Tumors send out signals that impair normal blood flow, which makes them hard to treat with multiple therapies, including radiation, chemotherapy, targeted therapies, and immunotherapy. Impaired blood supply creates an environment low in oxygen levels, which causes the tumors to take on aggressive characteristics and become immunosuppressed. To address this challenge, a team led by researchers at Massachusetts General Hospital (MGH) developed two approaches to repair tumor blood vessels and improve their function.
Also, by devising a method to assess the effects of these approaches and testing it in a study published by Martin et al in Clinical Cancer Research, the investigators found that each approach may help to restore blood flow to enhance chemotherapy’s access to cancer cells and alleviate hypoxia—and that combining them may be especially effective. The scientists’ assessment method involves measuring oxygen levels as an indicator of the extent of hypoxia and abnormal blood flow within tumors.
Rakesh K. Jain, PhD
“This study reports the development and application of a novel microscopy system with unique characteristics,” explained senior author Rakesh K. Jain, PhD, Director of the E.L. Steele Laboratories for Tumor Biology at MGH and the Andrew Werk Cook Professor of Radiation Oncology at Harvard Medical School. “First, this system is capable of imaging oxygen concentration both within cells and throughout large volumes of tumor tissue in relation to blood vessels, which carry the oxygen. Second, this system can image oxygen concentration in tumor tissues over time so that changes in oxygenation can be observed during therapy.”
Use of Microscopy System
Dr. Jain and his colleagues used their microscopy system to examine the effects of their two approaches to repair tumor blood vessel abnormalities that reduce blood flow: one using an antiangiogenic therapy that targets a pathway affecting blood vessel formation, and a second that involves angiotensin system inhibitors, which can alleviate the compressive forces generated by growing tumors that collapse tumor blood vessels. Losartan, a drug approved to treat hypertension, is an example of an angiotensin system inhibitor.
“Our microscopy analyses revealed that although each approach alleviated hypoxia in tumors, the effects were mixed—for example, having different results depending on the tumor type and dose,” said co–lead author John D. Martin, PhD, who was a PhD student in the Steele Labs during this study and is now a research scientist at Nanocarrier Co, Ltd, in Tokyo. Complementary blood vessel changes in response to the two approaches suggest the potential of combining them to create a more powerful effect.
“Understanding hypoxia in tumors—and how antiangiogenic therapy and losartan affect hypoxia—has implications for disease progression and treatment resistance,” said co–lead author Ryan Lanning, MD, PhD, who was a PhD student in the Steele Labs during this study and is now Assistant Professor at the University of Colorado School of Medicine. “Antiangiogenic therapy is used as the standard of care in certain settings of lung, kidney, liver, and endometrial cancers in combination with chemotherapy and immunotherapy. Similarly, losartan is under clinical investigation with chemoradiation and immunotherapy in pancreatic cancer in a multi-institutional clinical trial led by our MGH collaborators.”
The study authors concluded, “High-resolution spatial and temporal responses of tumor vessels to two agents known to improve vascular perfusion globally reveal spatially heterogeneous changes in vessel structure and function. These dynamic vascular changes should be considered in optimizing the dose and schedule of vascular and stromal normalizing strategies to improve the therapeutic outcome.”
Disclosure: This work was supported by the National Cancer Institute, the Department of Defense, Jane’s Trust Foundation, the Niles Albright Research Foundation, the National Foundation for Cancer Research, the Ludwig Center at Harvard, and the Rullo Family. For full disclosures of the study authors, visit aacrjournals.org/clincancerres.
