Identifying novel targets for cancer using high throughput deformability screening

University Of California Los Angeles, Los Angeles CA

Investigators

Abstract

ABSTRACT The goal of this research is to discover novel regulators of cellular deformability that block cancer cell spread; to achieve this goal we will use a high throughput cell filtration platform that is unique to the Rowat Laboratory at UCLA. While most treatments for high grade serous ovarian cancer (HGSOC) are initially effective in reducing tumor growth and spread, cancer recurs in over 80% of ovarian cancer patients because cells become resistant to common, platinum-resistant chemotherapy drugs. There is a critical need for new therapeutics to block the spread of chemoresistant tumor cells. While much research focuses on characterizing the genetic and biochemical differences in chemoresistance, our proposed research will establish a new paradigm for screening in drug discovery. Our previous research demonstrates that platinum-resistant ovarian cancer cells are more compliant, or more deformable, than their drug-sensitive counterparts. These drug-resistant cells also showed characteristics of mesenchymal cells; epithelial-to-mesenchymal transition is implicated in disease progression. Using the novel High Throughput Filtration (HTF) screening technology that we recently invented, we can distinguish platinum-resistant and platinum-sensitive cells on the basis of their deformability. In the proposed research, we will use our HTF technology to screen platinum-resistant cell lines against large libraries of small molecules to identify novel compounds and targets that reverse the deformability of platinum-resistant cells to levels of the drug-sensitive controls. We hypothesize that the altered mechanical phenotype (or ‘mechanotype’) of platinum-resistant cancer cells is a hallmark feature that can be used to inform novel therapeutic strategies for ovarian cancer. Specifically, we postulate that we can identify novel molecules and targets that modulate cancer cell mechanotype by conducting a high throughput screen on the basis of cell deformability; the lead candidates that we discover will cause platinum-resistant cancer cells to become stiffer and reduce cell invasion. We will test this hypothesis through the following specific aims: 1) Identify molecules and targets with potential for anti-cancer treatment strategies using deformability screening; we will validate using functional assays as well as patient expression data and tumor microarrays. 2) Discover novel targets for anti-cancer therapeutics in platinum-resistant cancer cells using an unbiased genome-wide CRISPR-Cas9 screen with cellular deformability as a readout. Taken together, our findings could address the lack of treatment options for HGSOC. Ultimately the compounds that we discover could be used in combination with platinum-based therapies to target platinum- resistant cells and thereby prevent disease recurrence and improve patient outcome.