Robert Wechsler-Reya's Research Focus
The Wechsler-Reya Lab studies the signals that control cell growth and differentiation in the nervous system and how these signals are dysregulated in brain tumors. We focus on medulloblastoma, the most common malignant brain tumor in children, and use models to understand the disease and to develop novel approaches to therapy. Our current areas of interest include:
- Discovering oncogenic drivers and creating new models
- Elucidating the molecular mechanisms of metastasis
- Identifying new therapeutics and approaches to drug delivery
- Harnessing the immune system to target tumors
We also work closely with physicians at Rady Children’s Hospital and elsewhere to translate our findings into trials that can benefit patients. Our goal is to develop safer and more effective therapies for children with brain tumors.
Robert Wechsler-Reya's Research Report
Discovering oncogenic drivers and creating models
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
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
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
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.
Robert Wechsler-Reya's Bio
Dr. Wechsler-Reya's research focuses on the signals that control growth and differentiation in the cerebellum, and how these signals are dysregulated in the brain tumor medulloblastoma. As a postdoc, he demonstrated that Sonic hedgehog (Shh) is a critical mitogen for neuronal precursors in the cerebellum, and that mutations in the Shh pathway predispose to medulloblastoma by activating a mitogenic pathway that normally functions only in early development. Now in his own lab, he continues to study the relationship between brain development and brain tumor formation. His lab’s contributions include identifying N-myc as a key target of the Shh pathway in neuronal precursors and in tumor cells; discovering a novel population of neural stem cells in the neonatal cerebellum; demonstrating that both neuronal precursors and stem cells can serve as cells of origin for MB; and identifying a population of cancer stem cells that is critical for propagation of Shh-associated tumors. More recently, Dr. Wechsler-Reya and his group have begun developing new models of medulloblastoma and are using them to test novel therapeutic approaches. His work has garnered several awards, including a Kimmel Scholar Award, an Award for Excellence in Pediatrics Research from the Society for Neuro-Oncology and a Leadership Award from the California Institute for Regenerative Medicine (CIRM).
2001-2010: Associate Professor of Pharmacology and Cancer Biology, Duke University Medical Center
1997-2001: Postdoctoral Fellow, Stanford University, Neural Development
1995-1996: Postdoctoral Fellow, Wistar Institute, Molecular Oncology
1995: Ph.D., University of Pennsylvania, Immunology
1986: B.A., Harvard College, Psychology & Biology
Funding Awards and Collaborative Grants
Leadership Award from the California Institute for Regenerative Medicine (CIRM)
19th International Brain Tumor Research and Therapy Conference
A University of Toronto Hosted Conference
Niagara Falls, ON
June 21–24, 2012
"Developmental tumors of the nervous system," held in Barcelona on July 2012, as part of the 8th Forum of European Neuroscience Societies.
Honors and Recognition
2007: W.K. Joklik Award for Excellence in Basic Cancer Research
2007: DukeMed Scholar
2006: Award for Excellence in Pediatrics Research, Society for Neuro-Oncology
2003: Kimmel Scholar Award, Sidney Kimmel Foundation for Cancer Research
2003: Brain Tumor Society Research Award
2002: Children’s Brain Tumor Foundation Research Award
2000-2001: Postdoctoral Fellowship, American Cancer Society (California)
1995-1997: Postdoctoral Fellowship, Medical Research Council of Canada
1988: Award for Excellence in Scientific Writing, American Diabetes Association
1984-1985: John Harvard Scholarship for Academic Achievement of Highest Distinction
Lee C, Rudneva VA, Erkek S, Zapatka M, Chau LQ, Tacheva-Grigorova SK, Garancher A, Rusert JM, Aksoy O, Lea R, Mohammad HP, Wang J, Weiss WA, Grimes HL, Pfister SM, Northcott PA, Wechsler-Reya RJ
Nat Commun 2019 Jan 18 ;10(1):332
Wang J, Merino DM, Light N, Murphy BL, Wang YD, Guo X, Hodges AP, Chau LQ, Liu KW, Dhall G, Asgharzadeh S, Kiehna EN, Shirey RJ, Janda KD, Taylor MD, Malkin D, Ellison DW, VandenBerg SR, Eberhart CG, Sears RC, Roussel MF, Gilbertson RJ, Wechsler-Reya RJ
Cancer Res 2019 May 1 ;79(9):2208-2219
Rusert JM, Juarez EF, Brabetz S, Jensen J, Garancher A, Chau LQ, Tacheva-Grigorova SK, Wahab S, Udaka YT, Finlay D, Seker-Cin H, Reardon B, Gröbner S, Serrano J, Ecker J, Qi L, Kogiso M, Du Y, Baxter PA, Henderson JJ, Berens ME, Vuori K, Milde T, Cho YJ, Li XN, Olson JM, Reyes I, Snuderl M, Wong TC, Dimmock DP, Nahas SA, Malicki D, Crawford JR, Levy ML, Van Allen EM, Pfister SM, Tamayo P, Kool M, Mesirov JP, Wechsler-Reya RJ
Cancer Res 2020 Dec 1 ;80(23):5393-5407
Leskoske KL, Garcia-Mansfield K, Sharma R, Krishnan A, Rusert JM, Mesirov JP, Wechsler-Reya RJ, Pirrotte P
J Proteome Res 2022 Aug 17 ;
Combined MEK and JAK/STAT3 pathway inhibition effectively decreases SHH medulloblastoma tumor progression.
Zagozewski J, Borlase S, Guppy BJ, Coudière-Morrison L, Shahriary GM, Gordon V, Liang L, Cheng S, Porter CJ, Kelley R, Hawkins C, Chan JA, Liang Y, Gong J, Nör C, Saulnier O, Wechsler-Reya RJ, Ramaswamy V, Werbowetski-Ogilvie TE
Commun Biol 2022 Jul 14 ;5(1):697
Eisemann T, Wechsler-Reya RJ
Genes Dev 2022 May 1 ;36(9-10):514-532
Disruption of GMNC-MCIDAS multiciliogenesis program is critical in choroid plexus carcinoma development.
Li Q, Han Z, Singh N, Terré B, Fame RM, Arif U, Page TD, Zahran T, Abdeltawab A, Huang Y, Cao P, Wang J, Lu H, Lidov HGW, Surendran K, Wu L, Virga JQ, Zhao YT, Schüller U, Wechsler-Reya RJ, Lehtinen MK, Roy S, Liu Z, Stracker TH, Zhao H
Cell Death Differ 2022 Aug ;29(8):1596-1610
Conventional Therapies Deplete Brain-Infiltrating Adaptive Immune Cells in a Mouse Model of Group 3 Medulloblastoma Implicating Myeloid Cells as Favorable Immunotherapy Targets.
Abbas Z, George C, Ancliffe M, Howlett M, Jones AC, Kuchibhotla M, Wechsler-Reya RJ, Gottardo NG, Endersby R
Front Immunol 2022 ;13:837013
Hwang EI, Sayour EJ, Flores CT, Grant G, Wechsler-Reya R, Hoang-Minh LB, Kieran MW, Salcido J, Prins RM, Figg JW, Platten M, Candelario KM, Hale PG, Blatt JE, Governale LS, Okada H, Mitchell DA, Pollack IF
Nat Cancer 2022 Jan ;3(1):11-24