2016 Grantees

Carlos Campos, Ph.D., University of Washington, in the laboratory of Richard Palmiter, Ph.D. Cachexia is a common manifestation of many illnesses, including cancer. The syndrome consists of anorexia, muscle wasting, bodyweight loss, and distress – symptoms that decrease quality of life and increases patient morbidity and mortality. Nonetheless, the mechanisms underlying cachexia are poorly understood and current treatment strategies are disappointing. Our studies will examine the neural mechanisms contributing to cancer cachexia.

We have identified a specific neuronal subset in the brain that mediates many of the debilitating cachexia symptoms caused by cancer and chemotherapy (e.g. anorexia, lethargy, and anxiety). These findings are groundbreaking, not only because they implicate a discrete neuronal population in cancer cachexia, but also because inhibiting these neurons simultaneously alleviates most cachexia symptoms. This is in contrast to the current clinical strategy of treating cachexia symptoms individually with multiple nonspecific medications, which can actually exacerbate certain cachexia symptoms and produce additional negative side effects. The aim of our future studies is to understand how these neurons are activated by cancer and the mechanisms by which this neural circuit mediates cancer-induced symptoms. Moreover, because we can selectively inhibit neurons that cause cancer anorexia, we can study the impact of food intake on weight loss and tumor biology in a controlled experimental setting. Altogether, we expect that our findings will provide a fundamental understanding of mechanisms underlying cancer cachexia, and ultimately guide future development of therapeutic strategies for treating cachexia symptoms.

Dr. Campos received his B.S. in Neuroscience and Biology, B.A. in Psychology and Ph.D. in Neuroscience from Washington State University.

Leanne Li, M.D., Ph.D., Massachusetts Institute of Technology, in the laboratory of Tyler Jacks, Ph.D. Traditionally, cancer is viewed as a disease driven by genetic mutations, which convey growth and survival advantage in developing cancer cells; a form of natural selection leads to outgrowth of the most fitted clone and tumor formation ensues. To inhibit tumor formation, the traditional approach to cancer research and treatment has been to identify drugs that target the effects of those mutations. Therefore, many targeted therapies have been developed, aiming to eliminate cancer by abolishing their growth/survival advantage. Unfortunately, this widely-used approach to develop targeted therapies has yielded survival benefits merely in a minor subset of patients bearing corresponding mutations. Tumors develop resistance to the drugs, leading to relapse, often depressingly soon after treatment. Furthermore, recent research have demonstrated that cancer is not a purely clonal disease, but rather strikingly heterogeneous. Multiple subpopulations carrying different mutations may arise within each tumor. Whether and how these subpopulations may contribute to tumor progression remains largely unexplored. Our current study takes an innovative approach and aims to elucidate the crosstalk between the heterogeneous populations within a tumor using mouse models of small cell lung cancer, a highly aggressive and metastatic cancer. Our data demonstrates that different subpopulations in this cancer type collaborate for growth and the formation of distant metastases, potentially through a novel mechanism in which one subpopulation provides an appropriate niche for the other subpopulation during the metastatic process. We hypothesize that disrupting the cooperation between these different subpopulations in cancer could potentially diminish or even abolish cancer metastasis.

Dr. Li received her Ph.D. from ISREC, Ecole Polytechnique Federale de Lausanne in Switzerland and her M.D. from National Taiwan University.

Leanne Li is the Hope Funds Bernard & Judy Cornwell Fellow

Srivatsan Raghavan, M.D., Ph.D., Dana-Farber Cancer Institute, in the laboratory of William C. Hahn, M.D., Ph.D. is applying therapeutic and functional genomic screening approaches in patient-derived tumor organoid models to identify novel therapeutic targets in pancreatic cancer. We hypothesize that these 3D organoid models better recapitulate in vivo tumor behavior and will facilitate new insights into pancreatic cancer biology. We are employing novel genetic perturbation techniques in these 3D models to define new tumor vulnerabilities. We are also using these models to screen novel compound libraries with the goal of identifying new therapeutic agents. Lastly, we are performing real-time drug response profiling on pancreatic cancer patient samples to guide clinical therapeutic decision-making and clinical trial enrollment, and have begun to identify patterns in organoid response profiles that may help to functionally classify patients toward specific therapies. We anticipate that these studies integrating functional genetic and therapeutic testing in patient-derived organoid models will further our understanding of the mechanisms underlying therapeutic sensitivity and resistance in pancreatic cancer.

Dr. Raghavan received his B.S. and M.S. from the Massachusetts Institute of Technology and his Ph.D. and M.D. from Johns Hopkins University.

Karuna Ganesh, MA, MBBChir, Ph.D., Memorial Sloan Kettering Cancer Center, in the laboratory of Joan Massague, Ph.D. Metastasis is the major cause of cancer death. Once a cancer has spread to organs outside its site of origin, chemotherapy and targeted therapies may induce partial remissions, but are invariably followed by resistance and lethal relapse. The molecular mechanisms underlying the persistence and therapy resistance of tumor-repopulating metastasis stem cells are poorly understood. To directly study metastasis stem cells in patient tumors, we are using a novel cell-surface marker to isolate quiescent, chemoresistant cells from colorectal cancer liver metastases of patients who have been treated with chemotherapy and then undergo liver surgery at Memorial Sloan-Kettering. Using cutting-edge organoid technology, we are growing 3-dimensional cultures from these tumors, enabling, for the first time, direct interrogation of the properties of patient-derived therapy-resistant metastasis stem cells. By profiling the RNA in these cells, we will identify crucial molecular pathways required for the survival and re-emergence of metastatic cancer. Further, we will use patient-derived organoids to screen for selective inhibitors of metastasis stem-cell propagation. This approach will identify novel mechanisms and therapeutic vulnerabilities of metastatic cancer, which will be poised for rapid clinical translation.

Dr. Ganesh received her B.A., M.A., MBBChir and Ph.D. from the University of Cambridge.