Potent inhibitor of Kinesin CENP-E demonstrates tumor cell inhibition

A first-in-class, targeted investigational therapy specifically designed to inhibit a single protein that functions only during cell division shows potent activity in a broad range of cancer cell lines, say researchers from GlaxoSmithKline.

Because the compound is so specifically targeted, it may help reduce some of the more common toxic side effects of chemotherapy, they say.

The experimental drug, GSK923295A, inhibits the mitotic kinesin centromere-associated protein E (CENP-E), which is required during mitosis, the process by which a cell duplicates its genetic information in order to generate two, identical, daughter cells. The resulting mitotic arrest can lead to apoptosis, or cell death. A characteristic of CENP-E inhibition is the presence of misaligned or lagging chromosomes within cells attempting to replicate.

”Investigators were able to observe lagging chromosomes in most tumor cells treated with GSK923295A. These effects are rarely observed in untreated cells,” said the study's lead investigator, David Sutton, B.Sc., associate director of biology, within the Oncology division of GlaxoSmithKline in Collegeville, Pa. GlaxoSmithKline funded the study.

Although CENP-E is expressed in all dividing cells, GSK923925A is more likely to affect rapidly dividing cancer cells, Sutton says. Furthermore, because of the very low expression of CENP-E in non-dividing cells such as neurons, GSK923295A may not cause the peripheral nerve damage often seen with chemotherapy treatments such as taxanes and vinca alkaloids, which also inhibit mitosis, he says.

Studies conducted in animal models have shown complete tumor regression in some cancer types, says Sutton. In preclinical tests conducted in 214 solid and 85 hematological tumor cell lines, sensitivity to GSK923295A was seen in 16 out of 17 breast tumor cell lines, 20 out of 25 colon cancer lines, 24 out of 26 lung cancer lines, 11 out of 11 ovarian cancer lines, and six out of six prostate cancer lines, he says. Additionally, laboratory analysis suggests that anti-tumor activity might be achieved with minimal suppression of the bone marrow, which could reduce the typical myelosuppression (reduction in production of blood cells) seen with chemotherapy treatment, he says.

“It is a big leap from doing laboratory experiments to understanding what will happen in patients, but we think it is very encouraging that this first-in-class drug candidate shows both broad activity and the potential for enhanced tolerability in preclinical studies,” Sutton said. GSK923295A, a small molecule drug given intravenously, is now being evaluated in a Phase I clinical trial in patients with advanced solid tumors. It was discovered and optimized by GSK, in partnership with Cytokinetics Inc.

Because the compound is so specifically targeted, it may help reduce some of the more common toxic side effects of chemotherapy, they say.

The experimental drug, GSK923295A, inhibits the mitotic kinesin centromere-associated protein E (CENP-E), which is required during mitosis, the process by which a cell duplicates its genetic information in order to generate two, identical, daughter cells. The resulting mitotic arrest can lead to apoptosis, or cell death. A characteristic of CENP-E inhibition is the presence of misaligned or lagging chromosomes within cells attempting to replicate.

”Investigators were able to observe lagging chromosomes in most tumor cells treated with GSK923295A. These effects are rarely observed in untreated cells,” said the study's lead investigator, David Sutton, B.Sc., associate director of biology, within the Oncology division of GlaxoSmithKline in Collegeville, Pa. GlaxoSmithKline funded the study.

Although CENP-E is expressed in all dividing cells, GSK923925A is more likely to affect rapidly dividing cancer cells, Sutton says. Furthermore, because of the very low expression of CENP-E in non-dividing cells such as neurons, GSK923295A may not cause the peripheral nerve damage often seen with chemotherapy treatments such as taxanes and vinca alkaloids, which also inhibit mitosis, he says.

Studies conducted in animal models have shown complete tumor regression in some cancer types, says Sutton. In preclinical tests conducted in 214 solid and 85 hematological tumor cell lines, sensitivity to GSK923295A was seen in 16 out of 17 breast tumor cell lines, 20 out of 25 colon cancer lines, 24 out of 26 lung cancer lines, 11 out of 11 ovarian cancer lines, and six out of six prostate cancer lines, he says. Additionally, laboratory analysis suggests that anti-tumor activity might be achieved with minimal suppression of the bone marrow, which could reduce the typical myelosuppression (reduction in production of blood cells) seen with chemotherapy treatment, he says.

“It is a big leap from doing laboratory experiments to understanding what will happen in patients, but we think it is very encouraging that this first-in-class drug candidate shows both broad activity and the potential for enhanced tolerability in preclinical studies,” Sutton said. GSK923295A, a small molecule drug given intravenously, is now being evaluated in a Phase I clinical trial in patients with advanced solid tumors. It was discovered and optimized by GSK, in partnership with Cytokinetics Inc.

The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, AACR is the world's oldest and largest professional organization dedicated to advancing cancer research. The membership includes nearly 26,000 basic, translational, and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and more than 70 other countries. AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants. The AACR Annual Meeting attracts more than 17,000 participants who share the latest discoveries and developments in the field. Special Conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment, and patient care. AACR publishes five major peer-reviewed journals: Cancer Research ; Clinical Cancer Research ; Molecular Cancer Therapeutics ; Molecular Cancer Research ; and Cancer Epidemiology, Biomarkers & Prevention . Its most recent publication, CR , is a magazine for cancer survivors, patient advocates, their families, physicians, and scientists. It provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship, and advocacy.

The National Cancer Institute, founded in 1971, is the principal United States government agency charged with coordinating the National Cancer Program. It facilitates international cooperation in clinical trials involving U.S. and foreign collaborating institutions.

The European Organisation for Research and Treatment of Cancer was organized in 1962 to conduct, develop, coordinate and stimulate laboratory and clinical research in Europe, and to improve the management of cancer and related problems by increasing the survival and quality of life for patients.