The dense fibrosis and abnormal tumor vasculature in pancreatic ductal adenocarcinoma (PDAC) cause hypoperfusion and increased interstitial fluid pressure (IFP) within the tumor microenvironment. This severely impedes the delivery of therapeutic agents and thus limits drug efficacy. Therefore, agents that reduce fibrosis or normalize tumor vasculature can potentially improve drug delivery and enhance drug efficacy. In fact, there is some evidence to show that the nab-paclitaxel + gemcitabine combination recently approved FDA for treatment of PDAC attacks tumor stroma and increases drug uptake. Other fibrosis-targeting agents including hyaluronidase, losartan, and CTGF inhibitors were also reported to improve drug delivery and enhance drug efficacy in animal models. However, one class of novel stromal targets that have not been extensively studied in PDAC is the Prolyl Hydroxylases Domain Proteins (PHDs). PHDs target hypoxia-inducible factors (HIFs) for degradation. PHD2, the key member of the PHD family, has been shown to play an important role in tumor angiogenesis and vessel normalization. In this proposal, we propose to investigate the effect of PHD2 inhibition on tumor fibrosis and vasculature and evaluate the anticancer activity of PHD2 inhibitors in the KPC mouse model for PDAC. Our hypothesis is that PHD2 plays an important role in regulating tumor stroma and vasculature in PDAC and inhibition of PHD2 will normalize tumor vasculature, reduce fibrosis, and subsequently enhance drug delivery and improve the efficacy of chemotherapeutics in PDAC.
The specific aims of this project are: 1) to investigate the effects of PHD2 inhibition on tumor vasculature and stromal structure in the KPC mouse model for PDAC. We will examine the effect of PHD2 inhibitors on vessel density and integrity and stromal content. We will also determine the changes in tumor perfusion and drug update upon treatment of PHD2 inhibitors in the KPC mice; and 2) to investigate the ability of PHD2 inhibitors to enhance the efficacy of nab-paclitaxel and gemcitabine in extending the overall survival of KPC mice. Our hypothesis is that improved tumor perfusion resulted from PHD2 inhibition can be translated to improved response to chemotherapeutics such as nab-paclitaxel and gemcitabine and give extended patient survival. We will perform survival studies to evaluate the ability of PHD2 inhibitors to improve the activity of nab-paclitaxel and gemcitabine in the KPC mice.
Pancreatic cancer is the fourth leading course of cancer death with estimated 46,400 new cases and over 39,500 deaths every year in the US. The current proposal seeks to investigate the role of vasculature normalizing agents in enhancing the activity of chemotherapeutics. The results generated from this proposal therefore have the potential to directly benefit pancreatic cancer patients with improved treatment for their disease.
