Bcl-2 inhibitor may enhance chemotherapy treatment in patients with prostate cancer

Oct 28 2009

In trying to better predict a patient's response to chemotherapy for cancer treatment, a team of investigators at The Cancer Institute of New Jersey (CINJ) and Rutgers, The State University of New Jersey, has identified a way to better manipulate a gene product to cause cancer cells to die. And in order to further examine this mechanism, researchers also created a new vehicle for pre-clinical testing of cancer treatments that acts as a bridge between experimental models and human subjects. CINJ is a Center of Excellence of UMDNJ-Robert Wood Johnson Medical School.

A gene common in many cancers known as Bcl-2 produces a protein that plays a role in blocking programmed cell death (apoptosis). Bcl-2 is often over produced in tumors, thus helping to maintain a cancer cell's existence and resulting in resistance to cancer-fighting drugs. By looking at ways to block Bcl-2's actions thereby promoting apoptosis of cancer cells, scientists believe promising new cancer therapies can be developed.

Researchers in this study -- led by Eileen White, PhD, associate director for basic science at CINJ and Robert S. DiPaola, MD, CINJ director, and recently published in Molecular Cancer Research (2009; 7 (9))

(http://mcr.aacrjournals.org/content/7/9/1487.abstract) -- looked at the role of Bcl-2 in prostate cancer that does not respond to therapy. Study has shown it is difficult to kill prostate cancer in particular due to blockage of apoptosis by Bcl-2 and thus few therapeutic options are available. There is now great excitement in the field of cancer research with the development of a Bcl-2 inhibitor, ABT-737, by Abbott laboratories with the potential to overcome this block to apoptosis. And while positive response in stimulating apoptosis has been seen in laboratory tests in human small cell lung cancer and lymphoma cell lines, whether or not a Bcl-2 inhibitor would be effective in prostate cancer was not known.

In order to better assess ABT-737's impact on Bcl-2, the team developed a test of human tumor tissue called the Tumor Tissue Assessment for Response to Chemotherapy (TTARC). Investigators in this study looked at prostate cancer tissue that was extracted from patients through prostatectomy. Shortly after the surgery, the live tissue was placed in TTARC's incubation environment, where it was tested with ABT-737, the chemotherapy agent cisplatin, or a combination of both drugs. The latter showed immediate elimination of tumor cells by activation of apoptosis and degradation of tumor tissue, thus providing pre-clinical justification in the development of therapeutic treatment of prostate cancer with the new Bcl-2 inhibitor. Clinical trials using the orally available version of the Abbott Bcl-2 inhibitor, ABT-263, in solid tumors including prostate cancer, are in progress or in the planning stages at CINJ.

Assessing the response of tumor tissue at the time of treatment is valuable to investigators, says Dr. White, as they can see immediately if the desired effect is being achieved. White, who is also an adjunct professor of surgery at UMDNJ-Robert Wood Johnson Medical School, and a professor of molecular biology and biochemistry at Rutgers University, anticipates TTARC to become a critical assessment tool. "Predicting a patient's response to chemotherapy is often difficult. By utilizing TTARC, clinicians will be able to directly measure the effect of a drug on a patient's own tumor prior to treatment to determine what works best for them. This will help preserve the patient's quality of life, as it possibly will help prevent the patient from being exposed to unnecessary side effects, and that of having to switch treatments mid-stream," she said. Importantly, she emphasized, the availability now of a Bcl-2 inhibitor to potentially enhance the effectiveness of chemotherapy in prostate cancer and other cancers is very exciting.