Gene expression signature that identifies DNA repair and predicts tumor sensitivity to drugs
Inventors: Andrea Richardson, Nicolai Birkbak, Zoltan Szallasi
Invention Types: Diagnostic/Prognostic, Therapeutics
Research Areas: Oncology/Hematology
Keywords: Drug ScreeningFor More Information Contact: Yen, Alan
Genotoxic chemotherapy, one of the most widely-used cancer treatment strategies, forces cells to undergo apoptosis in response to DNA damage. Genotoxic chemotherapy is traditionally most effective in rapidly dividing cancer cells as they rely on high levels of DNA synthesis. Cancer resistance to genotoxic drugs, whether innate or acquired, is one of the major contributing factors in chemotherapy failure. Given the range of side effects attributed to these therapeutics (hair loss, vomiting, increased risk for heart issues and various cancers), it is essential to optimize treatment regimens to include only agents that are known to be effective in treating individual cancers.
Researchers at Boston Children’s Hospital hypothesized that genotoxic chemotherapy would also be particularly effective in treating cancers with impaired DNA damage repair pathways. Triple negative breast cancers (TNBCs) and BRCA1-associated cancers have abundant genomic aberrations, suggesting a particular susceptibility to DNA damage and potential deficiency in traditional repair pathways.
In research led by Dr. Szallasi, nine genes were identified from a single chromosomal region that was significantly associated with platinum sensitivity from two clinical trials on TNBC and ovarian cancer. Two of these genes, BLM and FANCI, are known to be involved in DNA repair mechanisms. These genes displayed higher expression levels in genotoxic-sensitive tumors. The researchers further demonstrated the specificity of BLM and FANCI expression and genotoxic chemotherapy efficacy by comparing TNBC clinical trials using epirubicin (genotoxic) therapy and taxane (non-genotoxic)-combination therapy. They also studied ovarian cancer trials using the taxane-only therapy group. In trials using genotoxic agents, BLM and FANCI expression was significantly correlated with increased treatment response. In the combination and taxane-only regimens, no significant association was discovered between the expression and treatment response. Therefore, BLM and FANCI present a novel gene expression signature with the ability to predict tumor sensitivity to genotoxic chemotherapy treatment strategies and optimize treatment regimens.
• Genetic diagnostic test to personalize therapeutic strategies for the treatment of TNBCs, BRCA1, and other cancers characterized by abundant genetic aberrations.
• Decreased toxicity of chemotherapy regimens and improved quality of life for patients through removal of agents that are predicted to have minimal efficacy
• Improved therapeutic efficacy through the incorporation of only chemotherapeutic agents predicted to have greater efficacy
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Key Publications: Birkbak NJ, Li Y, Wang ZC, Silver DP, Garber JE, Szallasi Z, Richardson AL, 2012. Copy number gain and increased expression of BLM and FANCI is associated with sensitivity to genotoxic chemotherapy in triple negative breast and serous ovarian cancer. Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research, Mar. 31-Apr. 4.
IPStatus: Pat. Pend.