Pancreatic cancer and especially the pancreatic ductal adenocarcinoma (PDAC) is an unmet medical need with dismal prognosis and no effective treatment. PDAC is the fourth leading cause of cancer-related death in the US and has a median survival of 6 months. Five-year survival is <5% and is limited to stage I and II patients who can benefit from pancreas resection in combination with chemotherapy and radiotherapy. Late stage (III and IV) unrespectable PDAC patients have only palliative chemotherapy (i.e gemcitabine or FOLFIRINOX regimen) yielding a median survival rate of 6-11 months. These therapies are both short lived and associated with significant toxicities and thus would benefit of the synergistic effects of adjuvant therapies to increase efficacy and/or manage toxicity. To address this need, we have focused on plasmalemma vesicle associated protein-1 (Plvap /PV1), an endothelial specific protein with roles in vascular permeability and the diapedesis of leukocytes. PV1 is selectively expressed on a subset of endothelia in normal tissues and, importantly, PV1 is upregulated in the endothelium of most, if not all, human solid tumors, pancreatic cancer included. Our preliminary and published studies show that therapeutic blockade of PV1 with anti-PV1 monoclonal antibodies delivered systemically, endothelial deletion or intratumoral delivery of PV1 shRNA effectively inhibits tumor growth in mouse models of human PDAC. Our preliminary data show surprisingly that PV1 deletion inhibits tumor growth by mechanisms directly involving CD8 and CD4 T cells. Accordingly, PV1 blockade results in decreases in intratumoral regulatory T cells (CD4+FoxP3+) and myeloid cells (CD11b+Gr-1+), as well as concomitant increases in CD8 and CD4 helper T cells. Together, these findings establish PV1 as a novel target for cancer therapy that induces host adaptive immune responses. Based on the above, we hypothesize that PV1 blockade inhibits tumor growth by disabling the diapedesis of immune suppressive myeloid and regulatory T cell subsets into the tumor microenvironment, and also possibly by impairing tumor angiogenesis. Thus, we propose to test:
Aim 1 - the relevant tumor microenvironment changes underlying anti-PV1 therapy and, Aim 2- the efficacy of anti-PV1 therapy in combination with PDAC standard of care - gemcitabine - and with therapies that increase antitumor host responses in a genetic murine model of PDAC. The proposed studies employ genetic models of human cancer, endothelial cell isolation, biochemical assays, ultrasound, MRI, light and electron microscopy. In summary, the data we expect to obtain are relevant to the pathophysiology of cancer, establishing PV1 as a novel target for cancer treatment, which is one of NCI's stated goals.
Pancreatic cancer is an especially vicious form of cancer with no effective treatment. The research proposed in here will document the role of a new blood vessel protein in the growth and progression of pancreatic and other tumors. We also propose to determine the safety and efficacy of antibodies that block the function of this protein in pancreatic cancer therapy, as compared to the current standard of care.
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|Li, Xiujuan; Padhan, Narendra; SjÃ¶strÃ¶m, Elisabet O et al. (2016) VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread. Nat Commun 7:11017|
|Elkadri, Abdul; Thoeni, Cornelia; Deharvengt, Sophie J et al. (2015) Mutations in Plasmalemma Vesicle Associated Protein Result in Sieving Protein-Losing Enteropathy Characterized by Hypoproteinemia, Hypoalbuminemia, and Hypertriglyceridemia. Cell Mol Gastroenterol Hepatol 1:381-394.e7|