Defining and Targeting Novel Epigenetic Vulnerabilities in Heterogeneous Drug-Resistant Melanomas
Abstract
Malignant melanoma originates in melanocytes, the pigment-producing cells located in the bottom layer of the skin s epidermis. It is the deadliest form of skin cancer and characterized by predominant mutations that activate the RAS/RAF/MEK/ERK signaling pathway. Among these mutations, the most frequent are gain-of-function and mutually exclusive mutations in the BRAF and NRAS oncogenes as well as loss of the tumor suppressor gene neurofibromatosis 1 (NF1), a negative regulator of RAS. Therefore, despite genetic heterogeneity, melanomas exhibit significant dependency on ERK signaling. Such dependency has motivated the use of targeted inhibitors of ERK signaling as potential therapies for melanoma patients. Pathway inhibition in melanoma cells, however, results in a mixture of hitherto unpredictable phenotypic outcomes, generating heterogeneous populations of drug-tolerant cells that not only diminish drug efficacy, but also constitute a reservoir from which stably resistant clones are ultimately selected and drive disease progression. This poorly understood phenomenon, referred to as “phenotype switching,” causes fractional response even in genetically homogeneous populations of tumor cells exposed to highly selective drugs. Little is known about how such functionally diverse adaptive phenotypes emerge, but they appear to be regulated by poorly understood, lineage-dependent, epigenetic mechanisms that continuously reprogram the state of vulnerability in melanoma tumor cells. In this project, we seek to utilize a systems biology approach combining innovative experimental and computational techniques to dissect these poorly understood epigenetic states at a single-cell level in genetically diverse (BRAF-mutant, NRAS-mutant, and NF1-deficient) melanomas, identify their key regulators, and predict and test in vivo efficient ways to block the heterogeneous populations of drug-resistant cells and maximize tumor cell killing. The proposed project and the career development plan outlined in this proposal will provide a unique opportunity to expand my knowledge of melanoma biology and will greatly enhance my personal experiences and practical skills that will be essential for launching an independent career at the forefront of cancer research. Furthermore, an important outcome of this research will be the identification and validation of actionable targets to block the heterogeneous populations of drug-resistant cells in genetically diverse melanomas. Overcoming drug resistance and achieving durable responses in patients is currently the major challenge associated with the use of targeted therapies for melanoma. Therefore, promising targets validated in our studies will be examined in preclinical mouse models. Promising results in the preclinical space will urge clinical exploration and drug development if the target(s) are novel. Such insights are of substantial therapeutic interest, given the prevalence of acquired drug resistance to targeted therapies for melanoma. Importantly, melanoma shows a higher incidence rate in active duty military personnel as compared with general population, most likely due to their longer exposure to ultraviolet ionizing radiation in comparison with the average civilian population. Thus, a better understanding of melanoma biology and finding more effective therapies for metastatic melanoma is highly relevant to military personnel, families, and beneficiaries.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810427
Entities
People
- Mohammad Fallahi-Sichani
Organizations
- United States Army
- University of Michigan