PARP inhibitors (PARPi) are particularly efficacious in tumors deficient in the BRCA1/2 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 BRCA1/2 wild type cancers and to increase chemo- radiosensitivity in these malignancies. BRCA1/2 proteins are essential components of the homologous recombination (HR) double-strand DNA repair mechanism. PARPi'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 BRCA1/2 deficiencies or other DNA repair pathway mutations as found in some triple negative breast cancers. A recent report demonstrated that PI-3 kinase (PI-3K) inhibition impairs BRCA1/2 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-3K inhibitors (PI-3Ki)/ PARP inhibitor will attack the cancer cells DNA repair mechanisms via at least two orthogonal pathways and extend PARPi clinical activity beyond just those deficient in BRCA1/2 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-3K and PARP activity simultaneously (e.g. SRX3128; preliminary results). We have demonstrated proof of concept that SRX3128: 1) augments cell death following DNA damage 2) Inhibits both targets DNA repair and PI-3K simultaneously in the same tumor cell and 3) 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) #1. Develop a dual PI-3 kinase/PARP inhibitor. Aim (Task) #2. 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) #3. Determine therapeutic window for dual PI-3K/PARP inhibition. Approach: Compare toxicity towards neuronal cancer stem cells versus normal neuronal stem cells (NSCs) when exposed to single PARP inhibitor or PI-3K inhibitor versus dual PARP/PI-3K 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.
Public Health Relevance Statement: The planned research is relevant to public health because data we and others have acquired shows that our proposed development of a potent novel PI3 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 PI3K 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 NIH'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.
Project Terms: 1-Phosphatidylinositol 3-Kinase; Academia; Adult; analog; angiogenesis; Antineoplastic Agents; Biological Assay; BRCA1 gene; cancer cell; Cancer Patient; Cancer stem cell; cancer therapy; cancer type; Cell Death; Cells; Childhood; Clinic; Clinical; Collaborations; Computer Simulation; Data; Defect; design; Development; disability; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Pathway; Docking; Dose; Double Strand Break Repair; Drug Combinations; ds-DNA; Effectiveness; experience; Germ-Line Mutation; Goals; Growth; homologous recombination; Human; improved; Individual; Industry; inhibitor/antagonist; innovation; kinase inhibitor; Knowledge; Lead; Legal patent; Ligands; loss of function; loss of function mutation; Malignant Childhood Neoplasm; Malignant neoplasm of ovary; Malignant Neoplasms; Maximum Tolerated Dose; Medical; medulloblastoma; Mission; Modeling; molecular modeling; Molecular Models; Morbidity - disease rate; mortality; Mus; mutant; Mutate; Mutation; Neoplasm Metastasis; neoplastic cell; nerve stem cell; Neuroblastoma; neuroblastoma cell; Neurons; Normal Cell; novel; novel therapeutics; Outcome; Pathway interactions; patient population; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Poly(ADP-ribose) Polymerases; prevent; programs; Proteins; prototype; Public Health; Radiation Tolerance; radioresistant; radiosensitive; Reporting; Research; research clinical testing; response; scaffold; single molecule; small molecule; small molecule inhibitor; small molecule therapeutics; Somatic Mutation; Staging; targeted treatment; technology development; Testing; Therapeutic; Toxic effect; triple-negative invasive breast carcinoma; tumor; Tumor Suppressor Genes; Work
