Executive Summary : | Synthetic lethality is a phenomenon where the disruption of a single genetic pathway is tolerable for cell survival, while disrupting two or more pathways simultaneously results in cell death. Poly ADP ribose polymerase inhibitors (PARPi), a DNA damage repair modulator, have been approved as a molecularly targeted therapeutic for various cancers related to homologous recombination (HR) deficient phenotypes. However, challenges such as drug resistance and overexpression of other repair pathway genes persist. To address these gaps, a synthetic lethality-like strategy will be applied, ligating a combination of two or more drugs onto a metal ion platform to form bio-metal-drug conjugates (BMDCs) as a combination therapeutic regimen. The proposal will test the hypothesis that small molecule inhibitors of compensatory DNA damage repair molecular targets, such as polymerase eta, theta, ATM/ATR, HDACi, and RAD51/52, will induce synthetic lethality with PARPi in HR proficient and deficient tumors when developed as combination prodrugs and nano-formulations. The prodrugs and nanoparticle formulations are expected to enhance dissolution, improve pharmacokinetics, minimize off-target side effects, reduce drug dosage, and increase tumor accumulation. The project will utilize expertise in synthetic chemistry and cancer biology, including the design and synthesis of new molecules, nanoparticle formulations, BSL2 facility for in vitro cell culture experiments, availability of BRCA- and BRCA+ cancer cell lines, optimized 3D tumour spheroids, and preclinical mouse tumor xenograft models. |