Vice President for Translational Research
University of Texas
M.D. Anderson Cancer Center
Houston, TX 

"ARHI, an Imprinted Putative Tumor Suppressor Gene Whose Expression is Lost in Ovarian and Breast Cancer"

Understanding the Genetic Changes Behind Ovarian Cancer
This year in the United States, 25,000 women will develop epithelial ovarian cancer. More than half of them will die. That's why scientists are seeking to learn how molecular changes contribute to the development of ovarian cancer. By providing a better understanding of the genetic changes that underlie the development of this deadly cancer, basic science research can help guide new strategies for prevention, early detection, and more effective therapy for ovarian cancer.

Project Director Expertise
Dr. Robert C. Bast, Jr., is Vice President for Translational Research at The University of Texas M.D. Anderson Cancer Center in Houston.  For the past 20 years, Dr. Bast's laboratory has used the techniques of cellular and molecular biology to study early detection and growth regulation in ovarian and breast cancers, and he has contributed to major discoveries about cancer.  He has recently found that re-expression of ARHI (DIRAS3) can induce autophagy and dormancy in ovarian cancer cells, providing the first inducible model to study the elimination of dormant ovarian cancer cells.  His group was the first to identify CA 125, the first clinically useful marker for monitoring epithelial ovarian cancer.  Dr. Bast’s group is also exploring ways to improve the effectiveness of chemotherapy.

NFCR Research Overview and Findings
During the last two decades, Dr. Bast's laboratory has demonstrated that epithelial ovarian cancer is generally a clonal disease and has focused upon molecular changes that occur during malignant transformation.  Dr. Bast is working to identify the full spectrum of tumor suppressor genes associated with different cancers. Products of these genes are thought to exert negative regulation of critical signaling pathways in normal cells.  Isolating these genes and the pathways that regulate their expression should deepen understanding of the unique biology of ovarian cancer. 

Despite the ability of chemotherapy to shrink ovarian cancers in 70% of cases, the disease continues to be lethal, in large part due to the persistence of drug resistant cancer cells.  These chemotherapy resistant cancer cells can remain dormant for years and then awaken to grow progressively.  Dr. Bast’s laboratory has developed a model to produce dormant human ovarian cancer cells in immunosuppressed mice by re-expressing a protein called ARHI that had been lost as cancers had formed. Dormant cancer cells undergo “autophagy” or “self eating”, consuming themselves to produce energy to survive in the absence of an adequate blood supply.  During the last year, he has found that inhibiting autophagy with the anti-malarial drug chloroquine kills dormant cancer cells.  Dormant ovarian cancer cells also depend upon access to “survival factors” that we have identified and that can now serve as targets for treatment.  In addition, he and his colleagues have identified small inhibitory RNAs, agents that knock down critical enzymes, which enhance the ability of Taxol to kill ovarian cancer cells.

Future Research Goals
The long-term goal for Dr. Bast is to understand the molecular events that contribute to the development of ovarian cancer.  Several supposed suppressor genes have been identified whose function is lost in sporadic ovarian cancers, but a larger number remain to be discovered.
Impact on Cancer Prevention, Treatment, or Cure
By evaluating potential tumor suppressor genes for ovarian cancer, studying the expression of specific genes, and mapping genes that could be harnessed to inhibit tumor growth, Dr. Bast and his laboratory are bringing us closer to early detection and more effective treatment for this disease.

In addition to serving on The V Foundation Scientific Review Committee, Dr. Bast is one of the original members of the Foundation’s Board of Directors.