Grants - Translational Grants - Oregon - 2015

Alexander Guimaraes, M.D., Ph.D.

The poor survival of pancreatic adenocarcinoma (PDAC) patients is due partly to diagnosis at late-stages, concomitant with relatively ineffective cytotoxic therapies.  This poor chemotherapeutic response may relate to unique properties of the PDAC tumor microenvironment (e.g. poor perfusion, increased fibrous stroma), which may be a barrier to drug delivery.  We hypothesize a link between tumor stroma and microvasculature and have developed a steady-state MRI method that quantifies microvascular imaging biomarkers to study PDAC, using long-lived FDA-approved intravascular magnetic nanoparticles (MNP). By applying these techniques to angiotensin receptor-blockade, which directly effects fibrous stroma, we have demonstrated sensitivity to vascular normalization, a direct correlation with histologic assays, and improved drug delivery as measured by 18F-5 fluorouracil (5FU) positron emission tomography (PET). Based on exciting results from the Coussens, Varner, Bar-Sagi and Simon laboratories indicating that B cell-regulated pathways foster PDAC progression, and two reports from the Levy and Soucek laboratories, indicating that therapeutic targeting of Bruton’s tyrosine kinase (BTK) reprograms the immune microenvironment in PDAC to normalize vasculature and mobilize CD8+ T cells resulting in improve efficacy of gemcitabine (Gem) chemotherapy, we propose to quantitatively evaluate microvascular changes following BTK inhibition.  These provocative preclinical data are now being translated to the clinic in a funded (Stand-Up-2-Cancer (SU2C) Phase 2 trial).  The goal of this proposal, therefore, is to test the hypothesis that MRI measures of tumor microvasculature using MNP are surrogate biomarkers of therapeutic response to BTK inhibition by validating in mouse models and translating in humans participating in this SU2C trial.