Rakesh Jain, Ph.D.
Massachusetts General Hospital,
Boston, Massachusetts

Background:

Rectal and colon cancer, often called colorectal cancer, ranks the third most common cancer in both men and women in the United States, and accounts for about 10% of all cancer deaths each year.  For cancers that have not spread, surgical removal is often curative.  But for patients whose colorectal cancer has penetrated the bowel wall deeply or has spread to other body sites, a combinatorial approach of surgery, adjuvant chemotherapy, and radiation therapy is often required.  Sadly, the five-year survival rate of these patients is only 64%, and local treatment failure and systemic recurrence are commonly seen.  An improvement in the survival rates of colorectal cancer patients demands more effective therapies.

A recently developed new therapy called anti-angiogenic therapy (meaning blocking tumor blood vessel formation), offers a promising alternative way to save more lives from this disease.  Anti-angiogenic agents capitalize on tumors’ dependence on forming abnormal blood vessels to grow and to spread.  Scientists discovered that blocking critical factors for tumor angiogenesis such as the vascular epithelial growth factor (VEGF), can stop or slow down the tumor growth. These findings led to the development of anti-VEGF antibodies, which showed great promise in treating multiple types of cancer.

Bevacizumab is such an anti-VEGF antibody, and is able to specifically bind to and inhibit the VEGF. Recently, several clinical trials using bevacizumab in combination with chemotherapy and radiation therapy have been tested on patients with advanced colorectal cancer, and the clinical outcomes of extended survival are very encouraging.  In 2004, bevacizumab was approved by the U.S. Food and Drug Administration (FDA) for use in colorectal cancer.  Bevacizumab has also demonstrated anti-cancer activity in other types of cancer, such as kidney, ovarian, lung, and breast cancer.  If fully utilized, bevacizumab agent will likely become an effective life-saving treatment. 

In order to further improve and maximize the effect of this novel therapy, scientists must first gain more insights into how tumor cells respond to the drugs at the molecular level.  An important approach to acquire this data is through the utilization of molecular biomarkers in monitoring cellular responses to the drugs.  In addition, good biomarkers are easy to detect and to monitor clinically, thus provide invaluable information on selecting appropriate therapies, monitoring drug responses, and optimizing drug doses, thereby realizing personalized treatment in cancer patients.  However, no biomarker has yet been clinically validated to monitor the effect of anti-angiogenic therapy in cancer patients. 

Project Director and Research:

NFCR Project Director, Rakesh Jain, Ph.D., at Massachusetts General Hospital (MGH), is working against the clock to meet this need.  In collaboration with Drs. Jeffery Clark at MGH and Christopher Willet at Duke University, who are leaders in the fields of clinical oncology and new therapy development for colorectal cancer, Dr. Jain successfully set up a Phase II clinical trial using bevacizumab with chemoradiation therapy in rectal cancer patients.  Systemic analyses demonstrated that the blood VEGF and PIGF (placental growth factor) increased in rectal cancer patients after receiving bevacizumab.  Furthermore, these findings have been reproduced by Dr. Jain’s own team and other research teams in several other tumor types that use a variety of anti-angiogenic agents, making the blood VEGF and PIGF the most promising molecular markers for measuring the effect of anti-angiogenic agents.

Impact on Cancer Prevention, Treatment, or Cure:

Currently, these potential biomarkers are further validated in Dr. Jain’s laboratory.  Meanwhile, Dr. Jain’s team is making efforts to discover other molecular markers in rectal cancer patients.  The promising molecular markers discovered in Dr. Jain’s laboratory have the potential to become the first biomarkers in evaluating anti-angiogenic therapies, and provide powerful tools for further improving their effectiveness in treating advanced colorectal cancer and other types of cancer.  Moreover, these markers will allow in-depth understanding of the biological response of individual patients to a given treatment, thus making it possible to create individualized therapy, and maximizing the treatment efficacy to each patient.