Maximizing cancer synthetic lethality using dual PI-3K/PARP inhibitors

PARP inhibitors PARPi are particularly efficacious in tumors deficient in the BRCA tumor suppressor genes but of limited activity in BRCA competent tumors There is an unmet medical need to develop targeted therapeutic agents which will augment PARPi activity for BRCA wild type cancers and to increase chemo radiosensitivity in these malignancies BRCA proteins are essential components of the homologous recombination HR double strand DNA repair mechanism PARPiandapos s synthetic lethality derives from preventing the HR DNA double strand break DSB repair mechanism which the cancer cell cannot overcome resulting in lethal DNA damage PARPi are selectively toxic to cells with BRCA deficiencies or other DNA repair pathway mutations as found in some triple negative breast cancers A recent report demonstrated that PI kinase PI K inhibition impairs BRCA expression and can sensitize BRCA proficient cancers to PARP inhibition Hence our central hypothesis to be tested in this proposal is that a combination dual PI K inhibitors PI Ki PARP inhibitor will attack the cancer cell s DNA repair mechanisms via at least two orthogonal pathways and extend PARPi clinical activity beyond just those deficient in BRCA and or other DNA repair defects An innovative component of our proposal is that we have developed in silico the first small molecule inhibitory chemotype which inhibits both PI K and PARP activity simultaneously e g SRX preliminary results We have demonstrated proof of concept that SRX augments cell death following DNA damage Inhibits both targets DNA repair and PI K simultaneously in the same tumor cell and displays less toxicity in normal cells compared with individual inhibitory chemotypes at equivalent potency against targets The significance of our proposal lies in our capacity to provide an optimizable promising single anticancer agent which will potently inhibit DNA repair via multiple orthogonal mechanisms and chemo radiosensitive tumor cells to DNA damaging agents This proposal will evaluate this approach by achieving the following aims setting the stage for phase II efforts to optimize the expected dual inhibitor lead compound s to a clinical candidate Aim Task Develop a dual PI kinase PARP inhibitor Aim Task Develop a predictive computational PARP model for the in silico docking of designed compounds Approach Improve in silico PARP ligand fit parameters of our PARP model until a high PARP docking PARP assay inhibition correlation is achieved Aim Task Determine therapeutic window for dual PI K PARP inhibition Approach Compare toxicity towards neuronal cancer stem cells versus normal neuronal stem cells NSCs when exposed to single PARP inhibitor or PI K inhibitor versus dual PARP PI K inhibition conditions The significance of this research is it will greatly expand the reach of PARP inhibition into BRCA proficient cancers This innovative approach attacks cancer using two distinct proven mechanisms with a single compound challenging the one drug one target dogma The planned research is relevant to public health because data we and others have acquired shows that our proposed development of a potent novel PI kinase PARP dual inhibitor to target cancer cell DNA repair mechanisms Moreover the proposal is designed to produce a platform technology for the development of dual small molecule inhibitors of PI K combined with inhibitors of other targets thereby having a broad impact on public health Thus the proposed research which will involve a close collaboration between academia and industry is relevant to the part of the NIHandapos s mission that pertains to the development of new therapeutics able to reduce the burden of human disability via improved treatment of adult and childhood cancer