Development of tumor-targeted PARP inhibitors for the treatment of solid cancers

PROJECT SUMMARY Monotherapy regimens of poly(adenosine diphosphate [ADP]) ribose polymerase inhibitor (PARPi) have demonstrated clear efficacy in the clinic against metastatic solid tumors, with the greatest activity observed in homologous recombination deficient HRD cancers, but have limited activity against non-HRD cancers. As such, there is great interest in combining PARPiandapos;s with other systemic therapies, including chemotherapy. Pre- clinical studies indicate the potential for exquisite synergy between PARPiandapos;s and DNA-damaging chemotherapies, including the alkylating agent, temozolomide (TMZ). Furthermore, PARPi combinations with TMZ have the potential to greatly enhance anti-tumor activity against non-HRD cancers. However, bone marrow suppression is a major barrier to treatment efficacy when PARPiandapos;s are combined with chemotherapy, which substantially reduces treatment efficacy. Hence, there is a great unmet need to enable safer and more effective means to combine PARPis with conventional chemotherapy. In this fast-track SBIR proposal, Cybrexa Therapeutics (“Cybrexa”) will use a proprietary drug delivery technology to create an entirely new class of tumor-targeted PARPiandapos;s, which will (a) address the issues of off-target toxicity, and (b) increase treatment efficacy against both HRD and non-HRD cancers, when used in combination with chemotherapy. These tumor- specific drugs (TSDs) thus will have a greatly enhanced therapeutic index. Our technology is based on a novel variant of pH-low insertion peptides (pHLIPs), which were originally discovered at Yale University. pHLIP is a ~36-amino acid peptide that can be triggered by low pH (≤ 6.5-7.0) to insert its C-terminus across the cell membrane into the cytosol. Cargoes attached to the C-terminus of pHLIP can be targeted and delivered into cancer cells based on the acidity in the tumor microenvironment. Multiple independent laboratories across the world have now shown that pHLIP is a highly selective and effective tumor targeting platform. Our team has established a comprehensive set of protocols and process-flows to create TSDs, characterize them in vitro, and then validate their activity in vivo. We have successfully conjugated a diverse range of structurally unique PARPiandapos;s to pHLIPs thus far, and our preliminary results indicate that PARPi-TSDs are capable of the following: (1) pH-dependent delivery of functionally active drug into tumor cells in vitro; (2) sustained and selective in vivo tumor localization, without free drug detection in systemic circulation; (3) target engagement by the drug specifically in tumor tissue, at levels similar to that observed with free drug; and (4) prevention of bone marrow toxicity when combined with TMZ, again compared with free drug. These preliminary results strongly support the feasibility of our objective to advance the development of a PARPi-TSD. If successful, our approach will greatly increase the safety and efficacy of PARPiandapos;s in combination with chemotherapy, and will expand their use into a wider range of HRD and non-HRD solid tumor types. Finally, these studies will form the basis for a wide range of TSD-based therapeutic combinations that Cybrexa will develop in the future.PROJECT NARRATIVE Monotherapy regimens of poly(adenosine diphosphate [ADP]) ribose polymerase inhibitor (PARPi) have demonstrated clear efficacy in the clinic against metastatic solid tumors, but bone marrow suppression is a major barrier to treatment efficacy when PARPiandapos;s are combined with chemotherapy, which substantially reduces treatment efficacy. Cybrexa Therapeutics (“Cybrexa”) will use a proprietary drug delivery technology to create an entirely new class of tumor-targeted PARPiandapos;s, which will greatly enhanced therapeutic index of PARPi.