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

Introduction

Cancer progression is closely associated with the generation of mechanical stresses that cause the compression of tumor vessels, drastically reducing the delivery of drugs. My co-workers and I found that host cells and the extracellular matrix in tumors generate these stresses.

Discovery of Losartan

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.

Challenges with Mechanoresistance

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.

Urgent Clinical Need

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.

Proposed Methodology

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.

1. Identify intracellular mechanisms promoting mechanoresistance.
2. Employ inhibitors/drugs of the identified mechanisms to overcome mechanoresistance in vitro and in vivo.
3. Determine if these inhibitors/drugs increase the efficacy of chemotherapy.

Combination with Losartan

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.

Clinical Translation

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.

Conclusion

The project will introduce novel, patient-specific therapeutic strategies to directly boost clinical trials in pancreatic cancer patients.