Journal of Stem Cell Research & Therapy

BRCA2 inhibition enhances cisplatin-mediated alterations in tumor cell proliferation, metabolism, and metastasis

4^th International Conference and Exhibition on Cell & Gene Therapy

August 10-12, 2015 London, UK

James Koropatnick

Keynote: J Stem Cell Res Ther

Abstract:

Tumor cells have unstable genomes relative to non-tumor cells. Decreased DNA integrity resulting from tumor cell
instability is important in generating favorable therapeutic indices. However, intact DNA repair mediates resistance to
therapy. Targeting DNA repair to promote the action of anticancer agents is therefore an attractive therapeutic strategy. BRCA2
is involved in homologous recombination repair. BRCA2 defects increase cancer risk but, paradoxically, cancer patients with
BRCA2 mutations have better survival rates. We queried TCGA data and found that BRCA2 alterations led to increased
survival in patients with ovarian and endometrial cancer. We developed a BRCA2-targeting second-generation antisense
oligonucleotide (ASO), which sensitized human lung, ovarian, and breast cancer cells to cisplatin by as much as 60%. BRCA2
ASO treatment overcame acquired cisplatin resistance in head and neck cancer cells, but induced minimal cisplatin sensitivity
in nontumor cells. BRCA2 ASO plus cisplatin reduced respiration as an early event preceding cell death, concurrent with
increased glucose uptake without a difference in glycolysis. BRCA2 ASO and cisplatin decreased metastatic frequency in
vivo by 77%. These results implicate BRCA2 as a regulator of metastatic frequency and cellular metabolic response following
cisplatin treatment. BRCA2 ASO, in combination with cisplatin, is a potential therapeutic anticancer agent.

Biography :

James Koropatnick is Director of the Cancer Research Laboratory Program of the Lawson Health Research Institute and University of Western Ontario. His research program
is focused on development of novel antisense drugs to enhance effectiveness of anticancer chemotherapy, development of new platinum-based anticancer compounds,
development of novel anticancer compounds based on in silico targeting prediction, and development of novel antibody-drug conjugates for treatment of breast and colorectal
cancer. He is also the Chief Scientific Officer and cofounder (with Dr. Mark Vincent) of Sarissa, Inc. (a biotech discovery company) and sits on the Scientific Advisory Boards
of Critical Outcomes Therapeutics, Inc., AvidBiologics, Inc., ID Laboratories, Inc., and MedVax Pharma, Inc.