Development of a new combination therapy for pancreatic ductal adenocarcinoma treatment

Abstract public domain (NIH RePORTER)

Abstract Pancreatic cancers are devastating diseases with five-year survival rates of less than 10%. 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 (PSC) or activated cancer associated fibroblasts (CAF) produce the stromal collagen. The ECM laid down by PSC/CAF is considered to be one of the major contributors of resistance to established therapies of diseases. Furthermore, activated PSC/CAF and abnormal tumor vessels contribute to an immunosuppressive environment. High levels of PD-L1 on the activated PSC/CAFs and angiogenic endothelial cells (aEC) also form a chemical trap to prevent administered immune checkpoint inhibitor (ICI) reaching cancer cells. Depleting PSC/CAF and altering abnormal tumor vessels could significantly improve the efficacy of existing pancreatic ductal adenocarcinoma (PDAC) treatments. However, currently, there are no approved therapies that are able to simultaneously deplete PSC/CAF and alter abnormal tumor vessels in PDAC. We have developed a novel therapeutic protein (ProAgio) using rational protein design. ProAgio is designed to target integrin v3 at a novel site (not the ligand binding site). ProAgio specifically induces apoptosis of integrin v3 expressing cells with high efficacy by a novel mechanism of drug action (recruiting & activating caspase 8 at cytoplasmic domain of). We reasoned that, since both PSC/CAF and aEC express high levels of integrin v3, and since ProAgio is very effective in inducing apoptosis of integrin v3 expressing cells, ProAgio should both deplete PSC/CAF and eliminate new blood vessels in and around pancreatic tumors. This unique strategy may prove advantageous in treatment of PDAC. Our previous studies demonstrated the efficacy of ProAgio potentially as a PDAC treatment via various animal cancer models and patients. The studies support our hypothesis that ProAgio can provide treatment benefit by simultaneously depleting the collagen-producing PSC/CAF 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 previous studies also provides evidence that ProAgio alters tumor immunity and enhances the effects of ICI therapy. The main objective of this application is to test the safety and effectiveness of the combination of ProAgio + Gemcitabine (Gem) + Abraxane + Atezolizumab (Ref to as P-GnP-A) as a viable therapeutic option for PDAC. Aim 1 will determine the tolerability and preliminary anti-cancer activity of the P-GnP + Atezolizumab (P-GnP-A) and characterize PK properties of ProAgio in patients with PDAC. Aim 2 will analyze the effects of the treatments in patient tumors and validate ProAgio MOA. This study will explore new therapeutic avenue for PDAC patients.

Public health relevance public domain (NIH RePORTER)

This research project develops and tests a novel combination therapy for pancreatic ductal adenocarcinoma treatment. The ultimate goal of the project is complete the phase 1b clinical study of ProAgio in combination with gemcitabine, abraxane, and Atezolizumab with pancreatic cancer patients, particularly the patients with advanced disease.