Enhancing chemotherapy's efficacy: new agent has synergistic effect with standard drugs

Integrating the use of drugs targeted to specific cancer proteins into current chemotherapy regimens to improve the efficacy of systemic treatment is an important clinical goal at Fox Chase Cancer Center. Fox Chase research presented during the 97th Annual Meeting of the American Association for Cancer Research in Los Angeles has found that a new chemical agent, MCP110, has a synergistic effect both in vitro and in vivo when used with current chemotherapy drugs such as taxanes (Taxol and Taxotere) and vinca-alkaloid compounds such as vincristine.

This synergistic effect—in which the effect of two agents is greater than the sum of their individual effects—appeared when using the combination of MCP110 and Taxol on laboratory cell cultures of human Kaposi’s sarcoma and mouse models carrying human lung and colon cancer cells.

“Together, these findings indicate that MCP compounds have potential to be effective in combination with other anticancer agents,” the authors concluded.

Vladimir Khazak, Ph.D., now director of biology at NexusPharma, Inc., in Langhorne, Pa., and formerly a postdoctoral associate in the Fox Chase laboratory of molecular biologist Erica A. Golemis, Ph.D., presented the research in an AACR poster session. The work also appears in the March 1 issue of the AACR journal Molecular Cancer Therapeutics (“In vitro and in vivo synergy of MCP compounds with mitogen-activated protein kinase pathway—and microtubule-targeting inhibitors”).

The work builds on prior findings published by the team in the Proceedings of the National Academy of Sciences, which first identified MCP compounds, and demonstrated that MCP compounds have the ability to inhibit the growth of cultured cancer cells that depend on interactions of the Ras and Raf oncogenes—growth-promoting genes that can transform cells to cancerous ones if the oncogene is activated inappropriately.

The growth signals sent by these oncogenes use a well-traveled enzyme pathway called MAPK (mitogen-activated protein kinase). This pathway is responsible for cell response to various growth factors and is involved in the action of many cancer-causing genes.

A number of new cancer drugs in development such as MCP110 target this pathway to inhibit one or more steps in the growth signaling process. However, many established cancer chemotherapy drugs are cytotoxic—cell-killing—drugs that work in different ways, such as damaging their DNA or attacking the cells’ architecture. Several widely used drugs, including paclitaxel (Taxol), docetaxel (Taxotere) and long-time standby vincristine, take the latter approach, targeting important cell components called microtubules.

“Very few clinical agents are as successful by themselves as they are in combination,” Golemis pointed out. “Combination chemotherapies may use two drugs that either have the same target or two different targets. Another approach—the one we’ve taken here—is to combine a pathway-targeted drug with conventional chemotherapy.

“We’ve found that MCP110 synergizes both with other small molecules targeting the MAPK pathway and with multiple cytotoxic drugs. These studies predict that MCP110 is a potentially useful treatment agent for combination chemotherapy.” In addition to Khazak and Golemis, co-authors include Fox Chase visiting scientist Natalia Skobeleva, Ph.D., of St. Petersburg Polytechnical Institute in St. Petersburg, Russia, NexusPharma chemistry director Sanjay Menon, Ph.D.(formerly associated with NexusPharma and now at Boehringer Ingelheim Pharmaceuticals, Inc.,), and NexusPharma executive director Lutz Weber, Ph.D.