Seminars

For more than three decades, our research has focused on one challenge: improving the delivery and efficacy of anti-cancer therapies. Working on the hypothesis that the abnormal tumor microenvironmentfuels tumor progression and treatment resistance, we developed an array of novel 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, which together create a hostile biochemical and physical tumor microenvironment (e.g., hypoxia, high interstitial fluid pressure, high solid stress). Our work also revealed how these abnormalities fuel malignant properties of a tumor while preventing treatments from reaching and attacking tumor cells.

We next hypothesized that if we could reengineer the tumor microenvironment, we should be able to 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 radiation, chemotherapy and immunotherapy in a number of animal models. Moreover, our trials of antiangiogenics in newly diagnosed and recurrent brain tumor (glioblastoma) patients supported this concept. They revealed that the patients whose tumor blood perfusion/oxygenation increased in response to cediranib – a pan-VEGFR TKI – survived 6-9 months longer than those whose blood perfusion/oxygenation did not increase. The normalization hypothesis also explained how anti-VEGF agents could improve vision in patients with wet age-related macular degeneration, and opened doors to treating other non-malignant diseases harboring abnormal vasculature that afflict more than 500 million people worldwide (e.g., neurofibromatosis-2 NF2), which can lead to deafness; tuberculosis; plaque rupture). Our clinical finding led to the approval of bevacizumab for NF2 patients in UK in 2014.

In parallel, by imaging collagen and measuring perfusion in tumors in vivo, we discovered that the extracellular matrix compresses blood vessels and impedes drug delivery in desmoplastic tumors (e.g., pancreatic cancer, hepatocellular carcinoma, certain breast cancers). We subsequently discovered that widely prescribed angiotensin blockers to control hypertension are capable of “normalizing” the extracellular matrix, opening compressed tumor vessels, and improving the delivery and efficacy of molecular and nanomedicine. This finding offers new hope for improving treatment of highly fibrotic tumors and has led to a clinical trial at MGH on losartan and chemotherapy in pancreatic ductal adenocarcinomas (NCT01821729).

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: 358-369 (2009).
3) Snuderl M, et al. Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. Cell 152, 1065–1076 (2013).
4) Jain RK. An indirect way to tame cancer. Scientific American 310: 46-53 (2014).
5) Jain RK. Antiangiogenesis strategies revisited: From starving tumors to alleviating hypoxia. Cancer Cell 26: 605–622 (2014).
6) Stylianopoulos T and Jain RK. Design considerations for nanotherapeutics in oncology. Nanomedicine: Nanotechnology, Biology and Medicine 11: 1893-1907 (2015).