Functional Role of Epigenetic Regulation in Melanoma Brain Metastasis
Abstract
Scientific Objective and Rationale for the Proposed Project: Melanoma is one of the deadliest skin cancers due to the high propensity of malignant cells to disseminate to vital organs. One of the most devastating complications of melanoma is its spread or metastasis to the brain, after which most patients survive less than 6 months. Since the prognosis is so poor, patients with melanoma brain metastasis have been excluded from clinical trials of new drugs because their inclusion might make the drug appear less effective. Autopsies have shown that 75% of patients that succumb to metastatic melanoma harbor melanoma cells that has spread to the brain. With no current treatment to offer, it is of utmost importance to decipher the biological mechanisms leading to melanoma dissemination to the brain. The Cancer Genome Atlas (TCGA), a project funded by the US government for the last decade, unifies the efforts of several national research centers in order to catalogue genetic mutations leading to aberrant gene expression and responsible for cancer, using high-throughput sequencing techniques. Analysis of TCGA data obtained from melanoma patients shows the overexpression of two genes, PHF8 and CHD7, in metastatic tissues. High expression of these genes is significantly correlated with bad prognosis and mortality. Moreover, our preliminary results suggest that PHF8 and CHD7 are necessary for melanoma metastasis. Therefore, the causality between this aberrant gene expression and melanoma metastasis to the brain and ultimate morbidity should be explored. Hypothesis: It is our hypothesis that altered regulation of the genes PHF8 and CHD7 plays an important role in facilitating the escape of melanoma cells from the early-stage tumor in the skin to the blood stream, through the circulation, and into the brain. We also postulate that PHF8 and CHD7 regulation is altered before the tumor spreads from the skin to other organs. Thus, these genes could serve as markers that may help predict, at the time of diagnosis, which patients are at risk of suffering from melanoma spread to the brain. Specific Aims: (1) Determine the role of PHF8 and CHD7 in melanoma spread to the brain. (2) Identify the genes and processes controlled by PHF8 and CHD7 that modulate melanoma brain metastasis. (3) Identify the genes that in turn control PHF8 and CHD7, leading to their high expression in melanoma cells that spread to the brain. (4) Evaluate the ability of PHF8 and CHD7 to predict melanoma brain metastasis at the time of diagnosis. Principal Investigator (PI) Career Goals in Cancer Research: The PI has received the required training in molecular and cellular biology in general and cancer research in particular. She obtained compelling evidence for the role of two genes that have never been studied so far in melanoma general metastasis and probably in brain metastasis. The present Career Development Award will allow her to pursue her project and gain a position of scientific maturity and independence. Ultimately, the proposed study should lead to scientific publications that will put the PI at the forefront of cancer research and increment her chances to pursue a successful academic career. Ultimate Applicability of the Research: This research will ultimately affect positively many patients. If our efforts to discover novel markers of melanoma metastasis succeed, they will help determine whether a patient is at high risk for spread of their melanoma to the brain. Also, our studies might provide proof-of-principle for PHF8 and CHD7, or their respective regulated genes, as plausible targets for the development of novel therapeutic agents against melanoma metastasis and brain metastasis in particular. Military Benefits: Sun and ultraviolet ray exposure is a major risk factor for melanoma. In the past years, a huge effort has been devoted to raise awareness against prolonged sun exposure and in favor of using blocking agent
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610437
Entities
People
- Rana Moubarak
Organizations
- Grossman School of Medicine
- United States Army