Research Portfolio

Funding Opportunities

Join our Mailing List
Join our mailing list to be notified of new funding opportunities.

Your Email

To receive information about funding opportunities, events, and program updates.

A Novel Anti-Cancer Therapy: Inhibition of MUS81-EME1

Institution: University of California, Davis
Investigator(s): Sucheta Mukherjee, B.S.
Award Cycle: 2011 (Cycle 20) Grant #: 20DT-0036 Award: $60,000
Subject Area: Cancer
Award Type: Dissertation Awards

Initial Award Abstract
Treatment of cancer is often associated with adverse side affects caused by the anti-cancer therapy. Cancer can arise in cells after a number of mutations have changed the genetic make-up of cancer cells to make them different from normal cells. For example, tobacco smoke contains cancer-causing agents that can produce mutations in genes that are responsible for maintaining the integrity of the genome, e.g., tumor suppressor genes. When genome maintenance genes are mutated, this causes genetic instability in the cancer cells. Exploiting the genetic differences between cancer cells and normal cells presents a novel avenue for anti-cancer therapy that will target cancer cells selectively and spare normal cells. Synthetic lethality is a genetic concept based on disrupting two biological pathways leading to cell death; whereas disruption of only one biological pathway has non-lethal effects. For example, genome wide studies have identified many gene pairs that when individually defective cause minimal adverse affects, but the combined defects of both genes can cause cell death. The concept of synthetic lethality is emerging as a potential strategy of cancer treatment because it can take advantage of existing mutations in cancer cells. With an additional inhibition of another biological pathway, cancer cells can be directly targeted by synthetic lethal anti-cancer therapy. For example, mutations in genome maintenance genes can cause genomic instability, which in turn may create a genomic environment where cancer cells are able divide uncontrollably. For this reason, cancer cells experience a higher level of \"replicative stress\", meaning that the misregulated division of the cancer cells causes damage to their DNA that requires repair before the cancer cells can keep dividing. Therefore, cancer cells rely on a process called homologous recombination, a DNA repair process that resolves \"replicative stress\" and allows for successful replication of DNA before the cell can divide. We hypothesize that cancer cells are addicted to homologous recombination because they are in a state of constant \"replicative stress\". The goal of this project is to isolate inhibitors for a key homologous recombination protein that specifically responds to \"replicative stress\". This inhibitor is envisioned to target the highly-replicating cancer cells and spare normal cells from adverse affects. A replication-specific homologous recombination protein, MUS81-EME1, has been identified as a promising target for inhibition and a strategy for a high-throughput inhibitor screen has been developed. This is a novel proposal strategy that will develop inhibitors for replication specific proteins involved in homologous recombination to be used in anti-cancer therapy. This inhibitor holds promise because genes involved in homologous recombination have been reported to be synthetic lethal with other genes that may be mutated in lung cancer. In the least, these inhibitors can potentiate the effects of current anti-cancer therapies to specifically sensitize cancer cells to the treatment because they are highly replicating and rely on homologous recombination for repair. This proposal represents a study towards drug development that may benefit a significant portion of lung cancer patients.