Exemplifying how bench research can be applied to achieve a direct patient benefit, two clinical trials will explore whether a specific genetic pattern can be utilized to enhance the effects of chemotherapy in colon cancer.
Heinz-Josef Lenz, professor of medicine in the division of oncology, has extensively studied polymorphisms in the Thymidylate synthase, or TS gene.
Within the population, any random person may have a single six-base-pair deletion, two six-base-pair deletions, or no six-base-pair deletions in the gene that expresses the TS protein. In patients with advanced colorectal cancer, Lenz found that the more six-base-pair deletions a patient has, the less a tumor expresses TS.
“Tumors need TS to reproduce their DNA,” said Lenz, scientific director of the USC/Norris Cancer Genetics program. “Decreased TS levels have been shown to be associated with superior clinical outcome for patients treated with flourouracil (5-FU), a chemotherapy that is the mainstay in the treatment of colorectal cancer.”
In collaboration with Robert Ladner, assistant professor of pathology, Lenz found that SAHA, one of the novel drugs developed for the treatment of cancer and lymphomas, is able to substantially decrease the expression level of TS. Together with Susan Groshen, professor of preventive medicine, they have designed a clinical trial to test these findings for the first time in patients.
They will check the expression levels of TS prior to the start of the treatment and after one week of therapy and then combine SAHA with 5-FU. If they can show that SAHA (an oral medication) can also decrease TS in the tissue of colon cancer patients, this would be a significant step to further increase the efficacy of chemotherapy combination, since all of the treatments use 5-FU.
The trial will involve metastatic colon cancer patients who have failed standard treatment.
Another drug currently in clinical trial was specifically designed to be activated by the TS protein.
“Usually the normal tissue has low levels of TS,” said Lenz. “We take advantage of the special characteristic that tumors upregulate it with this drug, which only hits the tumor sites that have elevated levels of TS.”
That trial is in Phase I and Phase II testing, but Lenz remains hopeful. “It recognizes the TS, which turns on the drug and allows the drug to kill the cancer cells,” he said.
Lenz noted that this is the first time a drug has been specifically developed for TS, based mainly on the research done by USC investigators, including Peter and Kathleen Danenberg and Lenz.