New treatment may bolster the effectiveness of radiation and chemotherapy

Scientist at Massachusetts General Hospital (MGH), the University of North Carolina at Chapel Hill (UNC), and Millennium Pharmaceuticals Inc. have found that using an agent called a proteasome inhibitor in conjunction with radiation or chemotherapy can enhance the power of these therapies. These findings are significant because more than 50 percent of non-germ cell cancers are resistant to radiation and chemotherapy treatment. These studies, conducted in the laboratories of James Cusack, Jr, MD, surgical oncologist at MGH, and his collaborator, Albert Baldwin, Jr., PhD, of the Lineberger Comprehensive Cancer Center at UNC, are published in Cancer Research and the International Journal of Radiation Oncology, Biology, Physics.

�Our whole premise is to make traditional cancer treatments better by combining them with proteasome inhibition,� says Cusack. Proteasome inhibitors are currently being evaluated as single agent treatments for certain cancers. Phase I trials have shown that they have biological activity and are safe.

In the current studies, the researchers have shown that inhibiting the proteasome blocks a key survival protein that is activated in cancer cells following treatment with radiation or chemotherapy. This protein is called nuclear factor kappa-B, or NF-kappa-B. �Essentially, NF-kappa-B activates a shield that blocks the cancer-killing effects of chemotherapy,� says Cusack.

Knocking down that shield may be an effective way to enhance cancer therapy. �This shield seems to be a principal defense mechanism in cancer cells that is activated when the cells are subjected to chemotherapy,� says Cusack. He speculates that normal cells likely have other or redundant defense mechanisms besides NF-kappa-B, but for cancer cells, NF-kappa-B appears to be crucial for their survival against anti-cancer therapies.

In the laboratory, Cusack and his team found that various cancer cell lines were susceptible to chemotherapy plus proteasome inhibition. In addition, this combo approach provided encouraging results in several mouse models of cancer. �We�ve found that we can dramatically shrink large tumors in these mice,� says Cusack. The only way that Cusack and his colleagues could shrink the tumors was to combine the chemotherapy treatments with proteasome inhibition. Either treatment alone yielded only moderate responses.

�In our colon cancer model, one of the most active agents for treating this disease induces cell death in only 10 percent of cancer cells. By combining this with the proteasome inhibitor, the rate of cancer cells dying increased to close to 90 percent,� says Cusack. The researchers also found similar laboratory results when proteasome inhibition was used in combination with radiation. Cusack performed the majority of these studies in his laboratory while he was at UNC.

Clinical trials are under way at MGH and the Dana-Farber/Harvard Cancer Center to explore these treatment approaches in patients with cancers that are resistant to chemotherapy.

The Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $300 million and major research centers in AIDS, the neurosciences, cardiovascular research, cancer, cutaneous biology, transplantation biology and photo-medicine. In 1994, the MGH joined with Brigham and Women�s Hospital to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups and nonacute and home health services.