LudwigLink November 2012

It’s all in the genes PEOPLE ON THE MOVE

Imagine a new type of treatment in SIR which drugs are tailored to match the Knight in shining armor genetic origin of a disease in each patient. Instead of prescribing medicine for a Sir David Lane, chief scientist at A*Star particular kind of , such as lung, in Singapore and a Ludwig Scientific breast or prostate, doctors could match Advisory Committee member, received genetic abnormalities in individuals to a the Cancer Research UK Lifetime drug designed just for them. Achievement in Cancer Research Prize in July. The award recognized his contribution It’s happening, and Ludwig researchers to the landmark discovery of , the most are making great strides in contributing commonly mutated gene in cancer. discoveries to the effort. In this issue you’ll read about how a single drug The p53 protein was discovered in 1979. treatment can silence the mutated Since then, David has dedicated his career gene responsible for Huntington’s to understanding how it protects against into new treatments for cancer,” said disease; which gene is a cancer-fighting cancer. This discovery revolutionized David. superhero; and how researchers are scientists’ understanding of how cells getting up close and personal with genes. grow and divide, and a highly promising p53 guards the body against tumors and is research avenue opened up. Dubbed the compromised in 50 percent of . It The last few decades have brought an ‘guardian of the genome,’ p53 blocks cells works to prevent cancer by suspending the enormous and exciting expansion of with damaged DNA from propagating normal cell division cycle and giving cells knowledge about the genetic factors and eventually becoming cancerous. p53 time to repair the dings and nicks in DNA involved in the development of cancer, doesn’t just play a key role in how cells that come from everyday environmental and Ludwig scientists have advanced grow and divide; it also influences how assaults. If the damage is too severe to be this understanding. The tangible benefits they behave, develop and die. repaired, p53 triggers cell death. of this knowledge are beginning to revolutionize the prevention, detection “Decades on from our discovery of p53, David’s recent work, which is focused and treatment of cancer. we are still making incredible strides in on controlling p53, has identified several understanding how it behaves and controls promising targets for developing new Rachel Steinhardt cells, and we’re now turning this knowledge cancer drugs. Director of Communications

P.S. Just a reminder that the 2011 PHIL GREENBERG Highlights Report is available online. Trailblazer You can find it here (pdf). If you need additional copies, please ask your branch For more than 30 years, Phil Greenberg director or email Susan Andrews at has been in the vanguard of adoptive [email protected]. immunotherapy, a treatment in which immune cells are transferred to tumor- bearing hosts. It is a potentially powerful tool for treating cancer and infectious INSIDE diseases such as HIV. His many 2 | Did you know ... contributions to the field have opened up 3 | Sir Derek Roberts looks back important avenues for the immunologic treatment of cancer. Phil is a professor 4 | News roundup of medicine and at the Center in Seattle. He’s the newest 6 | Company news University of Washington and a member member of Ludwig’s Scientific Advisory 6 | Required reading and head of the immunology program Committee, which he joined in July. at the Fred Hutchinson Cancer Research Continued on next page PEOPLE ON THE MOVE

(continued from previous page) in the tumor microenvironment with In 2011, Phil received the prestigious minimal side effects to the patient. His William B. Coley Award, which “Ludwig has a long history of supporting work has demonstrated that adoptive recognizes scientists whose discoveries the exploration of principles defining T-cell transfer, which has the ability to in immunology or tumor immunology the potential interactions between restore immunity and eradicate tumors, significantly advance – the immune system and cancer, and can produce potent anticancer immune based therapies for cancer. facilitating studies to translate insights responses, including dramatic remissions into strategies to treat patients,” said Phil. in some patients with , and Phil graduated from Washington “As a member of the committee, I look leukemia. University with a degree in biology. He forward to the opportunities not only to received his MD summa cum laude help shape the evolution of this effort Every year, melanoma and leukemia from the State University of New York but also to interact with and learn from claim more than 300,000 lives globally Downstate Medical Center in 1971. After the remarkable scientific community that and account for about 4 percent of completing postdoctoral training at the comprises the Institute.” all cancer deaths. It is estimated that University of California, San Diego, 1.35 percent of people born today will he joined the Fred Hutchinson Cancer His research involves isolating and develop leukemia in their lifetime, and Research Center and the division of expanding or genetically engineering existing therapies not only are associated oncology at the University of Washington T cells that can recognize and kill with severe toxicities but also commonly in 1976. cancer cells and remain functional cannot eradicate the disease.

“The most beautiful experience we can have is the mysterious—the fundamental emotion which stands at the cradle of true art and true science.” —Albert Einstein

“Being well rounded is one of the most important aspects of one’s life. Discovering the world from multiple perspectives offers me endless opportunities to enhance and improve my science and art.” —Rodica Stan

Did you know…?

Ludwig Melbourne-Austin scientist and photographer Rodica Click here to view award-winning photos and read Stan melds the two disciplines seamlessly. She grew up in the heartwarming story behind the photograph of Romania during the dictatorship of Nicolae Ceausescuç and the chuckwalla above. dreamed of investigating the world around her. Photography proved an ideal way to capture “permanent memories” to relive and share with family and friends.

2 REMINISCING WITH SIR DEREK ROBERTS “Research ought to be risky”

After serving 14 years on the Ludwig to attract leading international scientists; Board of Directors, Sir Derek Roberts allow the Institute to improve its use stepped down this past June. An of external funding opportunities; and engineer who twice served as provost provide adequately equipped, state-of-the- of University College London (UCL), art research facilities for basic research from 1989 to 1999 and later from 2002 activities. to 2003, Sir Derek oversaw several successful projects and expansion during What advice would you give your his tenure including the merger of successor? UCL and the Institute of Child Health in 1996. He remains a trustee of the Promote the common vision we share, Ludwig Fund, a position he has held build on the Institute’s strengths since 2002. We had an opportunity to and continue to sustain the superb chat with Sir Derek about his tenure on accomplishments Ludwig has achieved. the board and the Institute changes he My successor doesn’t need to be a witnessed during those years. cancer expert but he or she does need to appreciate that cancers are extremely What is special about being part diverse diseases and Ludwig researchers of Ludwig? the care of patients and will ultimately need the security of predictable, long- save lives and improve outcomes. term funding. This will allow them to Ludwig embodies several characteristics undertake groundbreaking research and that make it different from other What is the most important characteristic advance the frontiers of cancer research. research organizations. The mission and of an effective board member? resources of the Institute have never What will you miss the most? deviated from the ongoing commitment Curiosity. There has to be a willingness to innovative basic and clinical cancer to learn coupled with a clear Serving on the board was both a research. The Institute has also been understanding of his or her role and privilege and an honor. I’ll miss the extremely successful in identifying responsibilities on the board. The interaction and camaraderie of the outstanding individuals and giving Ludwig board has three primary roles: group and the wonderful work and them the freedom to develop their own to establish policies, approve significant intensity that the board brings to its research initiatives. And it offers an and strategic decisions, and oversee responsibilities and tasks. The frequent environment that allows its scientists to the Institute’s activity. An effective contact I enjoyed with Ed McDermott tackle risky research challenges and fully board member has to be open-minded, and Andy Simpson will be the biggest explore the potential of their work. focus on the Institute’s objectives and gap in my life. strategies, and resist the temptation to With your exposure to research, what do micromanage. What was it like being knighted by the you see as particularly distinct or unique Queen? about the Institute? What was the most important change in the Institute that you observed during The family joke is that I only accepted Research ought to be risky. What struck your tenure? to make my wife a lady. Seriously, I had me right from the very beginning and been to the palace on prior occasions. is particularly important today is the There were two. In the early years under Before I was given the knighthood, I was unwavering commitment to innovative Lloyd Old’s leadership, there was a awarded the Commander of the British research and the stable, long-term growing emphasis on clinical research that Empire. I also attended a small luncheon funding Ludwig offers its scientists. not all basic research institutions found with the Queen and the Duke of This allows them to concentrate on themselves in a position to undertake. Edinburgh, a Queen’s Award ceremony their research and not spend all of their The second was the recognition that the on behalf of UCL and a garden party time making unsuccessful bids from the widely dispersed, small-branch model with my wife. So I wasn’t so awestricken traditional funding agencies. Sustained was not sustainable given the available by being in the palace as I might have funding has and will continue to lead to resources. The decision to concentrate the been. Let me just say that I’m more of a fundamentally important advances in Institute’s research activities was designed Republican than a Royalist.

3 NEWS ROUNDUP It’s all Greek to me Forging a new path What do cells do when they’re ‘hungry’? The outcome of certain cancer cases can They cope by eating their own depend on activated immune cells that components, a process called autophagy. somehow manage to infiltrate tumors. In this process, which in Greek means ‘self-eating,’ a cell responds to starvation A team led by Ludwig investigator and other stresses by degrading Nicolas van Baren in has found damaged or unneeded parts of itself to one of ways these cells can be activated. produce energy. It is sometimes called In an article published in the August 15 the cell’s housekeeping pathway. Cancer issue of Cancer Research, they reported cells seem to have learned how to the presence of lymphoid structures in optimize this system to obtain the energy melanoma metastases, and showed that they need. B lymphocytes are activated within these structures. The data provide researchers with a new frame of reference in dealing Cross section of a Mig6 mutant mammary duct with melanoma. showing the over proliferating epithelial cells.

“Our findings appear as a paradox, because they indicate that the immune The team studied tumor cells in the system can be very active in the tumor blood system of a patient with recurring microenvironment, whereas the current malignant melanoma. Once they had view is rather to see this environment as identified the tumor cells in a regular immunosuppressive,” Nicolas explained. blood test, the team used Smart-Seq Xin Lu, Oxford Branch “There are two intriguing details. First, to analyze their gene expression. This the lymphoid structures are present in method helped them show that the In a study published in the August 14 metastases, but they are never observed tumor cells had activated membrane issue of Proceedings of the National Academy in primary , from which these proteins that allow the cells to evade the of Sciences, Ludwig Oxford researchers metastases derive. Secondly, among the body’s monitoring system and spread in discovered a critical molecular switch that antibodies generated we find a type of the blood or lymph. regulates autophagy. They also studied the antibody that is specialized in mucosal links between autophagy and a cellular defenses, and that we do not expect to “While our results are preliminary, we process called senescence that stops cell observe in skin tumors. Now we must try showed that it is possible to do studies growth permanently. Study here. to demonstrate that the locally generated of individual, clinically relevant cells. antibodies are directed at tumor Cancer researchers around the world “Some of the recently developed antigens, extend this analysis to local T will now be able to analyze these cells anticancer drugs are potent inducers cell responses and investigate whether more systematically to produce better of autophagy. The new findings may the presence of lymphoid structures methods of diagnosis and therapy in the also offer an explanation as to why impacts melanoma progression.” future,” Rickard said. patient response to these drugs can vary dramatically,” said Xin Lu of Ludwig Oxford. “While further study is Up close and personal Cancer-fighting superhero needed, these findings may in the longer Sometimes you need to get up close and PTEN is a tumor suppressor gene that term help doctors to identify patients personal to really see something clearly. boosts the body’s cancer-fighting powers. who are more likely to respond well to Geneticists and biologists have long Mutations in the gene can contribute to autophagic inhibition.” envisaged the possibility of analyzing the development of cancer, and PTEN profiles of genes at the single cell level, mutations have been found in as many The researchers identified ASPP2, a but limitations of available technology as 30 percent of . tumor suppressor, as a molecular switch meant they had to satisfy themselves that can dictate the ability of a common with viewing them at a distance. A study published on August 28 cancer gene, the RAS oncogene, to in Proceedings of the National Academy either stop or promote senescence. “Our But now a team of researchers led by of Sciences, coauthored by Ludwig next step will be to identify ways to alter Rickard Sandberg of Ludwig researchers Web Cavenee, Frank Furnari ASPP2 activity at that critical switch has shown that a new genomic sequencing and Paul Mischel and former Ludwig point. This could be an effective way method called Smart-Seq enables researcher Tim Fenton, found that to treat cancers with reduced ASPP2 ‘smarter’ analysis of individual cells. modification of PTEN affects sensitivity expression and mutated RAS, such as to a potential treatment. breast and colon cancers,” said Yihua Their findings are published in theJuly Wang of Ludwig Oxford. 22 issue of Nature Biotechnology. continued on next page

4 Resetting the clock With a single drug treatment, researchers led by Don Cleveland at Ludwig San Diego can silence the mutated gene responsible for Huntington’s disease, slowing and partially reversing progression of the fatal neurodegenerative disorder in animal models. The findings were published in the June 21 issue of Neuron.

Huntington’s has one known cause and no cure. It’s a disorder passed down through families in which nerve cells in certain parts of the brain degenerate. The disease is caused by the mutation of a single gene, which results in the production Don Cleveland, San Diego Branch and accumulation of toxic proteins in the brain. It affects roughly reverse the progression of the fatal Click here to see Don’s interview on 30,000 Americans, and those neuro-degenerative disorder. A NBC News. diagnosed develop uncontrolled single dose silenced the damaged movements frequently accompanied gene for months and led to partial The treatment is so promising by psychiatric problems. reversal of disease symptoms. The that the US Food and Drug benefit persisted at least nine months Administration gave it a fast-track A one-time injection of a new after the dosage. designation, which is often earned by DNA-based drug treatment agents that show promise in treating known as ASO (short for antisense “These findings open up the serious, life-threatening medical oligonucleotide) blocked the activity possibility that a very short-term conditions for which no other drug of the gene whose mutation causes treatment can lead to a long-term either exists or works as well. The Huntington’s disease. As a result, the benefit, including partial reversal of first trials in human patients could researchers could slow and partially the disease course,” Don said. start in 18 months.

EGFR, is altered in at least 50 percent of disable the suppressor function of the patients with glioblastoma. Yet patients gene, scientists may be able to target with glioblastoma either have upfront different molecules that can intervene to resistance or quickly develop resistance to stop resistance. inhibitors aimed at stopping the protein’s function, suggesting that there is another “The more we understand, the better signaling pathway involved. we can conceive of ways to restore Cavenee Furnari Mischel PTEN function in tumor cells and Previous research indicates that PTEN stop resistance to EGFR inhibitors in may be turned off in some cancer patients with glioblastoma,” said lead Despite years of research, glioblastoma, patients, disabling its function and author Tim Fenton, who conducted this the most common and deadly brain potentially causing the resistance to research while at Ludwig San Diego cancer in adults, continues to outsmart EGFR inhibitors. and is currently at the UCL Cancer treatments targeted to inhibit tumor Institute. growth. The Ludwig team identified two types of enzymes responsible for turning Biologists and oncologists have long off the brakes of PTEN, the fibroblast understood that a protein called the growth receptor and SRC family kinases. epidermal growth factor receptor, or By understanding how these enzymes

5 COMPANY NEWS REQUIRED READING

Brussels Proceedings of the National Academy of Cancer Research 2012 August 15 Sciences USA 2012 August 28. Neogenesis of lymphoid structures and Resistance to EGF receptor inhibitors in antibody responses occur in human melanoma glioblastoma mediated by phosphorylation metastases of the PTEN tumor suppressor at tyrosine Cipponi A, Mercier M, Seremet T, 240 Starting a business is no joke Baurain JF, Théate I, van den Oord J, Fenton TR, Nathanson D, Stas M, Boon T, Coulie PG, Ponte de Albuquerque C, Kuga D, “Jump off a cliff and assemble an airplane van Baren N. Iwanami A, Dang J, Yang H, on the way down.” Tanaka K, Oba-Shinjo SM, —Reid Hoffman, Stockholm Uno M, Del Mar Inda M, Wykosky J, LinkedIn co-founder Nature Biotechnology 2012 July 22 (Epub Bachoo RM, James CD, Depinho RA, ahead of print) Vandenberg SR, Zhou H, Marie SK, That’s what four enterprising Ludwig Full-length mRNA-Seq from single-cell levels Mischel PS, Cavenee WK, scientists have done in creating TCMetrix, a of RNA and individual circulating tumor Furnari FB. start-up company that evolved from a former cells tetramer facility in Lausanne, Switzerland, Ramsköld D, Luo S, Wang YC, Li R, Melbourne-Austin that serviced Ludwig’s global cancer vaccine Deng Q, Faridani OR, Daniels GA, Cancer Immunology Immunotherapy 2012 programs. A competitive advantage of Khrebtukova I, Loring JF, August 26 (Epub ahead of print). the company is its close ties to the Cancer Laurent LC, Schroth GP, Sandberg R. Inhibitor of apoptosis protein (IAP) Vaccine Collaborative, a joint program of antagonists demonstrate divergent Ludwig and the Cancer Research Institute, Oxford immunomodulatory properties which has conducted more than 40 cancer Proceedings of the National Academy of in human immune subsets with implications vaccine and immunotherapy clinical trials Sciences USA 2012 August 14. for combination therapy over the last decade involving over 1,000 Autophagic activity dictates the cellular Knights AJ, Fucikova J, Pasam A, patients. For many years the TCMetrix team response to oncogenic RAS Koernig S, Cebon J. has reliably supplied these international user Wang Y*, Wang XD*, Lapi E, groups with quality reagents at no charge; Sullivan A, Jia W, He YW, Ratnayaka Stanford the team hopes to continue to serve them as I, Zhong S, Goldin RD, Goemans CG, Science Translational Medicine 2012 future customers. Tolkovsky AM, Lu X. August 29. Clonal evolution of pre-leukemic The company will begin to commercialize San Diego hematopoietic stem cells precedes human acute technologies developed by the tetramer Neuron 2012 June 21. myeloid leukemia facility and provide researchers in clinical Sustained therapeutic reversal of Huntington’s Jan M*, Snyder TM*, and basic sciences with innovative, state-of- disease by transient repression of huntingtin Corces-Zimmerman MR*, Vyas P, the-art T-cell monitoring reagents of the synthesis Weissman IL*, Quake SR*, Majeti R. highest quality—think the Swiss watch of the Kordasiewicz HB, Stanek LM, tetramer industry. Wancewicz EV, Mazur C, *These authors contributed equally to this McAlonis MM, Pytel KA, Artates JW, work Right now it’s offering 300 off-the-shelf Weiss A, Cheng SH, Shihabuddin LS, and custom-made reagents. All reagents Hung G, Bennett CF, Cleveland DW. are provided with quality control data and recommended instructions for applications Nature 2012 August 2. and storage. A map of the cis-regulatory sequences in the mouse genome Since becoming operational, TCMetrix Shen Y, Yue F, McCleary DF, Ye Z, has established an international network of Edsall L, Kuan S, Wagner U, Dixon J, academic and biopharma clients. Lee L, Lobanenkov VV, Ren B.

To learn more about this exciting new venture, click here.

©2012, Ludwig Institute for Cancer Research. All rights reserved.