Genes Identified that Enhance Tumor Cell Sensitivity to CTI's Cancer Drug Brostallicin
News Apr 22, 2009
Systems Medicine, LLC (SM), a wholly-owned subsidiary of Cell Therapeutics, Inc. (CTI), has presented data from a preclinical study, which utilized RNA interference (RNAi) and bioinformatics to identify genetic markers - "contexts of vulnerability" - that enhance the anti-tumor response to the experimental drug candidate brostallicin, at the 2009 American Association for Cancer Research (AACR) annual meeting in Denver, Colorado.
"Contexts of vulnerability" refers to the genetic configuration in a patient's tumor that makes it susceptible to a specific drug thus providing the genetic rationale for targeted therapy.
The study's objective was to identify molecular determinants of brostallicin's anti-tumor response that could guide clinical development and drug combination studies by incorporating an integrated pharmacogenomics approach. The study was conducted by SM in collaboration with the Translational Genomics Research Institute's Pharmaceutical Genomics Division in Scottsdale, Arizona.
"This study has identified certain patient groups which might be more likely to benefit from therapy with brostallicin and have been invaluable in assisting us in identifying promising clinical development strategies for future development of this novel drug candidate," said Jack Singer, M.D., Chief Medical Officer of CTI. "Ultimately, we believe this approach should shorten the clinical development time and increase the success rate by bringing us closer to being able to offer the right drug to the appropriate patient."
Brostallicin is a small-molecule chemotherapeutic agent with a unique mechanism of action - it binds to the minor grooves located in the DNA double helix. To identify genes associated with cellular response to brostallicin, a high-throughput RNA interference screen was performed in selected ovarian cancer cell lines. RNA interference is a cellular process that results in the targeted knockdown of specific genes. The current screen assayed the effect of over 7,000 individual gene knockdowns, representing the "druggable" genome, on brostallicin response.
The identified genes, representing unique contexts of vulnerability to brostallicin, converged on cellular concepts relating to DNA repair and chromosome modification. These findings were further extended and confirmed in breast cancer cell lines, wherein the knockdown of specific genes involved in these concepts, mentioned above, resulted in an increased response to brostallicin.
To substantiate the brostallicin response observed in the RNAi studies, drugs that target selected genetic targets were tested for synergistic activity in combination with brostallicin. The outcome of this validation work has identified important contexts and rational drug combinations that will be critical for the clinical development of brostallicin.