New Cyclin Dependent Kinase Inhibitors May Help Overcome Chemotherapy Resistance

NEW YORK—Agents classified as cyclin dependent kinase (CDK) inhibitors show promise in overcoming chemotherapy resistance, Gary K. Schwartz, MD, said at a media briefing on new pathways to targeted treatments sponsored by the American Society of Clinical Oncology (ASCO).

CDK inhibitors do not generally by themselves induce apoptosis in cancer cells, said Dr. Schwartz, of Memorial Sloan-Kettering Cancer Center and Weill Medical College-Cornell University. When combined with such standard cancer drugs as fluorouracil, irinotecan (Camptosar), or paclitaxel (Taxol), however, they enhance tumor response and pave the way to apoptosis.

Cells require CDKs to move from one phase of the cell cycle to the next in order to proliferate, Dr. Schwartz said. Some of the CDK inhibitors now being developed and tested are small molecules that bind directly to the kinase. Others stimulate inhibitors intrinsic to cells.

Flavopiridol, an agent derived from Dysoxylum binectariferum, a plant indigenous to India, inhibits CDK 1, 2, 4, and 6 in nanomolar concentrations, Dr. Schwartz reported. Early laboratory studies focused on using the small molecule to induce apoptosis, but only about 5% of cells succumbed. "These cells are arrested at a particular phase of the cell cycle, but they’re not gone," he said.

If flavopiridol in the same concentration is combined with mitomycin (Mutamycin), however, profound apoptosis occurs (see Figure). "That is," Dr. Schwartz explained, "you can convert cells that were resistant to apoptosis by exposing them to chemotherapy and a CDK inhibitor, in this case flavopiridol."

When Dr. Schwartz and his associates combined flavopiridol and irinotecan in a study in colon cancer xenograft models, the response rate was 80%, double that seen with irinotecan alone. "And, for the first time, you can cure about one third of these animals," he said. This combination is being tested in a phase I trial.

The Sloan-Kettering researchers are also studying flavopiridol combined with paclitaxel in patients with advanced metastatic esophageal cancer. Earlier studies in gastroesophageal cancer cell lines, Dr. Schwartz reported, raised the apoptosis rate from 10% with paclitaxel alone to 60% with the combination.

Tumor invasion of the esophagus that prevented one patient from swallowing regressed significantly after two cycles of the therapy, he noted, as did mediastinal nodes. "This man ultimately went on to a complete response with the combination therapy," he said. He had undergone prior cycles of chemotherapy and radiation therapy.

Bryostatin-1 is another CDK inhibitor being studied in clinical trials, Dr. Schwartz reported. Derived from the sea plant Buglia neritina, it induces p21, a CDK inhibitor intrinsic to cells, and also suppresses cyclin B1, an activator of the CDKs. In a clinical trial, Dr. Schwartz and his associates are using the agent in combination with paclitaxel.

In a man with advanced esophageal cancer, multiple metastases to bone resolved with the combination therapy. "This man had a complete response to combination therapy," Dr. Schwartz said. "We generally do not see these responses in these particular diseases."

UCN-01

UCN-01, a staurosporine analog derived from a Streptomyces species that inhibits CDK 2, 4, and 6 in nanomolar concentrations is being studied for its potential to overcome fluorouracil resistance, Dr. Schwartz reported. Such resistance has been associated with high levels of thymidylate synthase mRNA expression in the cells of gastrointestinal cancers and breast cancers.

Laboratory studies show that fluorouracil induces the expression of this protein, but that treating the cells with UCN-01 depresses this process. Other studies have revealed that while apoptosis does not occur with either drug alone in resistant cell lines, the combination has a profound effect.

In a clinical trial now underway, Dr. Schwartz reported seeing significant regression of multiple lung metastases in a patient who had previously failed irinotecan therapy as well as fluorouracil.

"An understanding of the cell cycle has led to the identification of new therapeutic targets in cancer therapy," Dr. Schwartz concluded "CDK inhibitors augment chemotherapy-induced apoptosis, rendering a chemotherapy-resistant cell more sensitive to chemotherapy."

Preliminary results in clinical trials of the new agents, he commented, "are quite encouraging."