Abstract IA01: Reengineering the tumor microenvironment to improve cancer treatment: Bench to bedside

Abstract

Abstract For more nearly four 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 microenvironment fuels 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 effectively reaching and/or killing cancer 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 (Science 2005; Cancer Cell 2014). 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 tyrosine kinase inhibitor—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. These include patients with benign tumors around their nerves—known as vestibular schwannomas (associated with a genetic mutation called neurofibromatosis 2 (NF2)). These patients lose their hearing and there is no medical treatment for them. In collaboration with the clinicians at his MGH, we showed that bevacizumab (Avastin) can normalize the blood vessels and reverse hearing loss in these patients (New England J Medicine 2009). This finding formed the basis of approval of Avastin in UK for this patient population and is currently being evaluated in multiple clinical trials in US (Journal of Clinical Oncology 2016). 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 (Nature Comm 2013). Since approximately 25% of human tumors are fibrotic, and even more in obese patients, our finding offers new hope for improving treatment of highly fibrotic tumors and has led to a clinical trial at MGH on losartan with chemo- and radiation therapy in pancreatic ductal adenocarcinomas (NCT01821729). Finally, we are leveraging our insight into the treatment of adult solid tumors to improve the treatment of the most common solid malignancies of childhood that have limited therapeutic options. For example, the standard treatment for medulloblastoma, the most prevalent pediatric brain tumor, is surgery followed by chemo-radiation. Although potentially curative, treatment often leads to devastating treatment-induced morbidities, including severe cognitive impairment and socio-psychological problems. Moreover, a significant fraction of patients experience disease relapse, and there are virtually no therapeutic options for recurrent disease. We discovered a new target in the microenvironment of pediatric medulloblastomas: placental growth factor (PlGF)—that is expressed across all molecular subtypes of these tumors. PlGF is a member of VEGF-family, but unlike VEGF, PlGF is not required for growth of normal blood vessels. Therefore, in 2007, we proposed that targeting PlGF would be safer in children compared to VEGF (Cell 2007). In 2013, we demonstrated that indeed targeting PlGF blocks medulloblastoma growth and spread, and prolongs survival of mice with these tumors—without causing significant side effects (Cell 2013). We also found that the pediatric patients that express high levels of Neuropilin 1—a receptor of PlGF—in their tumors have a poor prognosis. This finding has led to a phase I/II clinical trial in pediatric brain tumor patients this year using an anti-PlGF antibody (TB-403) (NCT02748135).