December 19, 1997

Investigator targets second culprit in AIDS-related cancer

Investigator targets second culprit in AIDS-related cancer

The AIDS virus appears to set the stage for development of several aggressive cancers rarely seen in adults before the AIDS epidemic.

Evidence has suggested that HIV, the virus that causes AIDS, may work with yet another sexually transmitted infectious agent to cause the particularly aggressive form of Kaposi's sarcoma (KS) often seen in AIDS patients.

Now, Vanderbilt Cancer Center researchers have uncovered additional clues that point to a member of the herpes virus family as the second culprit in AIDS-related KS. Their findings also raise hope of a possible target for treatment.

In the Dec. 17 issue of the Journal of the National Cancer Institute, VCC researchers and their colleagues from Germany and the University of Maryland report that they have isolated a gene from the human herpes virus 8 (HHV-8) that is predominantly expressed in tumor cells of Kaposi's sarcoma.

"We know that HHV-8 is found in all forms of KS, AIDS-associated and non-AIDS-associated," said Dr. Philip J. Browning, assistant professor of Medicine and Cell Biology and senior author of the JNCI article.

"The point of this paper was to go beyond the fact that the virus is there. We identified one viral gene – a potential viral 'oncogene' – that may contribute to the transformation of the HHV-8-infected cells."

HHV-8 is a large virus, and its DNA probably encodes for at least 70-80 gene products, Browning said. The researchers zeroed in on a gene that encodes for a protein called v-cyclin D, which they found to be predominantly expressed in KS tumor cells.

V-cyclin D is important for cell cycle progression. Moreover, overexpression of cellular cyclin D is associated with other malignancies, including B-cell lymphomas, breast cancer and prostate cancer, Browning said.

Before the beginning of the AIDS epidemic in the early 1980s, three varieties of KS were seen: a form common in sub-Saharan Africa, a variety seen in organ transplant recipients on immunosuppression therapy, and the classical version most often seen in men of Mediterranean and Eastern European descent. This most common classical form was typically so benign that men who developed it died first of other causes.

Since the advent of AIDS, however, a number of unusually aggressive cancers, including KS, are being seen in HIV-infected adults, especially between the ages of 18-45.

HHV-8 is closely related to the Epstein-Barr virus, which causes mononucleosis and is implicated in the pathogenesis of Burkitt's lymphoma and nasopharyngal carcinoma, Browning said. In addition to KS, HHV-8 has also been associated with primary effusion lymphoma, Castleman's disease and multiple myeloma.

HHV-8 has been found in semen and is believed to be sexually transmitted in patients with AIDS-related KS, but it is likely spread through other means, as well, he said.

"HHV-8 may be very ubiquitous," Browning said. "We don't think every HHV-8-infected individual will go on to develop a malignancy. Host factors may also predict for disease progression. In AIDS-related cases, we believe HHV-8 and HIV work together to produce the particularly aggressive form of KS."

In the work presented in JNCI, Browning and his colleagues isolated the v-cyclin D gene from KS biopsies, from the characteristic spindle-shaped cells derived from AIDS-related and classical KS patients, and from peripheral blood spindle cells from AIDS-related KS patients.

"Expression of v-cyclin D may be responsible, in part, for the increased cell proliferation observed in Kaposi's sarcoma," the authors conclude. "Therefore, a strategy to inhibit v-cyclin D function may represent a novel therapeutic approach."

With a four-year grant from the NCI, Browning will soon test that hypothesis. Using a drug called flavopiridol that interferes with v-cyclin D, the VCC will conduct a Phase 1/Phase 2 study in patients with AIDS-related KS.

The study will be conducted through the Eastern Cooperative Oncology Group. Enrollment is expected to begin next summer.

"I really believe that all the questions cannot be answered at the lab bench alone. Some questions must be answered with a combination of laboratory and clinical efforts," Browning said.

"We had the data to show that V-cyclin D appeared to be the principal HHV-8 gene product expressed in KS and primary effusion lymphoma. Moreover, several laboratories have demonstrated that V-cyclin D is a functional protein. Given the current hypothesis that HHV-8 may be the etiologic factor in KS, it makes sense to try to interfere with some of its gene functions."