Tumor Microenvironment EventDecember 10, 2021 | 10 a.m. - noon | Virtual Event
The Cancer Center at Illinois (CCIL) highlights distinguished speaker, Rakesh Jain, Ph.D., FAACR, who will be presenting his seminar, titled, “Normalizing the Tumor Microenvironment to Improve Cancer Treatment: Bench to Bedside.” Open discussion with experts in the field to follow.
Zoom details below.
A.W. Cook Professor of Radiation Oncology (Tumor Biology), Harvard Medical School
Director, E.L. Steele Laboratories for Tumor Biology at Massachusetts General Hospital
Jain is an expert in the abnormal tumor microenvironment and how it fuels tumor progression and confers resistance to molecular-, nano-, and immuno-therapies; developing innovative strategies to normalize the microenvironment; and translating these strategies from bench to bedside.
Panelists for open discussion to include:
- Rohit Bhargava, Ph.D., University of Illinois Urbana-Champaign
- Ovijit Chaudhuri, Ph.D., Stanford University
- Dennis Discher, Ph.D., University of Pennsylvania
- Brendan Harley, Ph.D., University of Illinois Urbana-Champaign
- Joseph Irudayaraj, Ph.D., University of Illinois Urbana-Champaign
- Roger D. Kamm, Ph.D., Massachusetts Institute of Technology
- Hyunjoon Kong, Ph.D., University of Illinois Urbana-Champaign
- Sanjay Kumar, Ph.D., University of California Berkeley
- King Li, M.D., MBA, University of Illinois Urbana-Champaign
- Zeynep Madak-Erdogan, Ph.D., University of Illinois Urbana-Champaign
- Marsha A. Moses, Ph.D., Harvard Medical School
- William A. Muller, M.D., Ph.D., Northwestern University
- Taher Saif Ph.D., University of Illinois Urbana-Champaign
- Kim Selting, Ph.D., University of Illinois Urbana-Champaign
- Michael Sheetz, Ph.D., University of Texas
- Andrew Smith, Ph.D., University of Illinois Urbana-Champaign
- Chi Van Dang, M.D., Ph.D., Ludwig Institute for Cancer Research
- Ralph R. Weischelbaum, M.D., Ph.D., University of Chicago
- Robert A. Weinberg, Ph.D., Massachusetts Institute of Technology
- Frank Winkler, M.D., Ph.D., German Cancer Research Center
For over four decades, my research has focused on one challenge: improving the delivery and efficacy of anti-cancer therapeutics by normalizing the tumor microenvironment. Working on the hypothesis that the abnormal tumor microenvironment fuels tumor growth and treatment resistance, we developed an array of sophisticated imaging technologies and animal models as well as mathematical models to unravel the complex biology of tumors. Using these tools, we demonstrated that the blood and lymphatic vasculature, fibroblasts, immune cells and the extracellular matrix associated with tumors are abnormal, and these collaborate together to create a hostile tumor microenvironment characterized by low oxygen levels (hypoxia), low pH and high interstitial fluid pressure and solid stress.
We next hypothesized that agents that induce “normalization” of the microenvironment can improve the treatment outcome. Indeed, we demonstrated that judicious use of antiangiogenic agents—originally designed to starve tumors—could transiently “normalize” tumor vasculature, alleviate hypoxia, increase delivery of drugs and anti-tumor immune cells, and improve the outcome of various therapies, including immunotherapy. In parallel, we provided compelling evidence for vascular normalization in cancer patients treated with antiangiogenic agents. In fact, vascular normalization and the resultant improvement in tumor perfusion and oxygenation associated with longer survival in patients (J Clinical Oncology 2013; Cancer Cell 2014; PNAS 2015). Our preclinical finding that vascular normalization can improve immunotherapy (PNAS 2012) was confirmed by others in multiple randomized phase III trials on combining antiangiogenic therapy with immune-checkpoint inhibitors for metastatic lung, liver, endometrial and kidney cancers (New England J Medicine 2018, 2019, 2020), and led to the FDA approval 7 such combinations for these cancers in the past 2 years.
The normalization hypothesis also opened doors to treating various non-malignant diseases characterized by abnormal vasculature that afflict >500 million people worldwide, such as, tuberculosis (PNAS 2015) and neurofibromatosis-2 (NF2) (New England J. Medicine 2009). Based on our findings, bevacizumab was approved for NF2-schwannoma patients in UK in 2014.
In parallel, by imaging collagen and measuring diffusion and perfusion in tumors in vivo, we discovered that the tumor cells and the extracellular matrix compress blood vessels and impede drug delivery in matrix-rich tumors (e.g., pancreatic cancer, triple negative breast cancers and ovarian cancer) (Science 2020). We subsequently discovered that angiotensin blockers – widely prescribed to control hypertension – are capable of “normalizing” the extracellular matrix, opening compressed tumor vessels, and improving the delivery and efficacy of molecular and nano-therapeutics. This finding offers new hope for improving treatment of highly fibrotic tumors and led to a successful phase II clinical trial at MGH on losartan and chemo-radiation therapy in pancreatic ductal adenocarcinomas (PDAC) (NCT01821729) (JAMA Oncology 2019). This trial demonstrated that the addition of losartan to the standard of care led to an unprecedented R0 resection rate of 61% in locally advanced PDAC and significantly improved survival of these PDAC patients. This finding has led to a multi-institutional randomized trial (NCT03563248). In my presentation I’ll also discuss how these two broad strategies – “vascular normalization” and “matrix normalization” – can improve the delivery and efficacy of various cancer therapies, including immunotherapy, as well as the outcome of treatment of various non-malignant diseases.
1) Jain RK. Normalization of the tumor vasculature: An emerging concept in anti-angiogenic therapy of cancer. Science 307: 58-62 (2005).
2) Plotkin SR et al. Hearing improvement after bevacizumab in patients with neurofibromatosis 2. New England Journal of Medicine 361: 358-367 (2009).
3) R. K. Jain and T. Stylianopoulos. Delivering nanomedicine to solid tumors. Nature Reviews Clinical Oncology 7:653-64 (2010).
4) RK Jain. Normalizing tumor microenvironment to treat cancer: Bench to bedside to biomarkers. J Clinical Oncology 31:2205-18 (2013).
5) Snuderl M, et al. Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. Cell 152, 1065–1076 (2013).
6) Chauhan V. et al. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumor blood vessels. Nature Communications 4: 2516 doi: 10.1038/ncomms.3516 (2013).
7) Incio J, et al. Obesity-induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy. Cancer Discovery 6: 852–869 (2016).
8) M Pinter and RK Jain. Targeting the renin-angiotensin system to improve cancer treatment: Implications for immunotherapy. Science Translational Medicine 9: eaan5616 (2017).
9) D Fukumura, J Kloepper, Z Amoozgar, DG Duda and RK Jain. Enhancing Cancer Immunotherapy Using Antiangiogenics: Opportunities and Challenges. Nature Reviews Clinical Oncology 15(5):325-340 (2018).
10) Murphy JE et al. Total Neoadjuvant Therapy With Folfirinox in Combination With Losartan Followed by Chemoradiotherapy for Locally Advanced Pancreatic Cancer: A Phase II Clinical Trial. JAMA Oncology 5(7):1020-1027 (2019).
11) Y Zhao, et al. Losartan treatment enhances chemotherapy efficacy and reduces ascites in ovarian cancer models by normalizing the tumor stroma. PNAS 116: 2210-2219 (2019).
12) VP Chauhan, et al. Reprogramming the microenvironment with tumor-selective angiotensin blockers enhances cancer immunotherapy. PNAS 116: 10674-10680 (2019).
13) LL Munn and RK Jain. Vascular regulation of anti-tumor immunity. Science 365: 544-545 (2019).
14) JD Martin, G Seano and RK Jain. Normalizing Function of Tumor Vessels: Progress, Prospects and Challenges. Annual Reviews of Physiology 81: 505-534 (2019).
15) F Mpekris, C Voutouri, JW Baish, DG Duda, LL Munn, T Stylianopoulosa and RK Jain. Combining microenvironment normalization strategies to improve cancer immunotherapy. PNAS. 117:3728-3737 (2020).
16) JD Martin, H Cabral, T Stylianopoulos and RK Jain. Improving cancer immunotherapy using nanomedicine: Progress, opportunities and challenges. Nature Reviews Clinical Oncology. 17(4):251-266 (2020).
17) H Nia, LL Munn and RK Jain. Physical Traits of Cancer. Science 370: aaz0868 (2020).
18) X Jin et al. MetMap: a map of metastatic potential of human cancer cell lines. Nature 588: 331-336 (2020).
19) G Ferraro et al. Fatty acid synthesis is required for breast cancer brain metastasis. Nature Cancer 2: 414–428 (2021).
20) Z Ammozgar et al. Targeting Treg cells with GITR activation alleviates resistance to immunotherapy in murine glioblastomas. Nature Communications 12: 2582 (2021).
21) L Wu et al. Losartan prevents tumor-induced hearing loss and augments radiation efficacy by normalizing the tumor microenvironment in NF2 schwannoma models. Science Translational Medicine 13(602): eabd4816 (2021).
22) C Voutouri, MR Nikmaneshi, CC Hardin, AB Patel, A Verma, MJ Khandekar, S Dutta, T Stylianopoulos, LL Munn and RK Jain. In silico dynamics of COVID-19 phenotypes for optimizing clinical management.
PNAS 118 (3): e2021642118 (2021).
23) LL Munn, T Stylianopoulos, NK Jain, CC Hardin, M Khandekar, and RK Jain. Vascular normalization to improve treatment of COVID-19: Lessons from treatment of cancer. Clinical Cancer Research 27 (10): 2706-2711 (2021).
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