Combination Therapy for Pancreatic Cancer

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ABSTRACT: Pancreatic cancer (PCa) is one of the deadliest forms of cancers and the fourth leading cause of cancer deaths in the United States. Combination of gemcitabine (GEM) and paclitaxel (PTX) or Nab-paclitaxel (nanoparticle (NP) albumin-bound PTX, Abraxane®) is one of the first-line treatments for locally recurrent or metastatic PCa. However, only limited benefits have been shown in clinic. In addition, this treatment is associated with significant toxicity. PCa is characterized by the presence of dense stroma that may limit effective penetration of relatively large-sized NPs. On the other hand, free GEM is rapidly eliminated from the blood circulation and is also subjected to rapid inactivation by deaminase. Therefore, there is an urgent need to develop small NPs that are capable of protecting the drugs and are effective in tumor accumulation and penetration. We have recently shown that conjugation of GEM to POEG-co-PVD polymer led to a significant decrease in the particle size from 160 to 13 nm. The resulting nanocarrier, named PGEM, was highly effective in tumor accumulation and penetration. As a GEM prodrug, PGEM showed significantly improved antitumor activity in vivo. In addition, PGEM is highly effective in codelivery of GEM and another hydrophobic drug such as PF-04136309 (PF), a CCR2 antagonist. Flow study showed that PGEM treatment also led to increased CD8+ T cell response. However, we also observed increased numbers of myeloid-derived suppressor cells (MDSCs). Mechanistic study showed upregulation of CCL2 and CCL7 following treatment with PGEM. CCL2 and CCL7 are known to act on CCR2 on tumor cells and immune cells and promote tumor invasion and metastasis through both direct impact on tumor cells and recruitment of immunosuppressive cells. Our preliminary data showed that incorporation of PF into PGEM NPs led to significant improvement in PANC02 model. More importantly this treatment resulted in a drastic improvement in tumor immune microenvironment, which boded well with combination with anti-PD-1 treatment. This application is focused on further improvement and characterization of PF/PGEM-based therapy. An improved PGEM (PGEMi) will also be developed to improve the bioavailability of both PF and PGEM in tumor tissues. Three specific aims will be pursued in this application: Aim 1 will develop and characterize PGEMi and PF/PGEMi with respect to biophysical and in vitro biological properties. Aim 2 will define the tumor penetration efficiency of PGEMi, and the PK and biodistribution of PF/PGEMi in murine and human PCa models including PDX model.Aim 3 will investigate the toxicity profile and the therapeutic efficacy of PF/PGEMi in various PCa models. Completion of this study may lead to the development of a new and improved combination therapy that will advance the treatment of PCa.