MechanoResistance · Overcoming Mechanically-Induced Resistance to Chemo-Immunotherapy in Pancreatic Cancer

Cancer progression is closely associated with generation of mechanical stresses that cause the compression of tumor vessels, drastically reducing delivery of drugs. My co-workers and I found that host cells and extracellular matrix in tumors generate these stresses. Furthermore, we identified the anti-hypertensive losartan to alleviate intratumoral stresses and decompress vessels, allowing drugs to enter the tumor. My colleagues tested losartan in pancreatic cancer patients and found improved responses to chemo-radiation. Nonetheless, losartan cannot alleviate all stresses, and my preliminary data indicate that they induce chemotherapy resistance (“mechanoresistance”). Thus, even though vessel decompression facilitates drugs entering the tumor, mechanoresistance renders cancer cells insensitive to drugs. Alleviating mechanoresistance is an urgent clinical need, but this mechanism has not been well studied and strategies to overcome it have not been developed successfully. To address this challenge, I will employ a mixture of cutting-edge bioengineering and biology methods to identify the intracellular mechanisms that promote mechanoresistance, using in vitro and mouse models of pancreatic cancer. I will then employ inhibitors/drugs of the identified mechanisms to overcome mechanoresistance in vitro and in vivo to determine if they increase the efficacy of chemotherapy. I will also confirm whether these drugs work more effectively with losartan or alone. Using the best performing regimen, I will assess the immunological effects and efficacy in combination with immunotherapy, which has yet to induce a benefit in pancreatic cancer trials. In parallel, in order to take this ground-breaking goal of improving pancreatic cancer therapy to the clinic, I will examine the existence of the same mechanoresistance mechanisms in human tumors. The project will introduce novel, patient-specific, therapeutic strategies to directly boost clinical trials in pancreatic cancer patients.