Development of a protein drug for pancreatic cancer treatment

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Abstract Pancreatic cancers are devastating diseases with five year survival rate less than 9%. Currently, there is no effective treatment for advanced disease. One major barrier to efficacy of anti-tumor therapeutics is the dense desmoplastic stromal response. Evidence suggests that cancer associated pancreatic stellate cells (CaPSC) produce the stromal collagen. The ECM laid down by CaPSC is considered to be one of the major contributors of resistance to established therapies of the diseases. Depleting CaPSC and altering vessel density could significantly improve efficacy of existing pancreatic ductal adenocarcinoma (PDAC) treatments. However, currently, there are no approved therapies that are able to deplete CaPSCs in PDAC. We have developed a novel therapeutic protein (ProAgio) using rational protein design. ProAgio is designed to target integrin αvβ3 at a novel site (not the ligand binding site). ProAgio specifically induces apoptosis of integrin αvβ3 expressing cells with high efficacy by a novel mechanism of drug action (recruiting & activating caspase 8 at cytoplasmic domain of β3). We reasoned that, since both CaPSC and angiogenic endothelial cells express high levels of integrin αvβ3, and since ProAgio is very effective in inducing apoptosis of integrin αvβ3 expressing cells, ProAgio should both deplete CaPSC and eliminate new blood vessels in and around pancreatic tumors. This unique strategy may prove advantageous in treatment of PDAC. Our STTR phase I&II studies demonstrated efficacy of ProAgio potentially as a PDAC treatment via various cancer models. The studies support our hypothesis that ProAgio can provide treatment benefit by simultaneously depleting the collagen-producing CaPSCs that support tumor desmoplasia and cancer cell growth, while also eliminating newly grown cancer associated blood vessels that feed cancer cells and enable cancer metastasis. Data from our STTR phase I&II studies provides proof of principle for future clinical tests. Results from our phase II studies have led to IND application of ProAgio as a pancreatic cancer treatment drug. The main objective of this phase IIB application is to generate a definitive dataset to enable the development of ProAgio as a viable therapeutic option for PDAC patients. Aim 1 will characterize the toxicity and tolerability and determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of ProAgio as a single agent and in combination with G-nP. Aim 2 will characterize PK property of ProAgio in cancer patients and to obtain preliminary anti-cancer activity data of ProAgio and ProAgio + G-nP in PDAC patients. Aim 3 will analyze the effects of ProAgio in patient tumor to validate the mechanism of drug action in patients. This study will explore new therapeutic avenue for PDAC patients.