Engineer Turned Cancer Biologist Receives 2012 Science of Oncology Award

This year’s Science of Oncology Award recipient began his career as a chemical engineer whose journey into oncology has been a “wonderful accident.” Rakesh K. Jain, PhD, of Harvard Medical School and Massachusetts General Hospital, will be awarded ASCO’s 2012 Science of Oncology Award for his 3 decades of pioneering work in the field of oncology.

“I feel enormously honored that ASCO should recognize the work of an engineer and an outsider who ventured into this field. I am very fortunate to have terrific students and collaborators who have made this journey compelling and productive,” Dr. Jain said in an interview with ASCO Daily News. Dr. Jain—noted for his bench-to-bedside translational discoveries—will accept the award and deliver his accompanying lecture during today’s Plenary Session, 1:00 PM-4:00 PM, N Hall B1.

As a graduate student in chemical engineering at the University of Delaware, Dr. Jain was introduced to the late Pietro M. Gullino, MD, a pathophysiologist who developed a system in which a tumor mass in an animal was connected to a single artery and a single vein. The engineer in Dr. Jain was excited at the prospect of applying a chemical engineering concept—input-output analysis—to drug delivery within a tumor mass. Here, Dr. Jain made his rst surprising observation and a seminal contribution to the eld of oncology: the drugs meant to kill tumor cells never actually reached all the cells they were supposed to kill.

After 3 years as an assistant professor of chemical engineering at Columbia University, Dr. Jain accepted a faculty position in chemical engineering at Carnegie Mellon University in 1978. There he began his ground-breaking work in understanding barriers to drug delivery in tumors. Using in vivo microscopy, the research team in Dr. Jain’s laboratory was instrumental in showing that blood vessels in tumors are abnormal both structurally and functionally.

“The tumor vasculature is chaotic in its organization and leaky in some places and not in others,” Dr. Jain said.

To reveal the underlying mechanisms, he developed a mathematical model that showed that the fl uid pressure is uniformly elevated within a tumor but drops precipitously at the margins. This elevated pressure within a tumor pushes its fluid into the surrounding normal tissue and blocks the entry of drugs into tumors. Most importantly, this fl uid carries cancer cells and growth factors made by cancer cells into the surrounding normal tissue, which helps create new blood and lymphatic vessels and further fuels tumor growth and metastasis. These model predictions were subsequently validated in animals and patients with different types of solid tumors.

In 1991, Dr. Jain was named Andrew Werk Cook Professor of Tumor Biology in the Department of Radiation Oncology at Harvard Medical School, where his research team showed that the abnormal structure and function of tumor vessels was a consequence of an imbalance between angiogenic and antiangiogenic factors within the tumor microenvironment.

“Restoring order to the chaotic blood vessels opens a window of opportunity for attacking it,” Dr. Jain proposed in a 2001 Nature Medicine commentary.¹

However, the concept of bringing about normalcy to blood vessels in tumors was provocative in 2001 when researchers were looking for different ways to suffocate tumors by killing the tumor vasculature. Working on the hypothesis that order may be restored through “mopping up” excess angiogenic growth factors that tumors generate, Dr. Jain’s research team showed that a number of antiangiogenic agents successfully reorganize the chaotic vasculature and remodel them close to normalcy.

This “normalization” leads to a transient functional improvement in the tumor vasculature, which includes a lower interstitial fluid pressure, higher oxygenation, and remarkable improvement in treatment efficacy.

Taking these observations from animal models to the clinic, however, was not an easy task. Again, Dr. Jain was struck by paradoxical data from clinical studies that showed bevacizumab—an antibody against vascular endothelial growth factor—improved overall survival in patients with metastatic colorectal cancer only when used in combination with chemotherapy. Working on the hypothesis that a “window of opportunity” or “normalization window” exists in the tumor vasculature and allows for improved drug delivery to the tumor and treatment efcacy, Dr. Jain’s laboratory first tested the hypothesis in an animal model of a brain tumor and then validated it in clinical studies across different types of solid tumors. In patients with rectal tumors, his multidisciplinary team of scientists and clinical collaborators showed that the density and number of tumor microvessels in patients’ tumors signicantly decreased along with a drop in interstitial pressure within 2 weeks of receiving bevacizumab. A second study on patients with recurrent glioblastoma treated with antiangiogenic therapy showed this normalization window was open for approximately 1 month. Moreover, the patients with normalized blood vessels and increased tumor blood flow survived longer.

Dr. Jain believes that, in solid tumors, it is possible to have a unifying theory where normalizing the entire tumor microenvironment through the judicious use of antiangiogenic or other normalizing drugs may help improve the outcome of chemotherapy, radiation therapy, and immune therapy. His team is searching for better normalizing drugs and seeking imaging, circulating, and/or tissue biomarkers that may help in the personalization of therapy.

“In the next 5 years, there will be major developments in personalizing cancer therapy, using not only the genetic signature but also the microenvironmental signature of cancer,” Dr. Jain said.

Dr. Jain has mentored more than 200 doctoral and postdoctoral fellows across multiple disciplines and has successfully collaborated with a similar number of basic scientists and clinicians. These collaborations have resulted in more than 550 publications. He has served on advisory panels to government, industry, and academic institutions and has received more than 50 awards and honors, including a Guggenheim Fellowship, Humboldt Senior Scientist Award, National Cancer Institute’s Outstanding Investigator Grant, and the Department of Defense Breast Cancer Research Innovator Award. Dr. Jain is one of only a few who is a member of all three U.S. National Academies—the Institute of Medicine, the National Academy of Engineering, and the National Academy of Sciences—as well as the American Academy of Arts and Science.

Reference:

1. Jain RK. Normalizing tumor vasculature with antiangiogenic therapy: a new paradigm for combination therapy. Nature Medicine. 2001; 7:987- 989.