International Conference on Biomedical and Cancer Research
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Accepted Abstracts

Developing novel anti-cancer agents targeting the DNA damage response pathway in glioblastoma

Anthony J Berdis*
Cleveland State University, USA

Citation: Berdis AJ (2019) Developing novel anti-cancer agents targeting the DNA damage response pathway in glioblastoma. SciTech Biomed-Cancer Sciences 2019. Tokyo: Japan

Received: April 08, 2019         Accepted: April 19, 2019         Published: April 22, 2019

Abstract

DNA damaging agents such as cisplatin, doxorubicin, and temozolomide are widely used in oncology to treat both hematological and solid cancers. At the cellular level, the damage inflicted by these compounds is processed by the DNA-damage response (DDR) which detects damaged DNA and the signals its presence to various secondary protein messengers which promote DNA repair. Unfortunately, many cancer cells are DDR-defective which subsequently causes drug resistance to these anti-cancer agents. A mechanism for this drug resistance occurs by the ability of DNA polymerases to efficiently replicate unrepaired DNA lesions in a process termed translesion DNA synthesis (TLS). Our lab has extensively studied the molecular mechanism of TLS with the ultimate goal of developing small molecules to inhibit this process and combat drug resistance. The presentation today will describe our work with the DNA damaging agent, temozolomide, which is a frontline therapeutic agent used to treat brain tumors. This drug creates a number of DNA lesions, most notably abasic sites, which are frequently misreplicated to cause drug resistance and increased mutagenesis. We provide evidence that the therapeutic efficacy of temozolomide is significantly increased by co-administration of an artificial nucleoside designated as 5-nitro-indolyl-2’-deoxyriboside (5-NIdR) that efficiently and selectively inhibits the replication of DNA lesions generated by temozolomide. In vivo conversion of 5-NIdR to the corresponding nucleoside triphosphate, 5-NITP, creates a potent inhibitor of several human DNA polymerases that replicate damaged DNA. When tested using a murine xenograft model of glioblastoma, treatment with temozolomide only delayed tumor growth while co-administering 5-NIdR with temozolomide caused complete tumor regression. Preliminary toxicology studies demonstrate that high doses of 5-NIdR do not produce the side effects typically observed with conventional nucleoside analogs such as fludarabine and gemcitabine. Collectively, our cell-based and animal studies  provide pharmacological proof of concept for the coordinate inhibition of translesion DNA synthesis as a strategy to improve chemotherapeutic responses in aggressive brain tumors.