Targeting Oncoprotein-Adapted Amino Acid Metabolism in Atypical Teratoid Rhabdoid Tumors
Abstract
Childhood cancer disproportionately affects military personnel and their beneficiaries but is grossly underrepresented in government-supported research. Cancer is now the number one disease killer of this population, and brain tumors are the number one killer of children with cancer. We are in dire need of new treatments that improve survival for children diagnosed with brain tumors. The proposed research focuses on atypical teratoid rhabdoid tumors (AT/RT), which are the most common malignant brain tumors of infancy. Despite aggressive radiation and chemotherapy, median survival remains 6 to 11 months. Few diseases have as high of a mortality rate as AT/RT with so many years of life lost. This proposal aims to develop combination therapies that can rapidly translate into new clinical trials to improve AT/RT survival. We are in the late stages of translating our previous work into a first-in-pediatrics clinical trial treating relapsed pediatric brain tumors. This proposal was designed with the help of my mentoring team made up of world-renowned researchers with extensive experience translating laboratory findings into new treatments. We expect the completion of this proposal will lead directly to three new clinical trials and could support the rationale for further trials in the future. This research will also add to our understanding of AT/RT tumor biology. As high-throughput genetic and epigenetic studies have become more sophisticated, we are learning that there is considerable inter-tumor molecular heterogeneity leading to distinct tumor subgroups. Many of these subgroups are defined by the oncoproteins driving their transformation and growth. We study the impact of oncoproteins on cancer cell metabolism to identify differences between tumor cells and normal human cells that can be precisely targeted to improve survival with minimal side effects. Preliminary survivorship data suggest MYC driven AT/RT is especially aggressive. MYC leads to a dependence on glutamine for the metabolic needs of these rapidly dividing cancer cells. We find that the glutamine metabolic inhibitor, DON targets MYC driven AT/RT while other subgroups are relatively resistant. We explore specific MYC-driven metabolic changes in AT/RT that make cells susceptible to DON therapy as we design rational combination therapies that will further improve its efficacy. While adult cancers are driven by the multitude of genetic mutations acquired over a lifetime, pediatric tumors are driven by epigenetic abnormalities that dysregulate key oncogenic pathways that drive tumor growth. AT/RT has a single recurring genetic mutation that alters its epigenetic landscape leading to the translation of oncoprotein drivers of tumor growth. We further explore how metabolic inhibitors can alter the regulatory control of cancer epigenetics. This work will improve our understanding of the cross-talk between oncoproteins, cancer cell metabolism, and epigenetics. The biology that we learn from these studies can help identify vulnerabilities in this regulatory network. These studies will have important implications not just for AT/RT but also for other MYC-driven tumors like neuroblastoma and medulloblastoma. I am pursuing a pediatric neuro-oncology academic career developing new therapies to improve the treatment of childhood brain tumors. My mentoring committee is made up of world-renowned researchers in the fields of cancer metabolism, epigenetics, cell signaling pathways, and drug development. These mentors are extraordinarily brilliant and successful scientists who have mentored countless researchers to successful academic careers. This proposed research and my career development plan will help me establish an important niche in pediatric cancer research. I will meet frequently with my mentoring committee to present my work and develop my experimental plans. I will also attend annual metabolomics and epigenetic workshops to further de
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810310
Entities
People
- Jeffrey Rubens
Organizations
- Johns Hopkins University
- United States Army