Robert Wechsler-Reya, Ph.D.

Discovering oncogenic drivers and creating models

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Aggressive therapies – including surgery, radiation and high-dose chemotherapy – have improved outcomes for medulloblastoma patients, but many patients still die of their disease, and survivors suffer severe long-term side effects from therapy. To develop safer and more effective treatments, we need to understand the genes and pathways that are important for tumorigenesis. But for many forms of medulloblastoma, the oncogenic drivers are still unknown. A major focus of our research is to identify these drivers and use them to create robust animal models of the disease. Sequencing studies have identified genes that are altered in human medulloblastoma, and we are using functional assays to determine which of these genes can promote tumor growth in vivo. We have also established a large bank of patient-derived xenograft models that we use to perturb candidate genes and test their roles in tumorigenesis. In addition to identifying new drivers of medulloblastoma, these studies generate models that can be used to test novel approaches to therapy. 

Elucidating the molecular mechanisms of metastasis

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Most medulloblastoma research has focused on the primary tumors growing in the cerebellum. However, most medulloblastoma patients do not die from the primary disease, but from leptomeningeal metastasis: the dissemination of tumor cells from the cerebellum into the brain and spinal cord. Metastatic lesions cannot be surgically removed, and there are no effective therapies to eliminate them or stop them from growing. To understand the molecular basis of metastasis, we are using animal models to study the differences between primary and metastatic tumors, and screening for genes that can promote or inhibit metastatic dissemination. We are also integrating our results with molecular data from medulloblastoma patients, to identify genes that are critical for metastasis. Understanding the function of these genes will allow us to design novel strategies for early detection, prevention, and treatment of metastasis in patients with medulloblastoma and other types of brain tumors. 

Identifying new therapeutics and approaches to drug delivery

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Genomic analyses have revealed that medulloblastoma is an extremely heterogeneous disease, with at least 4 distinct subtypes that differ in terms of mutations, gene expression, epigenetic changes, and patient survival. Despite this heterogeneity, most medulloblastoma patients currently receive the same therapy. A major goal of our research is to discover new therapeutic strategies that are tailored to specific medulloblastoma subgroups. To this end, we have assembled a large panel of patient-derived xenografts and are using them for high-throughput drug screening. Working with experts in genomics and computational biology, we are using statistical and mathematical tools to understand the relationship between molecular alterations and drug responses. These studies not only highlight new targeted therapies for medulloblastoma, but also provide insight into drug response biomarkers and help prioritize agents for clinical trials.

In addition to identifying therapeutics, we are also exploring novel approaches to drug delivery. A major obstacle to treating brain tumors is that the majority of small molecule drugs are not able to cross the blood brain barrier, and those that do are often pumped out by multi-drug transporters. To solve this problem, we are collaborating with bioengineers with expertise in nanotechnology. By encapsulating drugs in nanoparticles and delivering them directly to the central nervous system, we hope to increase the concentration of drugs in brain tumors and reduce the concentrations in other tissues, thereby mitigating systemic side effects. We have already identified several drugs that are effective at killing medulloblastoma cells in vitro; if we can develop strategies for effective delivery of these drugs to tumors, we can markedly improve outcomes for medulloblastoma patients.

Harnessing the immune system to target tumors

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Immunotherapy is emerging as a powerful approach to treating cancer. Antagonists of immune checkpoint regulators, T lymphocytes engineered to recognize tumor antigens, and vaccines that amplify tumor-specific lymphocytes are being tested against a variety of human malignancies. Although some remarkable successes have been reported, only a subset of patients respond to these therapies, and the mechanisms that underlie resistance are poorly understood. Pediatric brain tumors, in particular, have not yet benefited from immunological targeting. We are studying the mechanisms brain tumors use to evade the immune system and suppress immune responses, and developing therapeutic strategies to overcome these mechanisms. We are also using genomic and proteomic approaches to identify antigens that might represent novel targets for vaccines, CAR T cells and natural killer cells. Finally, we are “humanizing” our PDX models so we can explore interactions between the immune system and patient-derived tumor cells. By increasing the immunogenicity of tumor cells and enhancing anti-tumor immune responses, we hope to bring the benefits of immunotherapy to medulloblastoma patients.