants. Ludwig understood this four Center at MSKCC that allow a physician decades ago. I think it’s a big reason to define their clinical practice and give why its reach and impact have been so people that space to really try to succeed phenomenal. The secret is to identify in both worlds. promising scientists it has confidence in who will make a difference in cancer research, and to put the resources behind Can you Cancer can be recognized by our own them. Instead of worrying about money, explain what immune systems as something foreign all I have to worry about is the next great immunotherapy is and dangerous that can be gotten rid of experiment. Or the therapy or clinical and why it holds so like an infection. And immunotherapy trial. It’s a much more effective use of much promise? is an intervention that aims to recruit a my time. With this model, Ludwig was patient’s immune system to do just that. ahead of the curve. It’s a wonderful Immunologists have long hypothesized feeling, knowing that all of the projects I that specific interventions could am working on right now will continue to stimulate and ‘re-educate’ patients’ own develop and grow over the next five years. immune systems to attack their cancer. Immunotherapies are designed to help activate the immune system by blocking Worldwide deaths Use sunscreen and stay out of the tanning the ‘stop sign’ that prevents immune cells from melanoma bed. There’s no such thing as a safe tan. from destroying cancer cells. Malignant have reached And getting one—whether artificially or cells are able to proliferate because of almost 73,000 a from the sun—is unhealthy, increasing an driver mutations but also because they year. What steps individual’s risk of developing cancer. In hide from the body’s immune system. can be taken to fact, people who begin tanning younger Sometimes the body doesn’t recognize reduce this number? than age 35 experience a 75 percent them as foreign and it doesn’t fight them, higher risk of melanoma. or the tumors actively thwart an immune response as a means of survival. The goal is to get the patient’s defenses up so cancer You and Dr. Old Tuba. I play in a group called the is recognized as an invader, and it gets shared a love Brooklyn Wind Symphony, a community- controlled as an infection would. of music as well based organization. The majority of as both being its members are music teachers who With immunotherapy, we’ve entered a accomplished are looking for a way to hone their new era of cancer therapy. It’s helped musicians. What performing skills. We perform and raise us turn advanced cancer into a chronic instrument do you money and support for a public high rather than an acutely deadly disease play? school in Brooklyn that is a magnet by enabling the immune system to school for the performing arts. We continuously monitor against the commissioned a new work, Requiem, by reappearance of ‘foreign’ cancer cells. David Maslanka, which was performed on June 15. We’re actually the first group from New York to win a performing spot If you were just Money. We need more of it devoted to at the Midwest Clinic, an international named magic czar scientific and medical research. The lack band and orchestra competition, which of all of cancer in of knowledge and lack of effective drugs will be held in Chicago this December. It’s the United States, are obstacles we’ve overcome. We have the World Cup of wind bands and quite what would you collaborative and collegial relationships an honor. change about the with industry. Contracted research system to move is a thing of the past and we’re now Click here to listen to Rolling Thunder by research from undertaking collaborative research to Henry Fillmore bench to bedside advance our goals. Too much time and faster? energy is expended on the constant need to secure funding. And unfortunately much of the time spent on it doesn’t bear fruit.

10 REQUIRED READING

Ludwig Lausanne Inzunza HD, Feely W, Horak CE, Hong SF, Yong WH, Cavenee WK, Cloughesy Immunity 2013 April 18 Q, Korman AJ, Wigginton JM, Gupta A, TF, Christofk HR, Black DL, Mischel PS. MicroRNA-155 is required for effector CD8(+) Sznol M. T cell responses to virus infection and cancer Carcinogenesis 2013 March 1 Dudda JC, Salaun B, Ji Y, Palmer Ludwig Oxford (Epub ahead of print) DC, Monnot GC, Merck E, Boudousquie Cancer Cell 2013 April 23 A tale of two approaches: complementary C, Utzschneider DT, Escobar TM, (Epub ahead of print) mechanisms of cytotoxic and targeted therapy Perret R, Muljo SA, Hebeisen M, Rufer Restoring p53 function in human melanoma cells resistance may inform next-generation cancer N, Zehn D, Donda A, Restifo NP, Held by inhibiting MDM2 and cyclin B1/CDK1- treatments W, Gattinoni L, Romero P. phosphorylated nuclear iASPP Masui K, Gini B, Wykosky J, Zanca Lu M, Breyssens H, Salter V, Zhong S, C, Mischel PS, Furnari FB, Cavenee WK. Cancer Research 2013 April 30 Hu Y, Baer C, Ratnayaka I, Sullivan A, (Epub ahead of print) Brown NR, Endicott J, Knapp S, Nature 2013 April 21 Dual blockade of PD-1 and CTLA-4 combined Kessler BM, Middleton MR, Siebold C, Tension sensing by Aurora B kinase is with tumor vaccine effectively restores T cell Jones EY, Sviderskaya EV, Cebon J, independent of survivin-based centromere rejection function in tumors John T, Caballero OL, Goding CR, localization Duraiswamy J, Kaluza KM, Freeman Lu X. Campbell CS, Desai A. GJ, Coukos G. Ludwig San Diego Current Opinion in Cell Biology Clinical Cancer Research 2013 May 6 Cancer Discovery 2013 March 27 (Epub 2013 March 2 (Epub ahead of print) (Epub ahead of print) ahead of print) Genome organization and long-range regulation TIE-2 and VEGFR kinase activities drive De-repression of PDGFRb transcription of gene expression by enhancers TIE-2-expressing monocytes immunosuppressive promotes acquired resistance to EGFR tyrosine Smallwood A, Ren B. function in human breast tumors kinase inhibitors in glioblastoma patients Ibberson M, Bron S, Guex N, Faes- Akhavan D, Pourzia AL, Nourian Ludwig Stanford Van’t Hull E, Henry L, Ifticene-Treboux AA, Williams KJ, Nathanson D, Babic Proceedings of the National Academy of Sciences A, Lehr HA, Delaloye JF, Coukos I, Villa GR, Tanaka K, Nael A, Yang H, USA 2013 May 20 G, Xenarios I, Doucey MA. Dang J, Vinters HV, Yong WH, Flagg Anti-CD47 antibody–mediated phagocytosis M, Tamanoi F, Sasayama T, James of cancer by macrophages primes an effective Ludwig Melbourne CD, Kornblum HI, Cloughesy TF, antitumor T-cell response PLoS Genetics 2013 February 9 Cavenee WK, Bensinger SJ, Mischel PS. Tseng D, Volkmer JP, Willingham Autophagy induction is a Tor- and Tp53- SB, Contreras-Trujillo H, Fathman independent cell survival response in a zebrafish Proceedings of the National Academy of Sciences JW, Fernhoff NB, Seita J, Inlay MA, model of disrupted ribosome biogenesis USA 2013 March 12 Weiskopf K, Miyanishi M, Weissman IL. Boglev Y, Badrock AP, Trotter PML mediates glioblastoma resistance to AJ, Du Q, Richardson EJ, Parslow mammalian target of rapamycin (mTOR)- Science 2013 May 30 AC, Markmiller SJ, Hall NE, de Jong- targeted therapies (Epub ahead of print) Curtain TA, Ng AY, Verkade H, Ober Iwanami A, Gini B, Zanca C, Matsutani Engineered SIRP variants as immunotherapeutic EA, Field HA, Shin D, Shin CH, Hannan T, Assuncao A, Nael A, Dang J, Yang adjuvants to anticancer antibodies KM, Hannan RD, Pearson RB, Kim H, Zhu S, Kohyama J, Kitabayashi Weiskopf K, Ring AM, Ho CC, Volkmer SH, Ess KC, Lieschke GJ, Stainier I, Cavenee WK, Cloughesy TF, Furnari JP, Levin AM, Volkmer AK, Ozkan DY, Heath JK. FB, Nakamura M, Toyama Y, Okano E, Fernhoff NB, van de Rijn M, H, Mischel PS. Weissman IL, Garcia KC. Ludwig MSKCC New England Journal of Medicine Cell Metabolism 2013 May 22 2013 June 2 (Epub ahead of print) (Epub ahead of print) Ludwig University of Chicago Nivolumab plus ipilimumab in advanced EGFR mutation-induced alternative splicing of Journal of Immunology 2013 June 1 melanoma max contributes to growth of glycolytic tumors in Radiation-induced equilibrium is a balance Wolchok JD, Kluger H, Callahan MK, brain cancer between tumor cell proliferation and Postow MA, Rizvi NA, Lesokhin AM, Babic I, Anderson ES, Tanaka K, Guo T cell-mediated killing Segal NH, Ariyan CE, Gordon RA, Reed D, Masui K, Li B, Zhu S, Gu Y, Villa Liang H, Deng L, Chmura S, Burnette K, Burke MM, Caldwell A, Kronenberg GR, Akhavan D, Nathanson D, Gini B, Liadis N, Darga T, Beckett SA, Agunwamba BU, Zhang X, Lowy I, B, Mareninov S, Li R, Camacho MA, Lingen MW, Witt M, Weichselbaum CE, Kurdistani SK, Eskin A, Nelson RR, Fu YX.