Combination of tumor targeted therapy with stroma modulating agent for PDAC

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Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer. It is the seventh leading cause of cancer-related mortality worldwide with the 5-year survival rate standing only at less than 9%. Three major issues in pancreatic tumor treatment are; poor availability of anticancer molecules due to limited blood supply to pancreas, development of resistant to first line agent e.g. Gemcitabine and extensive fibrosis in tumor stroma. There is an urgent need for a novel and effective therapeutic strategy for PDAC via simultaneously targeting tumor and its tumor microenvironment. Given the central role of Myc as a mediator of multiple cell proliferation and survival pathways, it is very essential to target the proto-oncogenic expression of Myc and controlling K-Ras mediated drug resistance in pancreatic cancer. On another side, collagen type I dense extracellular matrix of solid tumor severely restricts the uptake of drug, monoclonal antibodies and nanotherapeutics within pancreatic tumor. Overexpressed focal adhesion kinase (FAK) in pancreatic cancer plays role in angiogenesis, fibrosis and metastasis. We hypothesize that oral delivery of FAK inhibitor (PND1186) will facilitate the uptake and penetration of BRD4 PROTAC albuminosomes. PROTAC is novel class of anticancer molecules which selectively degrades the targeted protein instead of mere inhibiting it. Preliminary studies in our laboratory revealed that BRD4 Proteolysis Targeting Chimera (PROTAC) and FAK inhibitor – PND1186 inhibit the growth of pancreatic cancer cells, and endothelial cells in 2D and 3D culture. Nanoformulation showed significant enhancement in solubility and stability. Thus, we propose a combination therapy using a long circulating albumin coated nanoliposome of BRD4 PROTAC and PND1186 (Albuminosomes). The aim of proposed SuRE award is to explore the albuminosomes for pancreatic tumor specific delivery of BRD4 PROTAC and role of PND in tumor uptake of nanoparticle. To achieve this goal, we propose two specific aims; Specific aim 1. Systematic characterization of ARV-loaded albuminosomes (AAnano) and PND nanoformulation (PNDnano). Specific aim 2. Anticancer efficacy, tumor uptake and toxicity evaluation of AAnano and PNDnano in human pancreatic tumor xenograft model. Considering the scarcity of effective therapy for PDAC, the proposed idea has significant clinical relevance.