Abstract A80: Targeted depletion of extracellular matrix components in PDA eases barriers to treatment
Authors: Carlson Markus A. , Dufort Christopher C. , DelGiorno Kathleen E. , Brockenbrough J. Scott , Dotson Ashley M. , Hingorani Sunil R. 
Published: December 2016

The complex microenvironment found in pancreas cancer is characterized by an extremely dense extracellular matrix (ECM), excessive desmoplasia, hypocellularity, and a scarcity of functioning vasculature. This stromal imbalance helps drive the progression of this devastating disease, and one of the most prominent features is the aberrant overexpression of distinct ECM components. One such element, hyaluronic acid (HA), has the ability to bind and immobilize a large amount of water, thereby increasing the interstitial fluid pressure (IFP) in portions of these tumors to levels capable of completely collapsing blood vessels and inhibiting the perfusion of small molecules via passive transport. Targeted depletion of other ECM components should lower IFP, inflating previously compressed vessels, and permit therapeutic agents that have hitherto been ineffective to enter the tumor and exact an effect. We have seen a sharp increase in the effectiveness of treatments when combined with the enzymatic degradation of HA in the tumor stroma in the murine KPC model of pancreas cancer, as well as in human patients in a phase II clinical trial. In efforts to understand more precisely the contributors to elevated IFP and vascular collapse in PDA we took two approaches. First, we targeted ECM components, including collagen, integrins, and RhoC Kinase, through enzymatic or pharmacologic methods. Although these therapies had varying impact on IFP, they all induced notable changes to the histological architecture and vascular patency of tumors. Direct injections of collagenase into the tumor depleted collagen types I, II and III, as expected, while leaving HA largely unaffected. Rho kinase inhibitors also induced a significant increase in vascular patency after direct injection into the tumor. Continuous subcutaneous administration of relaxin-1 over a 72 hour period substantially lowered IFP and resulted in removal of much of the interstitial collagen. Somewhat surprisingly, this treatment also resulted in large areas of the tumor epithelium becoming necrotic. As a second method to elucidate the biophysical and biomechanical features of PDA, we carried out a series of in vitro and in vivo experiments using both the wick-in needle (WN) and piezoelectric catheter (PC) methods of measuring IFP. In gel-like fluid model systems, the accumulation of an immobilized fluid phase was undetectable via the WN while the PC responded to the asymmetrical swelling and contracting of this gel as it absorbed water. In the KPC mouse model, direct injection of a pegylated hyaluronidase (PEGPH20) into the tumor led to a small increase in the WN reading, with a dramatic decrease in the PC measurements. Taken together, these results suggest the lower pressures recorded by the WN are due to an inability to sense immobilized fluid in the tumor interstitium, which greatly outweighs the scant free fluid. By further characterizing the biophysical properties of PDA and investigating the barriers to drug delivery, we envision identifying a repertoire of complementary and/or context specific interventions to alleviate IFP and allow drug penetration in as many patients as possible.

Citation Format: Markus A. Carlson, Christopher C. Dufort, Kathleen E. DelGiorno, J. Scott Brockenbrough, Ashley M. Dotson, Sunil R. Hingorani.{Authors}. Targeted depletion of extracellular matrix components in PDA eases barriers to treatment. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A80.