Cybrexa, Inc. — Department of Health and Human Services SBIR Phase I: 102

Description

PROJECT SUMMARY Monotherapy regimens of poly adenosine diphosphateADPribose polymerase inhibitorPARPihave demonstrated clear efficacy in the clinic against metastatic solid tumorswith the greatest activity observed in homologous recombination deficient HRD cancersbut have limited activity against non HRD cancersAs suchthere is great interest in combining PARPiandapos s with other systemic therapiesincluding chemotherapyPreclinical studies indicate the potential for exquisite synergy between PARPiandapos s and DNA damaging chemotherapiesincluding the alkylating agenttemozolomideTMZFurthermorePARPi combinations with TMZ have the potential to greatly enhance anti tumor activity against non HRD cancersHoweverbone marrow suppression is a major barrier to treatment efficacy when PARPiandapos s are combined with chemotherapywhich substantially reduces treatment efficacyHencethere is a great unmet need to enable safer and more effective means to combine PARPis with conventional chemotherapyIn this fast track SBIR proposalCybrexa TherapeuticsCybrexawill use a proprietary drug delivery technology to create an entirely new class of tumor targeted PARPiandapos swhich willaaddress the issues of off target toxicityandbincrease treatment efficacy against both HRD and non HRD cancerswhen used in combination with chemotherapyThese tumorspecific drugsTSDsthus will have a greatly enhanced therapeutic indexOur technology is based on a novel variant of pH low insertion peptidespHLIPswhich were originally discovered at Yale UniversitypHLIP is aamino acid peptide that can be triggered by low pHto insert its C terminus across the cell membrane into the cytosolCargoes attached to the C terminus of pHLIP can be targeted and delivered into cancer cells based on the acidity in the tumor microenvironmentMultiple independent laboratories across the world have now shown that pHLIP is a highly selective and effective tumor targeting platformOur team has established a comprehensive set of protocols and process flows to create TSDscharacterize them in vitroand then validate their activity in vivoWe have successfully conjugated a diverse range of structurally unique PARPiandapos s to pHLIPs thus farand our preliminary results indicate that PARPi TSDs are capable of the followingpH dependent delivery of functionally active drug into tumor cells in vitrosustained and selective in vivo tumor localizationwithout free drug detection in systemic circulationtarget engagement by the drug specifically in tumor tissueat levels similar to that observed with free drugandprevention of bone marrow toxicity when combined with TMZagain compared with free drugThese preliminary results strongly support the feasibility of our objective to advance the development of a PARPi TSDIf successfulour approach will greatly increase the safety and efficacy of PARPiandapos s in combination with chemotherapyand will expand their use into a wider range of HRD and non HRD solid tumor typesFinallythese 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 diphosphateADPribose polymerase inhibitorPARPihave demonstrated clear efficacy in the clinic against metastatic solid tumorsbut bone marrow suppression is a major barrier to treatment efficacy when PARPiandapos s are combined with chemotherapywhich substantially reduces treatment efficacyCybrexa TherapeuticsCybrexawill use a proprietary drug delivery technology to create an entirely new class of tumor targeted PARPiandapos swhich will greatly enhanced therapeutic index of PARPi