Let’s now look for genetic needles in cancer’s haystack. It is not a simple quest. But against the backdrop of an explosion in the discovery of biologically and therapeutically significant aberrations in human tumor genomes, that’s exactly what scientists and clinicians at Memorial Sloan Kettering are doing — with remarkable success.
Until about 1980, most research on cancer therapy was directed at tumor cells that were rapidly dividing, not “targeted” in the sense that the word is used today. The aim was to discover universal cancer drugs that would stop tumor cells from growing in all patients with a certain cancer type.
More recently, scientists have shown that cancers are highly genetically variable. Identification of genetic and molecular targets in individual tumors can be used to help select effective therapies and create new ones. And with the development of newer technologies, identification of these genetic and molecular targets has accelerated exponentially over the past few years. MSK established several new centers in 2013 to allow our researchers to harness a tumor’s genetic information and exploit it to its full clinical potential.
The new Marie-Josée and Henry R. Kravis Center for Molecular Oncology (CMO), made possible by a transformative $100 million gift from the Marie-Josée and Henry R. Kravis Foundation, is undertaking a wide-ranging effort to correlate tumor molecular profiles with clinical outcomes and responses to therapy. CMO investigators will aim to identify the functional significance of genetic alterations in tumors and the opportunities they offer for treating cancer patients in a more individualized manner.“In an era of personalized cancer therapy, the CMO brings together the diverse expertise and advanced technology required to perform molecular profiling of tumors,” says MSK physician-scientist David B. Solit, inaugural Director of the CMO. “This multidisciplinary team includes clinicians, pathologists, cancer biologists, and bioinformaticians. By using next-generation sequencing [one of the methods by which scientists extract genetic information from tumors], we are able to rapidly decode tumor genomes. Our goal is to perform genomic profiling for all patients at Memorial Sloan Kettering. The CMO provides the infrastructure and expertise to accomplish this goal. It also brings physicians together with scientists who are working to discover new molecular changes that promote tumor formation, which may represent new drug targets.”
Over the past decade, MSK has compiled a remarkable record of achievement focused on understanding cancer at its most fundamental levels and using that knowledge to guide treatment decisions. For example, MSK was the first academic center to perform large-scale tumor profiling when Marc Ladanyi, the William J. Ruane Chair in Molecular Oncology and Chief of the Molecular Diagnostics Service, developed methods to genotype lung cancer patients for genetic mutations in their tumors that predict for response to targeted drugs.
Another approach, developed by CMO Associate Director Michael F. Berger — who also holds an appointment in the Department of Pathology — Dr. Ladanyi, and colleagues in the Department of Pathology including Maria Arcila and Donavan Cheng, is a cancer genomic assay called MSK-IMPACT™, which uses next-generation sequencing to capture and analyze 341 select genes.
During this time, Memorial Sloan Kettering researchers drew upon a range of resources. Of special importance to studies of the molecular underpinnings of cancer is the institution’s extensive collection of tumor samples, taken from virtually all patients whose tumors have been removed at Memorial Hospital in the past ten to 15 years. No institution in the world has a comparable resource.
“We have collected tens of thousands of tumors that can be used by MSK scientists to determine the spectrum of molecular changes that underpin the development of specific cancer types,” explains Dr. Solit. “Among many other initiatives, Marie-Josée and Henry Kravis’s gift will allow for a more comprehensive collection of tumor samples and the associated clinical histories of the patients treated by MSK physicians. For example, it will allow for the creation of a comprehensive centralized database linking the tumor archive with the relevant information associated with each sample, including molecular and pathological characterization of the tumor and the clinical course of the disease of the patient from whom the tumor was removed.”
One of the challenges investigators face is making as many of these tissue samples available for DNA sequencing as possible. Dr. Berger will work to accomplish this. “We are optimizing our protocols and computational methods to be able to analyze the vast majority of clinical samples, many of which may contain very small amounts of cancer cells or may have been stored using preservatives that can reduce the quality of the DNA,” he says.
MSK-IMPACT sequences genes that previously have been implicated in the development or behavior of tumors, and many can be targeted with existing drugs or with newer therapies now being tested in clinical trials at MSK.
“Targeted sequencing makes genomic research on needle biopsy samples or low-quality tissue more feasible,” Dr. Berger explains. “And in some cases we have a better chance of making clinically relevant discoveries if we focus on deep sequencing these previously characterized genes in many specimens, rather than broadly analyzing the genome.”
He and his colleagues are also working to develop new assays to detect mutations that the MSK-IMPACT assay may miss.
Another challenge MSK researchers face is the rapid development of new technologies. To help make certain that the institution remains ahead of the curve, Agnès Viale was recruited as Associate Director of the CMO and head of the MSK Integrated Genomics Operation (IGO). Dr. Viale, who created and has directed the MSK Genomics Core Laboratory for the past ten years, says, “My role is to ensure that our investigators have access to the technologies they need to conduct cutting-edge research. Our goals are not just to foster this crucial research but also to enable clinicians to use these genomics technologies as new, precise diagnostic tools that can guide cancer treatment decision-making. We want to develop new tests that will help our patients get the best treatments for their individual cancer.”
“This is a very exciting time,” she continues. “Sequencing is changing the way we study cancer in the laboratory and provide cancer care to patients. During the next ten years, I expect that we will move beyond the classification and treatment of cancers based upon the ‘geographic’ location of the tumor — for example, breast, lung, or brain cancers — but instead will tailor therapy to the genetic landscape of the tumor. That’s where we’re headed: We’re going to sequence each individual’s cancer to identify the therapy mostly likely to beat it.”Researchers at the CMO will also work closely with MSK’s Center for Mechanism-Based Therapies (CMBT) to bring new findings into the clinic. “There are two aspects to what we’re doing,” says Dr. Solit. “First, find the mutations that are important and figure out which ones predict for a response to treatment, treatment resistance, early onset of cancer, or prognosis. Second, after we have identified the relevant mutations, we need to develop therapies that directly target the mutant proteins or the pathways activated as a result. The CMBT will be the ‘effector’ arm of the CMO and will help translate our findings into clinical trials.”
When mutations are discovered that may be targets for drug treatment — whether with currently available targeted drugs or new therapies — novel trials are needed to test these hypotheses. One such trial is called a “basket” study. Traditional clinical trials focus on a particular cancer type. Basket studies, however, are not tumor type specific but gene or mutation specific. “We enroll patients in basket trials based on a specific mutation found in their tumor and not on the basis of where their cancer originated,” explains Dr. Solit. “We have patients in these studies with different cancer types, such as ovarian, colorectal, and lung cancers, all being treated with the same drug because their tumors carry a similar molecular signature. What we’re trying to figure out is whether patients with a specific mutation all respond to a particular targeted drug.”
“We predict that the work performed within the Center for Molecular Oncology will eventually impact the care of all patients at Memorial Sloan Kettering,” he says. “Our vision is nothing less than to revolutionize the treatment of cancer, and I do not believe that there is another institution in the world as well-equipped to perform this work on such a large scale.”
The CMBT, the next chapter in this story, involves the patient as a partner in both research and care. Co-chaired by physician-scientist Neal Rosen and Memorial Hospital Physician-in-Chief and Chief Medical Officer José Baselga, the CMBT’s patient focus represents a paradigm shift in cancer medicine that illuminates, on a molecular level and over time, a tumor’s adaptation to therapy.
It remains an unfortunate fact of treatment that even with the use of the latest targeted drugs, eventually most cancers will develop resistance. Yet the mechanics by which this happens are still largely unexplored. CMBT investigators aim to discover the mechanisms of tumor adaptation and the predominant molecular targets for halting this process.
“Our investigations will lay a foundation for developing new combination therapies that strike a primary tumor target as well as key secondary targets that underlie tumor adaptation,” says Dr. Rosen. “The goal is to eradicate the tumor while preempting its ability to adapt and develop drug resistance.”
Research at the CMBT will begin with targeted therapies involving close collaborations with the CMO and MSK’s Human Oncology and Pathogenesis Program, among other divisions. The genetics-based research of these groups focuses on primary cancer-driving pathways and novel drugs that specifically inhibit them. “The CMBT takes the next step, emphasizing an integrated approach and looking at the physiology of the cell as a unified system,” Dr. Rosen explains. “We’ll study how a drug hits its target, how it shrinks a tumor and causes toxicity as a result of how often it’s given, and how the cell adapts when the drug inhibits a targeted pathway. We’ll then investigate ways to prevent this adaptation.”
Finally, CMBT researchers will translate findings into clinical trials. As part of this work, they will closely monitor patients to determine the molecular course of their disease as well as the most effective mechanism-based therapy and schedule of therapy to increase their chances for a cure. In such studies, they will use many of the novel technologies developed by scientists in the CMO.
As part of a robust new effort to address some of the most “difficult” cancers — those that have proved especially treatment-resistant — MSK has established the David M. Rubenstein Center for Pancreatic Cancer Research (CPCR), directed by surgeon, developmental biologist, and pancreas cancer expert Steven D. Leach. Dr. Leach is a recent recruit from Johns Hopkins, where he was the Paul K. Neumann Professor in Pancreatic Cancer. The CPCR will be co-directed by medical oncologist Eileen M. O’Reilly, surgical oncologist Peter J. Allen, and pathologist Christine Iacobuzio-Donahue.“The resources provided by Mr. Rubenstein [a member of MSK’s Boards of Overseers and Managers] are transformative,” says Dr. Leach. “They allow us to assemble a truly multidisciplinary team of physicians and scientists. There has never been a gift like this, focused completely on pancreatic cancer. This cancer has historically been under- studied and funding is woefully deficient, even as the vast majority of patients still die of their disease. There is an urgent need for much more study and better results, which this gift will accelerate.”
Partnering with MSK clinicians and scientists, researchers at the CPCR will attack pancreatic cancer in a number of ways, including uncovering alterations in the genome responsible for the onset, growth, and spread of the disease. Dr. Iacobuzio- Donahue, another recent recruit from Johns Hopkins, has done seminal work in showing how pancreatic cancer cells with a series of mutations evolve into ever-more-complex lineage trees, and has started to look at the disease from an evolutionary biology perspective.
One of the initiatives she pioneered — which will be deployed by the CPCR — is a rapid medical donation program. In the program, patients with end-stage disease consent to have a rapid autopsy, in which living tumor cells can be taken from both the primary tumor and metastatic disease in other organs. “By engaging these patients, Dr. Iacobuzio-Donahue has been able to understand — in ways that nobody else has before — how different mutations are linked to the spread of the disease and how different subpopulations of cancer cells undergo evolutionary selection and growth,” says Dr. Leach.
Working with biologist Scott W. Lowe, Chair of the Geoffrey Beene Cancer Research Center at MSK, CPCR scientists will also support the distribution of innovative mouse research technologies that Dr. Lowe has created. These methods can rapidly and inexpensively create mice with pancreatic cancers that biologically are very similar to those in their human counterparts. “These mouse models will be made available to the MSK community so that they can be readily used in preclinical studies, allowing us to rapidly screen new therapeutic strategies for pancreatic cancer,” Dr. Leach says.
Beyond mice, Dr. Leach adds that “we will create an infrastructure that fosters increased investigation related to pancreatic cancer throughout MSK. We want to make sure that clinicians and scientists interested in the study of pancreatic cancer tissue have ready access to tumor material, tumor microarrays, and tumor DNA and RNA.”
An expanded program of clinical trials will also be launched under the umbrella of the CPCR. And, says Dr. Leach, “there are aspects of the biology of this cancer that make it an often- fatal disease, even when diagnosed early, so we’ll also be exploring ways for ever-earlier diagnosis.”
“The CPCR’s mission statement is ‘To improve the lives of patients with pancreatic malignancies through bold, innovative, multidisciplinary research,’ and we want to devote all our energies to making this the best center in the world for pancreatic cancer research,” he concludes. “We want to do the highest-impact research and rapidly apply our findings to benefit patients.”