Date of Award

8-11-2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Zhi-Ren Liu

Second Advisor

Jenny Yang

Third Advisor

Charlie Garnett Benson

Abstract

Cancer-associated fibroblasts (CAFs) comprise a significant portion of the tumor stroma with diverse functions, including matrix synthesis and remodeling, production of growth factors and cytokines, angiogenesis, drug access, and therapy response. CAFs promote tumor growth, metastases, and chemotherapeutic resistance, thus represent a potential target for optimizing treatment strategies against cancer. We previously reported a rationally designed protein, ProAgio that binds to integrin αVβ3 at a novel site and induces integrin-mediated apoptosis. In this study, we show that CAFs express high levels of integrin αVβ3 and ProAgio effectively induces apoptosis in CAFs in Triple Negative Breast Cancer (TNBC), the most aggressive breast cancer subtype, wherein abundance of CAFs is associated with poor overall survival. Depletion of CAFs by ProAgio decreases intratumoral collagen, reduces growth factors and abolishes CAF and cancer cell crosstalk, resulting in decreased cancer cell proliferation and apoptotic resistance. ProAgio also eliminates leaky tumor angiogenic vessels, as these express high levels of integrin αVβ3, which consequently reduces tumor hypoxia and improves drug delivery. Depletion of CAFs and reduction in hypoxia decreases Lysyl oxidase (LOX) secretion, resulting in reduced metastasis. ProAgio stand-alone or in combination with a chemotherapeutic regimen provides a significant survival benefit in orthotopic and transgenic MMTV-PyMT mouse models of TNBC, highlighting the therapeutic potential of ProAgio as a treatment therapy. Pancreatic ductal adenocarcinoma (PDAC) is another deadly cancer abundant in fibrotic stroma. ProAgio specifically induces apoptosis in cancer-associated pancreatic stellate cells (CAPaSCs) that share similar characteristics with CAFs. Depletion of CAPaSCs results in resorption of collagen that opens collapsed vessels and enables drug delivery into the tumor. ProAgio alone or in combination with gemcitabine prolongs survival when tested in GEM-KPC and orthotopic mouse models of PDAC. Furthermore, ProAgio decreases intratumoral IGF-1 levels due to depletion of CAPaSCs and consequently decreases cytidine deaminase, a gemcitabine metabolism enzyme in cancer cells, thereby reducing resistance to gemcitabine-induced apoptosis. Our results for the first time demonstrate that ProAgio selectively targets CAFs and angiogenic vessels, representing a promising strategy for TNBC and PDAC treatment, particularly in combination with other anti-cancer chemotherapeutics.

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