Looking for genetic needles in cancer’s haystack 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 will be doing at the new Marie-Josée and Henry R. Kravis Center for Molecular Oncology.
On May 20, Memorial Sloan Kettering announced the establishment of the Marie-Josée and Henry R. Kravis Center for Molecular Oncology (CMO), named in honor of Marie-Josée and Henry R. Kravis and their transformative $100 million gift. This ambitious new initiative will make it possible to realize the promise of precision oncology by speeding the translation of novel molecular discoveries into routine clinical practice and reshaping the design of clinical trials.
In 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.
Marie-Josée and Henry R. Kravis
“Progress in our understanding of the biology of cancer has completely shifted the way we think about and treat it,” says MSK President and CEO Craig B. Thompson. “We’re moving away from the concept of treating cancer as many different types of the same disease and toward treating each person’s cancer as its own unique disease. Now, thanks to the inspiring generosity of the Marie-Josée and Henry R. Kravis Foundation, we will be able to expand and intensify this effort, ushering in what will truly be a new era of precision medicine.”
“Throughout the course of my involvement with Memorial Sloan Kettering, I have been deeply impressed by the dedication, experience, and competence of the physicians and scientists who are working to unravel the complexities of cancer,” says Mrs. Kravis, who has been a member of MSK’s Boards of Overseers and Managers since October 2000 and is Chair of the Sloan Kettering Institute. “Henry and I are delighted to support this exciting new initiative, which offers such hope to people around the world.”
“Memorial Sloan Kettering has already proven itself to be a leader in understanding cancer at the genetic level and in putting that knowledge to work for patients,” adds Mr. Kravis. “The new Center for Molecular Oncology will take these efforts to an entirely new level, and I look forward with great anticipation to the discoveries that lie ahead.”
The Genomic Revolution Sets the Stage
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 goal 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 genetically variable. Furthermore, 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.
“The first application of the genomic revolution of the past decade is now being applied to cancer,” elaborates Memorial Hospital Physician-in-Chief José Baselga. “We have learned that cancer is
actually a disease of the genome, and moving forward, we will need to integrate the vast amounts of molecular discoveries being made with clinical data to develop tumor-specific treatments. The CMO will be the first program in the country to span the full range of activities required to bridge these molecular insights into clinical innovations.”
“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 MSK patients. The CMO provides the infrastructure and skill to accomplish this goal and also brings physicians together with scientists who are working to discover new molecular changes that promote tumor formation, which may represent new drug targets.”
“In terms of structure, the CMO epitomizes the multidisciplinary approach to cancer research, which demands that we fully link programs and departments institution-wide so that we can inform each other’s work with our best and brightest ideas,” says Joan Massagué, Director of the Sloan Kettering Institute.
Advanced Technology, a Record of Achievement
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, led the development of methods to genotype lung cancer patients for genetic mutations in their tumors that predict for response to targeted drugs. The lung cancer program is now adopting a new sequencing test developed at MSK that will analyze tumors for mutations in several hundred cancer-associated genes.
Juan Li, group leader of the Integrated Genomics Operation and the Center for Molecular Oncology, works with a HiSeq Sequencer.
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, the Kravises’ 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 hurdles investigators face is making as many of these tissue samples amenable to DNA sequencing as possible. CMO Associate Director Michael F. Berger, who also holds an appointment in the Department of Pathology, will work to
accomplish this goal. “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 numbers of cancer cells or may have been stored using preservatives that can reduce the quality of the DNA,” he says.
Drs. Berger, Ladanyi, and colleagues in the Department of Pathology, including Maria Arcila and Donavan Cheng, have already developed and implemented a vital cancer genomics approach called MSK-IMPACT™, in which 341 select genes in a tumor are captured and analyzed by next-generation sequencing. The genes are ones 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.
“For some patients, this may be a game changer,” says Dr. Berger. “We can find mutations in their tumor that suggest they are going to respond to a drug that their oncologist never would have thought to try.”
Dr. Berger and his colleagues are also working to develop assays to detect mutations that the MSK-IMPACT™ assay may miss. New assays are also being explored that not only will detect mutations but also will be used to monitor therapy at the molecular level to determine more quickly whether a therapy is working. This work is performed in close collaboration with clinical laboratories and investigators in the Departments of Pathology and Laboratory Medicine to ensure that Memorial Sloan Kettering physicians and patients can benefit from these advances.
Another challenge MSK faces is the rapid development of new technologies. To help make certain that the institution remains ahead of the curve, Agnès Viale was recruited as an Associate Director of the CMO and head of the MSK Integrated Genomics Operation. “My role is to ensure that our investigators have access to the technologies they need to conduct cutting-edge research,” says Dr. Viale, who created and has directed the MSK Genomics Core
Laboratory for the past ten years. “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 that cancer.”
Basket Studies, Exceptional Responders — and a Breakthrough in Treatment
The CMO will also work closely with MSK’s Center for Mechanism-Based Therapies (CMBT) to bring new molecular findings into the clinic. “There are two aspects to what we’re doing,” explains Dr. Solit. “First, we aim to identify the biologically relevant mutations present in each cancer type and determine which ones predict for a response to treatment, treatment resistance, early onset of cancer, or prognosis. Second, once we have identified the relevant mutations, we work with investigators at MSK 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 responsible for translating novel biologic discoveries into clinical trials.”
When mutations are discovered that may be targets for drug treatment — whether with currently available targeted drugs or new therapies — novel clinical trials are needed to test these hypotheses. One such trial is called a basket study, and a major focus of the CMO will be to accelerate enrollment of patients in these trials.
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 tumors 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 independent of the site of origin of their cancer.”
The CMO will also focus on retrospectively analyzing tumors of exceptional responders. An exceptional responder is a patient who has a sustained response to treatment in a clinical trial in which almost all other participants failed to benefit from the study drug. For example, Dr. Solit’s research identified the biologic basis for an exceptional responder to the drug everolimus (Afinitor®), a targeted therapy approved for the treatment of kidney cancer. Among a group of patients with advanced bladder cancer, one patient had a a remarkable response compared to all others, whose conditions typically worsened weeks into treatment.
Normally this type of outcome, in which only one patient responds, would be considered a failure. However, as the exceptional responder had a complete response to everolimus, which has lasted several years and is still ongoing, Dr. Solit’s team sought to define the basis for this exquisite drug sensitivity in hopes that such insight could aid other patients with advanced, treatment-resistant bladder cancer.
MSK became the first academic institution to perform whole-genome sequencing on an exceptional responder. This resulted in the discovery of a mutation in the gene TSC1, known to activate the mTOR pathway, which everolimus targets. Based on this finding, MSK researchers developed a basket study in which the drug will be offered only to patients whose
tumors test positive for TSC1 mutations.
“We predict that the work performed within the CMO will eventually impact the care of all patients at Memorial Sloan Kettering,” Dr. Solit concludes. “Our vision is nothing less than to revolutionize the treatment of cancer. 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 generosity of Marie-Josée and Henry Kravis will allow us to build upon the molecular insights we’ve gleaned over the past decade to accelerate the development of more effective and less toxic cancer therapies.”