Dr. E. Premkumar Reddy from Temple University School of Medicine and colleagues, in a study examining the effects of Plk1 inhibitor ON01910 on tumor growth in several animal models have found that a small molecule inhibitor of polo-like kinase1 (Plk1) could lead to a new avenue for targeted cancer therapy.
ON01910 was found to be a powerful inhibitor of human tumors in a mouse model system and it has low toxicity. Their results have led to clinical evaluation of this compound in phase I clinical trials.
Plk1 plays a key role in driving cell division. High levels of Plk1 have been seen in many human tumors, and studies using various laboratory techniques have shown that inhibition of Plk1 activity leads to cell death. Signaling pathways that have gone awry in a cancer cell ultimately affect cell proliferation, a sensible approach to cancer therapy is to develop inhibitors that block the function of a critical molecule that is required by a tumor cell to complete cell division - Plk1 appears to be one such molecule.
The researchers found that ON01910 arrests cell division in a variety of human cancer cells, including cells that are very often resistant to commonly used chemotherapy. The compound significantly inhibited a wide variety of human tumors, including liver, breast, and pancreatic cancers that were grown in mice. ON01910 was also highly effective and, in many cases, strongly synergistic when tested in combination with other chemotherapies. Studies examining normal human cells show that, in contrast to tumor cells, they are not influenced by ON01910.
The research suggests that because ON01910 is highly effective in combination with other chemotherapies and appears to be nontoxic, it may be beneficial for treatment of some advanced cancers that are resistant to conventional therapies. "Clinical studies, which are currently in progress, should reveal the best way to utilize ON01910 in human cancer therapy," says Dr. Reddy.
The other members of the research team include Kiranmai Gumireddy, M.V. Ramana Reddy, Stephen C. Cosenza, R. Boomi Nathan, Stacey J. Baker, Nabisa Papathi, and E. Premkumar Reddy of Temple University School of Medicine; and Jiandong Jiang and James Holland of Mount Sinai School of Medicine. This work was supported by grants from Onconova Therapeutics Inc. and the Fels Foundation. This work was supported by a grant from Onconova Therapeutics Inc. drug discovery program, and E.P.R. and M.V.R.R. are stockholders of Onconova Therapeutics Inc. E.P.R., S.C.C., and M.V.R.R. are consultants to Onconova Therapeutics Inc.