Normalizing PDAC stroma with PCBP2 siRNA nanoparticles to improve the antitumor activity of chemotherapy and immunotherapy

Abstract public domain (NIH RePORTER)

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related mortality in the world. Desmoplasia is the most prominent characteristic of PDAC and comprises up to 80% of the tumor mass. Desmoplasia plays important roles in tumorigenesis and aggressiveness by promoting the proliferation and metastasis of tumor cells, enhancing angiogenesis, impeding drug penetration, and contributing to immune evasion. However, clinical trials employing strategies to deplete PDAC stroma have failed. The stroma acts not only as a barrier to the penetration of drug and effector T cells, but also as a barrier to restrain the metastasis of PDAC tumors. Complete depletion of the stroma, therefore, leads to a more aggressive tumor and a poor survival rate. By contrast, normalization, instead of depletion, of the stroma in combination with chemotherapy or immunotherapy to kill tumor cells within the stromal microenvironment is a promising strategy for PDAC therapy. In the stromal microenvironment, activated pancreatic stellate cells (PSCs) transform from a quiescent state into a myofibroblast-like phenotype and express a large amount of extracellular matrix (ECM). Type I collagen proteins are the main component of the ECM and are responsible for the major desmoplastic reaction. High levels of type I collagen are associated with a low survival rate for patients with PDAC. Type I collagen promotes the proliferation and migration of PDAC cells and inhibits apoptotic cells by binding to integrin. We discovered that silencing the poly(rC)-binding protein 2 (αCP2) with siRNA reverses the accumulation of type I collagen in activated PSCs. Our central hypothesis is that silencing αCP2 modulates the PDAC stroma, thus improving the therapeutic index of chemotherapy and immunotherapy. The long-term goal of the project is to develop a combination therapy strategy to treat PDAC.

Public health relevance public domain (NIH RePORTER)

Dense desmoplastic stroma is a fundamental characteristic of pancreatic ductal adenocarcinoma (PDAC) and comprises up to 80% of the tumor mass. While the strategy to deplete PDAC stroma has failed in clinical trials, normalization of the stroma to allow chemotherapy to kill the tumor cells in the “nest” could be a promising strategy for PDAC therapy. In this proposal, we will evaluate how the PCBP2 siRNA enhances the anti-tumor activity of chemotherapy and immunotherapy for PDAC.