(6 August 2012) Scientists at South Carolina College of Pharmacy (SCCP), University of South Carolina (USC), working in collaboration with Senex Biotechnology, a Columbia, SC company founded by SCCP Professor Igor Roninson, today announced results of research that yielded a novel class of anticancer drugs, identified a new molecular target for these drugs, and obtained laboratory and clinical evidence that this newly discovered class of drugs may offer significant benefits to patients with many different forms of cancer.
These results were published online on August 6, 2012 by the Proceedings of the National Academy of Sciences of the USA (PNAS). The publication contains results obtained with a novel drug that targets the undesirable effects of damaged and senescent cells. Such cells are believed to play a key role in cancer and other diseases of aging.
Full text of the article available at http://www.pnas.org/content/early/2012/08/03/1206906109.full.pdf+html.
“We recruited Dr. Roninson with the expectation his research would have a lasting impact on the healthcare and economy of South Carolina,” said Joseph T. DiPiro, SCCP executive dean. “This significant discovery reflects the value of that investment.”
Roninson relocated Senex to Columbia, S.C. when he became the SmartState Endowed Chair of Translational Cancer Therapeutics at the SCCP, in April 2011. He is based at the Columbia campus of SCCP founding institution USC and is also tenured at SCCP’s other founder, Medical University of South Carolina (MUSC).
“Conventional anticancer drugs, while essential for current cancer therapy, have side effects that can damage healthy cells and cause them to promote the growth of surviving cancer cells,” said Roninson, who led the study. “We needed to find a way to interrupt that process.”
Cellular senescence (aging) can result from changes in the chromosomes that develop with age, or it can be induced by DNA damage caused by traditional anticancer drugs and other factors. Senescent cells have been shown to produce cancer-supporting molecules as well as proteins implicated in other diseases of old age, such as Alzheimer’s disease and arthritis. The importance of this senescence-associated secretory pattern in aging has been convincingly demonstrated in recent studies, but no practical method for blocking this pattern was previously known. The PNAS paper reports the development of Senexin A, the first of Senex’s drugs that inhibit the secretory pattern of the senescent and other damaged cells.
Traditional anticancer drugs (and radiation), while essential for cancer therapy, produce numerous side effects, some of which, unfortunately, support, rather than inhibit, the growth of cancers. The cancer-supporting activity of conventional drugs appears to occur, in part, because these drugs damage both tumor cells and the patient’s normal tissues, causing numerous changes in drug-damaged cells including the induction of cellular senescence. The damaged cells start producing and secreting multiple proteins that promote the growth of the surviving cancer cells, their resistance to chemotherapy, and their spread throughout the body.
In one of the experiments reported in the PNAS article and conducted by collaborator Dr. Hippokratis Kiaris at the University of Athens (Greece), mice were treated with a commonly-used anticancer drug. After the mice recovered from this treatment, both drug-treated and untreated mice were injected with cancer cells. Strikingly, mice pretreated with the anticancer drug developed tumors much more efficiently than the untreated mice. Furthermore, the blood of mice pretreated with the anticancer drug had a higher content of proteins that stimulate the growth of tumor cells. Treatment of mice with Senexin A neutralized the cancer-supporting effects of the anticancer drug, blocking the increase both in the tumor growth and in the production of tumor supporting growth factors. Senexin A also potentiated the antitumor efficacy of the conventional drug.
The molecular target of Senexin A was identified as a protein kinase (an enzyme that modifies other proteins by adding a phosphate) called CDK8 (cyclin-dependent kinase 8). Senexin A is the first selective inhibitor of CDK8 and its nearest relative, CDK19. CDK8 is involved in the regulation of gene expression, i.e. changing the balance of proteins produced in a cell. Unlike better-known kinases of the CDK family, CDK8 does not have a role in the process of cell division.
CDK8 was already known to play an important role in colon cancer and melanoma. The PNAS paper now reports a striking correlation between the gene expression of CDK8 and the duration of relapse-free survival in patients with breast and ovarian cancer. For example, breast cancer patients with below-median expression of CDK8 survived without the disease approximately 7 years longer than patients who had above-median expression of CDK8. The new results implicate CDK8 in damage- and senescence-induced production of cancer-supporting proteins, and suggest that Senex’s new drugs may provide benefit in many different types of cancer.
The PNAS article represents a collaboration between Senex, USC, and the University of Athens, together with several other institutions, and it has Dr. Donald Porter, a senior scientist at Senex, as the first author. The study was led by Dr. Roninson and based on Dr. Roninson’s discovery in 2000 that p21, a protein that stops the division of damaged and aging cells, induces the production of multiple proteins implicated in cancer, Alzheimer’s and other aging-related diseases. The PNAS article shows that p21, which was known to inhibit other members of the CDK family, in contrast, promotes the activity of CDK8 and stimulates CDK8-regulated genes.
Dr. Lawrence Friedhoff, co-author of the PNAS paper and Chief Executive Officer of Senex, has a long history of successful development of new drugs, including Aricept®, the main drug used to treat Alzheimer’s disease.
“Although it will be a few years before we know with certainty, I believe Senexin A and related molecules represent a potentially valuable addition to the armamentarium of anticancer therapies with a real chance to make a difference in the treatment of cancer and other diseases of aging,” said Friedhoff. “We have already enhanced the chemical structure of Senexin A, and the newly optimized compound shows promising results in animal studies.”
The South Carolina SmartState Program was created by the South Carolina legislature in 2002 and is funded through South Carolina Education Lottery proceeds. The legislation authorizes the state's three public research institutions, Clemson University, the Medical University of South Carolina, and the University of South Carolina, to use state funds to create Centers of Economic Excellence in research areas that will advance South Carolina's economy. Each Center is awarded from $2 million to $5 million in State Lottery funds, which must be matched on a dollar-for-dollar basis with non-state investment. To date, 48 Centers have been created and 43 SmartState Endowed Chairs have been appointed to lead the Centers. The SmartState Program has resulted in more than $1.2 billion dollars in non-state investment into the South Carolina economy and is responsible for the creation of more than 7,000 jobs. www.SmartStateSC.org.
About South Carolina College of Pharmacy
The South Carolina College of Pharmacy (SCCP) was formed in 2004 through the integration of the Colleges of Pharmacy at the University of South Carolina in Columbia (USC) and the Medical University of South Carolina in Charleston (MUSC). In 2011, the College added a third site in Greenville, on the campus of the Greenville Hospital System University Medical Center (GHS). The SCCP is a statewide education, research, and service institution that combines the nationally recognized faculty, staff, and resources of MUSC, a major academic medical center; USC, a large comprehensive university; and GHS, a progressive hospital system, to create a statewide approach to pharmacy education that is on a par with some of the most highly regarded colleges in the United States.
Dr. Roninson is available for interviews.