Augmented homologous recombination as a mechanism of acquired temozolomide resistance in glioblastoma

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Project Summary/Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults and is universally fatal. These tumors are refractory to all conventional therapeutic modalities - surgical resection, radiotherapy and chemotherapy- resulting in a mortality rate of over 90% at 2 years. The only improvement in GBM therapy came from addition of the DNA alkylating agent temzolomide (TMZ) tor treatment regimens. Although TMZ is now routinely administered, concurrently with radiation and as an adjuvant, gains in survival are modest (2-3 months) as these tumors eventually develop therapy-driven resistance and always recur. In order to improve GBM therapy further, it is important to understand how initial and acquired genetic and molecular changes occurring in these tumors modulate the response to TMZ. Loss of mismatch repair (MMR) and re-expression of MGMT enzyme are two mechanisms that underlie some but not all of the chemoresistance exhibited by GBMs. Work done in our and other laboratories has shown that TMZ induces secondary “one-ended” DNA double- strand breaks (DSBs) that are very toxic, and which can be correctly repaired only by the homologous recombination (HR) pathway. Exciting unpublished results from our lab reveal that protracted TMZ treatment of orthotopic GBM tumors in mice results in acquired resistance due to heightened HR repair of TMZ-induced DSBs. Moreover, we have recently published results demonstrating that HR repair is stimulated by cyclin- dependent kinases (CDKs 1&2), which opens up the possibility of combating acquired TMZ resistance with CDK inhibitors. We hypothesize that augmented HR may underlie GBM chemoresistance and recurrence and that targeting HR using CDK inhibitors (that are currently validated in clinical trials) might be a viable strategy for re-sensitizing recurrent GBMs to TMZ. We propose to test our hypothesis in pre-clinical mouse GBM models that closely mimic the characteristics of human GBM. In sum, the goals of the proposed project are to understand if augmented HR is a bona fide mechanism of acquired chemoresistance in GBM, and whether CDK inhibitors can be used to dampen HR thereby sensitizing recurrent tumors to TMZ.