The MRC has the structure of a collaborative research center, and, as such, it does not have a fixed membership but rather is an open venue for researchers who are interested in the problem of metastasis. The MRC's leadership group promotes scientific exchange and collaborations and coordinates access to resources.
Executive Committee
- Joan Massagué, PhD (Director)
- Robert Benezra, PhD
- Alan Hall, PhD
- Thomas Kelly, MD, PhD
- Charles Sawyers, MD
- David Spriggs, MD
Faculty
Robert Benezra, PhD
Metastasis of tumor cells to distant organs requires that specific properties be acquired by the tumor cell as well as the cells that support its growth, such as blood-vessel-forming cells and white blood cells. Dr. Benezra's laboratory focuses on a set of proteins called Id proteins, which are important in both processes. Members have shown that Id proteins present within breast cancer cells are essential for the growth of these cells at the lung metastatic site. In addition, expression within blood-vessel-forming cells is required to create a blood vessel network essential for metastatic cell growth. Recently, the team successfully targeted the Id proteins in the tumors of adult mice, which showed strong antimetastasis activity.
Cameron Brennan, MD
Approximately a third of brain tumor surgeries at Memorial Sloan-Kettering are for brain metastasis and many more cases of brain metastasis are treated by radiosurgery or fractionated radiation. Researchers have developed infrastructure for image-guided biopsy and banking of frozen biopsy tissue, derivation of short-term cell cultures, and detailed molecular characterization of tumors including brain metastases. Dr. Brennan has active collaborations with investigators in lung and colon cancer oncogenomics projects.
Ronald Blasberg, MD
The skeleton is a preferred site for the metastasis of several major cancers, including breast and prostate, particularly during the late stages of the disease. Dr. Blasberg's laboratory has shown the feasibility and advantages of multimodality imaging to monitor metastases and to image the activity of specific cell signaling pathways that are involved in bone metastases, such as TGF1/Smad signaling. Researchers have used and combined high-resolution micro-CT and MRI, as well as micro-PET and micro-SPECT and bioluminescence and fluorescence optical imaging techniques. These studies provide the opportunity for real-time noninvasive imaging assessments of the metastatic process and for the assessment of novel treatments that target specific cell-signaling pathways.
Lisa DeAngelis, MD
Dr. DeAngelis, Chair of Memorial Sloan-Kettering's Department of Neurology, is interested in those processes that lead to metastases in the nervous system, as well as developing appropriate therapies and minimizing the toxicities of those treatments on the nervous system.
Robert Downey, MD
Dr. Downey's work focuses on demonstrating how the hypothesis that cancers arise from disordered development of stem cells illuminates clinical observations. For example, the metabolic activity of cancers reflects the metabolic activity of stem cells, and this is the basis for FDG-PET imaging. It also suggests possible new therapies. For example, understanding the processes governing cancer metastases as a recapitulation of the processes governing stem cell trafficking may suggest novel targets for interrupting the metastatic process.
James Fagin, MD
The primary focus of Dr. Fagin's research is to explore the role of oncoproteins that signal along the MAP kinase pathway both in the biology of thyroid cancer and as therapeutic targets for this disease. Among these oncogenes, BRAF confers thyroid cancers with more aggressive properties, including the ability to metastasize to regional lymph nodes and to lung and bone. His team has developed mouse models that recreate the human disease faithfully and is interested in determining the molecular requirements for development of metastases in mouse thyroid cancers with BRAF mutations and in human thyroid cancer cell lines.
Filippo Giancotti, MD, PhD
Dr. Giancotti's laboratory studies a class of molecules called adhesion receptors, which allow cells to recognize other cells as well as to move along extracellular tracks. Members of his laboratory have shown that some of these receptors, the integrins, enable cancer cells to disrupt their attachment to neighboring cells and to migrate — through various tissue barriers — to a metastatic site. Furthermore, they have identified the chemical signals that these receptors use to mold cancer cells into their pliable servants. One of the identified genes directs cells to make a secreted protein called Coco, which blocks a signaling receptor called BMP-receptor. In the near future, the researchers hope to be able to isolate new metastasis genes and to study their mechanism of action.
Philip Gutin, MD
Dr. Gutin's research on metastatic brain tumors has been clinical, evaluating focal radiation techniques such as stereotactic radiosurgery for their ability to control cancer. His department also provides metastatic tumor tissue from the neurosurgical operating room to various laboratories for collaborative research projects.
Alan Hall, MD, PhD
During embryonic development, cells migrate to appropriate locations, adopt specialized shapes, and organize themselves into tissues and organs. In adults, defects in the integrity of tissues coupled with inappropriate cell migration are the defining characteristics of metastatic cancers. Dr. Hall's laboratory studies Rho GTPases, a family of proteins that regulate cell migration and tissue organization during normal development. Researchers use cell culture assays to determine the biochemical pathways through which they act and their contribution to the behavior of metastatic cancer cells.
Eric Holland, MD, PhD
Dr. Holland's laboratory focuses on developing mouse models of brain tumors. In this effort, the lab has developed several bioluminescence imaging reporter mice to visualize signaling activity in tumor cells as they interact with the surrounding brain. Further, the lab is investigating the biology of the blood-brain barrier and is screening for drugs that pass through this barrier into the brain. Finally, the mouse models are being used in preclinical trials to understand the biology of therapeutic response and to identify drug combinations that will be more effective than the ones available currently.
Clifford Hudis, MD
Dr. Hudis studies test drugs and regimens designed to prevent the development of first metastases in patients treated for early-stage breast cancer and others test drugs and strategies meant to slow or prevent the development of additional metastases in patients with cancer that has already spread. These studies are all designed to exploit the growing knowledge of the inner workings of breast cancer cells so that the treatments can be simultaneously more effective and less toxic. The team's most recent clinical research has demonstrated that, as predicted by laboratory experiments at Memorial Sloan-Kettering, a new class of drugs called HSP90 inhibitors is particularly effective in treating metastases from HER2-positive breast cancer.
Johanna Joyce, PhD
Cancer cells recruit and exploit stromal cells in their surrounding environment, not only to enhance their growth in the primary tumor site but also to facilitate their metastatic dissemination to distant organs. Dr. Joyce's laboratory is defining the mechanisms by which stromal cells, and in particular tumor-associated macrophages, promote cancer cell invasion, migration, and metastasis from primary breast cancers to the lung, brain, and other organs. The lab is also interested in understanding how metastatic cancer cells overcome the frequently hostile surroundings of a new metastatic site, to ultimately thrive in a foreign environment.
Jason Koutcher, MD, PhD
The In Vivo NMR Laboratory has equipment available to image experimental animals such as mice and rats to detect metastatic disease. These studies may focus on individual organs or, as most studies involving metastatic disease, on the mouse as a whole. The latter frequently involves imaging the whole mouse to define the metastatic potential of the tumor or genetic defect, both in terms of tumor burden and location. An interest of Dr. Koutcher's laboratory is determining how metastatic and primary tumors differ with regard to metabolism and physiologic properties, since these factors may affect growth and response to therapy.
Marc Kris, MD
The group Dr. Kris leads serves as the interface between laboratories and patients, testing new agents in patients with metastatic lung adenocarcinoma. The team provides clinical direction and annotated biospecimens to the research labs studying metastases, through the P01 grant (New Targets for the Treatment of Lung Adenocarcinoma), which Dr. Kris leads. Researchers have put in place a mechanism to collect and routinely genotype all tissue specimens available from people with lung adenocarcinoma. This information is used to select available therapies for individual patients (drugs like the EGFR tyrosine kinase inhibitor erlotinib) and to direct patients to clinical trials of agents that target the molecular lesions detected in their particular tumor specimen (such as mutations in PI3K or BRAF).
Steven Larson,MD
Dr. Larson's interest is in molecular imaging and targeted radiotherapy in oncology. At present, members of his laboratory are studying the biologic characteristics of endocrine response neoplasms — thyroid, prostate, and breast — using molecular imaging.
Neil Lipman, VMD
Dr. Lipman's interests relate to the use and development of in vivo (animal) and in vitro models to further understand the development, progression, and treatment of cancer. The Research Animal Resource Center, which Dr. Lipman heads, in concert with its Laboratory of Comparative Pathology, provide a host of resources to develop and utilize animal models of cancer and metastatic disease. Both non-rodent and rodent models are supported and employed. Syngeneic transplantable rodent tumors and human xenografts are used in both heterotopic and orthotopic model systems. Genetically engineered mouse lines are constructed and maintained to recapitulate various aspects of cancer and serve, along with other models, as tools to evaluate treatment strategies. A compliment of isotopic and non-isotopic imaging modalities, dedicated to animal imaging, are available to non-invasively study the temporal development and progression of cancer in these models. A team of veterinary and paraprofessional veterinary technical staff provide the expertise to support the enterprise. This staff is supported by comparative pathologists, medical technologists, and histotechnicians who provide clinical and anatomic pathologic services tailored to fully explore disease progression in the models employed.
Joan Massagué, PhD (Director)
Dr. Massagué's team is identifying genes and functions that enable tumor cells to invade and colonize vital organs. Different tumors have different patterns of spread to the bones, lungs, brain, and liver. By exploiting these differences, his group is defining genes whose altered activity allows breast cancer, lung cancer, and other cancers to overtake these various organs. The identification of the relevant genes is helping researchers to understand their functions in cancer and to develop new ideas for therapies that would specifically target metastasis.
Larry Norton, MD
Among the many aspects of the biology of metastases that attract Dr. Norton's interest, he is drawn to the possibilities of therapeutically targeting molecules involved in metastases. Based on the self-seeding model of cancer such treatments could not only address distant metastases (the major problem in clinical cancer) but primary tumor growth as well. The optimal use of novel agents in this regard will require mathematical modeling approaches that utilize our knowledge of the biomathematics of self-seeded tumor growth as well as pharmacokinetic dynamics.
Neal Rosen, MD, PhD
The work of Dr. Rosen's laboratory is focused on understanding the processes responsible for maintaining the growth and survival of metastatic carcinomas and on using this information to develop significant improvements in therapy. Recent work has revealed the mechanism of interaction of two of the major oncogene-activated pathways that drive the growth of a majority of advanced metastatic cancers and has led to the development of drugs that work together to inhibit their growth. Clinical studies of therapies based on these discoveries are in progress and have already shown promise in the treatment of metastatic breast and lung cancer and melanoma.
Valerie Rusch, MD
Dr. Rusch is a surgeon who specializes in treating patients with cancers of the lung, esophagus, mediastinum, and chest wall, and those with mesothelioma. Her research efforts focus on the genetics of lung cancer and mesothelioma, in an effort to predict how a patient will respond to a particular treatment, and on the development of methods to detect thoracic cancers at an early stage. She is participating in projects to define the molecular mechanisms of lung cancer metastasis.
Chris Sander, PhD
To discover prognostic biomarkers and drug targets, the group analyzes complex molecular and genetic profiles in different tumor types, including prostate, lung, brain, and ovarian cancers, as well as sarcomas. In collaboration with clinical researchers, Dr. Sander's laboratory applies computer algorithms to determine the effect of changes in genes on their function, and discover characteristic pathways and processes activated in primary and metastatic cancer subtypes. A novel experimental-computational method, Combinatorial Perturbation Analysis (CoPIA), is under development for the design of patient-specific therapies.
Charles Sawyers, MD
Dr. Sawyers' laboratory has elucidated mechanisms of resistance to targeted therapies with the current focus on metastatic prostate cancer. Through studies in mouse models and patient samples, his team's work has converged on dysregulation of the androgen receptor as a primary driver of disease progression. This insight, in collaboration with clinical research groups led by Howard Scher of the Genitourinary Oncology Service and Steve Larson of the Nuclear Medicine Service, has resulted in new molecular tools to track disease in men with metastatic prostate cancer using blood-based assays and PET-imaging probes and in the development of new drugs showing clinical benefit in men with late-stage disease.
Howard Scher, MD
Dr. Scher studies prostate cancer targeted therapies directed to the androgen-receptor signaling. His research presents an integrated preclinical and clinical drug development program directed at AR and PI3K/AKT signaling, key pathways in the progression of CRPC. Two AR-directed agents have recently demonstrated clinical activity: MDV3100, an anti-androgen selected for activity against tumors that overexpress AR, and abiraterone, an inhibitor of androgen synthesis. The overall goals are to determine combinations of targeted agents likely to have potent anticancer effects, and to establish models in which the biologic consequences of the agents can be studied. Separately, he is exploring methods to molecularly profile circulating tumor cells isolated from blood to understand the tumor progression and guide treatment selection.
David Solit, MD
The focus of Dr. Solit's laboratory effort is to identify genetic and epigenetic alterations that condition RAS/RAF/MEK-dependence in tumors with activating RAS and BRAF mutations. Because mutations in the RAS pathway have been shown to contribute to the metastatic phenotype, these studies may uncover gain-of-function alterations that cooperate with RAS activation to promote tumor progression and metastasis. The team's focus is to characterize the biology of these alterations and identify targeted treatment strategies, which will then be translated into human clinical trials.
David Spriggs, MD
Dr. Spriggs' laboratory has focused its research in the area of ovarian cancer and drug resistance. Ovarian cancer is unique in that newly diagnosed disease is almost uniformly sensitive to chemotherapy, yet nearly all patients will eventually develop resistant metastatic disease. His focus has been directed at transcriptional and post transcriptional regulation of ovarian cancer cells and their metastatic derivatives.
Pat Zanzonico, PhD
Dr. Zanzonico's research focuses on the application of unique, state-of-the-art techniques applied to small-animal (rodent) models for noninvasively detecting, localizing, and biologically characterizing primary and metastatic cancer cells in vivo and for characterizing the tumor microenvironment. This is primarily accomplished by ultra-high-resolution, quantitative imaging modalities such as SPECT/PET of radiolabeled tracers (molecular imaging), CT, optical imaging of luminescent and fluorescent probes, and structural and functional ultrasound scanning. Memorial Sloan-Kettering's world-class small-animal imaging resources thus provide unique capabilities for serial whole-body assay of metastases and various factors that promote metastasis.
