(512t) Re-Engineering the Tumor Mechanical Microenvironment Towards Enhancing Immunotherapy

Tumor blood vessels are leaky and compressed¹. These abnormalities impair blood flow thereby reducing oxygen delivery to below physiological levels. Low oxygenation, termed hypoxia, causes resistance to the host’s immune response and immunotherapies². Indeed, less than 1 in 5 cancer patients can benefit from the most popular type of cancer immunotherapy (i.e.immune checkpoint inhibition). The aim of my research is to develop rapidly translatable strategies that ameliorate tumor pathophysiology caused by the abnormal mechanical microenvironment towards enhancing immunotherapy.

As a graduate student in Professor Rakesh Jain’s laboratory, my research focused on decompressing collapsed tumor vessels. We confirmed that intratumor solid stress squeezes many tumor vessels shut and identified targets to alleviate this stress^3,4. Then, we repurposed anti-hypertensive drugs like losartan to cancer because they target tumor components that contribute to elevated solid stress^5,6. We found that re-engineering the tumor microenvironment with losartan potentiated chemotherapy efficacy. This work led to a successful phase II trial in pancreatic cancer (NCT01821729) that demonstrated historically high efficacy, although this must be confirmed in a multi-arm trial⁷. Indeed, a multi-armed, multi-institution trial of 160 patients is underway testing the combination of losartan, chemo-radiation and immunotherapy (NCT03563248). However, using anti-hypertensive drugs in certain hypotensive patients could be risky.

To develop an alternative approach, as a Japanese Society for the Promotion of Science Postdoctoral Fellow under the mentorship of Professors Horacio Cabral and Kazunori Kataoka, I investigated two types of drugs often required with chemotherapy. Specifically, a combination of glucocorticoid steroids and anti-histamine drugs are often needed to reduce hypersensitivity to certain chemotherapies whether they administered as free small molecules or encapsulated in a nanocarrier. First, we found that glucocorticoid steroids at an appropriate dose normalize tumor vessels by inhibiting angiogenesis and the extracellular matrix by reducing hyaluronan synthesis. This dexamethasone-induced microenvironment re-engineering increases the efficacy of cisplatin micelles in murine models of breast cancer metastasis⁸. Next, we found that the anti-histamine drug tranilast normalizes the extracellular matrix by reducing hyaluronan and collagen levels, thereby decompressing vessels. We confirmed that the efficacy of chemo-immunotherapy is enhanced with tranilast pretreatment⁹. Currently, we are performing research to understand how glucocorticoid steroids affect immunotherapy, because they are believed to interfere with each other. This research has the potential to rapidly affect clinical practice because these drugs have decades of safe use and are inexpensive. Additionally, this research helps to understand how to overcome mechanisms of resistance to various types of cancer immunotherapy.

Teaching Interests:

One important opportunity for professors is to serve as a mentor to junior scientists and engineers. As a graduate student and postdoctoral fellow, I had several mentorship opportunities. First, I closely mentored four pre-doctoral students who went on to earn advanced degrees. Second, I served as a teaching assistant for two courses at the Massachusetts Institute of Technology. Third, I performed several interactive lectures for high school students and professional organizations in Japan, introducing the members to cancer research. Fourth, I am currently a thesis committee member for a PhD student of the University of Connecticut.

As a professor, I am interested in teaching most of the major courses for Chemical Engineering. I would like to teach fluid mechanics and eventually develop a graduate course in fluid mechanics of cancer and an undergraduate course in scientific computing for bioengineering.

References:

1. Martin, J. D.; Seano, G.; Jain, R. K., Normalizing Function of Tumor Vessels: Progress, Opportunities and Challenges. Annual review of physiology 2019,81, 505-534.
2. Martin, J. D.; Cabral, H.; Stylianopoulos, T.; Jain, R. K., Improving Cancer Immunotherapy Using Nanomedicine: Progress, Opportunities and Challenges. Nat. Rev. Clin. Oncol. 2020,17, 251-266.
3. Stylianopoulos, T.; Martin, J. D.; Chauhan, V. P.; Jain, S. R.; Diop-Frimpong, B.; Bardeesy, N.; Smith, B. L.; Ferrone, C. R.; Hornicek, F. J.; Boucher, Y.; Munn, L. L.; Jain, R. K., Causes, Consequences, and Remedies for Growth-Induced Solid Stress in Murine and Human Tumors. Proc. Natl. Acad. Sci. U. S. A. 2012,109, 15101-15108.
4. Jain, R. K.; Martin, J. D.; Stylianopoulos, T., The Role of Mechanical Forces in Tumor Growth and Therapy. Annu Rev Biomed Eng 2014,16, 321-46.
5. Chauhan, V. P.; Martin, J. D.; Liu, H.; Lacorre, D. A.; Jain, S. R.; Kozin, S. V.; Stylianopoulos, T.; Mousa, A. S.; Han, X.; Adstamongkonkul, P.; Popovic, Z.; Huang, P.; Bawendi, M. G.; Boucher, Y.; Jain, R. K., Angiotensin Inhibition Enhances Drug Delivery and Potentiates Chemotherapy by Decompressing Tumour Blood Vessels. Nat Commun 2013,4, 2516.
6. Chauhan, V. P.; Chen, I. X.; Tong, R. T.; Ng, M. R.; Martin, J. D.; Naxerova, K.; Wu, M. W.; Huang, P.; Boucher, Y.; Kohane, D. S.; Langer, R.; Jain, R. K., Reprogramming the Microenvironment with Tumor-Selective Angiotensin Blockers Enhances Cancer Immunotherapy. Proc. Natl. Acad. Sci. U. S. A. 2019,116, 10674-10680.
7. Murphy, J. E.; Wo, J. Y.-L.; Ryan, D. P.; Clark, J. W.; Jiang, W.; Yeap, B. Y.; Drapek, L. C.; Ly, L.; Baglini, C. V.; Blaszkowsky, L.; Ferrone, C.; Parikh, A. R.; Weekes, C.; Nipp, R. D.; Kwak, E. L.; Allen, J. N.; Corcoran, R. B.; Ting, D. T.; Faris, J. E.; Zhu, A. X., et al., A Phase Ii Study of Neoadjuvant Folfirinox in Combination with Losartan Followed by Chemoradiotherapy in Locally Advanced Pancreatic Cancer: R0 Resection Rate and Clinical Outcomes. JAMA Oncology 2019,5, 1020-1027.
8. Martin, J. D.; Panagi, M.; Wang, C.; Khan, T. T.; Martin, M. R.; Voutouri, C.; Toh, K.; Papageorgis, P.; Mpekris, F.; Polydorou, C.; Ishii, G.; Takahashi, S.; Gotohda, N.; Suzuki, T.; Wilhelm, M. E.; Melo, V. A.; Quader, S.; Norimatsu, J.; Lanning, R. M.; Kojima, M., et al., Dexamethasone Increases Cisplatin-Loaded Nanocarrier Delivery and Efficacy in Metastatic Breast Cancer by Normalizing the Tumor Microenvironment. ACS Nano 2019,13, 6396-6408.
9. Panagi, M.; Voutouri, C.; Mpekris, F.; Papageorgis, P.; Martin, M. R.; Martin, J. D.; Polydorou, C.; Louca, M.; Kataoka, K.; Cabral, H.; Stylianopoulos, T., Tgf-Î’ Inhibition Combined with Cytotoxic Nanomedicine Normalizes Triple Negative Breast Cancer Microenvironment Towards Anti-Tumor Immunity. Theranostics 2020,in press.