Development of Targeted Damaging Agents for the Treatment of Drug-Resistant Gliomas

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PROJECT SUMMARY Loss of O6-methylguanine methyltransferase (MGMT) expression is common in cancers and confers sensitivity to DNA alkylators, such as temozolomide (TMZ). Epigenetic silencing of MGMT via promoter hypermethylation is found in ~50% of glioblastomas (GBMs), and in most lower grade gliomas with isocitrate dehydrogenase-1/2 (IDH1/2) mutations. MGMT is also silenced in other cancers, including up to 40% of colon cancers, 35% of small cell lung cancers, and 25% of non-small cell lung cancers. In cells that lack MGMT expression (termed MGMT-cells), TMZ-derived O6-methylguanine (O6MeG) lesions mispair with thymine, during DNA replication, due to altered hydrogen base pairing, leading to activation of the mismatch repair pathway (MMR). MMR attempts to repair these lesions by resecting the newly synthesized strand, but thymine once again is inserted opposite of O6MeG. This reinsertion again triggers MMR, leading to iterative “futile cycles” of DNA repair and ultimately apoptosis. Clinically, MGMT promoter demethylation is rare, whereas MMR mutations occur frequently as a dominant mechanism of resistance to TMZ in many tumor types. Because MGMT silencing is found in many cancers, DNA lesions that overcome the MMR resistance (while still being resolvable by MGMT, so as to maintain a therapeutic index (TI)) will have a broad impact. Furthermore, as this biomarker persists even in the treatment-refractory setting (i.e., in the context of MMR defects), we argue that loss of MGMT expression has not been fully exploited for therapeutic gain. Based on the findings presented above, we seek to develop a new class of agents discovered in the laboratory of Drs. Ranjit Bindra and Seth Herzon that generate O6MeG lesions that are susceptible to MGMT removal (“MGMT dependent”) in healthy cells, but which can overcome MMR resistance (“MMR independent”). To this end, Drs. Bindra and Herzon have co-founded KL50 Therapeutics, LLC, and their studies lead to the identification of KL50, a novel alkylation agent that is more active against MMR- cell lines than MMR+ cell lines, while retaining MGMT resolvability. This molecule demonstrates exquisite sensitivity in MGMT-deficient cells independent of MMR status, with negligible activity in MGMT-proficient cells, and has a TI approximately 30 times greater than TMZ. Building on these achievements, in this fast-track SBIR project, we propose to conduct lead optimization to improve central nervous system (CNS) penetration, identify a collection of small molecules with in vivo efficacy in mouse models of high-grade gliomas (HGG), and further develop these compounds for use in a Phase 1 clinical trial. These MGMT dependent–MMR independent alkylating agents are anticipated to possess the positive attributes of TMZ, while circumventing the unavoidable MMR loss mediated resistance mechanism and, thereby, have a major impact on the way we treat GBMs and other tumors lacking MGMT. These molecules could represent a paradigm shift in oncology by dramatically improving their therapeutic index. If successful, our approach will significantly increase the safety and efficacy of DNA alkylators and will expand their use for a broader range of recurrent gliomas and many other cancers.