Researchers at The University of Texas M. D. Anderson Cancer Center have identified a protein that marks the tumor suppressor p53 for destruction, providing a potential new avenue for restoring p53 in cancer cells.

The new protein, called Trim24, feeds p53 to a protein-shredding complex known as the proteasome by attaching targeting molecules called ubiquitins to the tumor suppressor, the team reported this week in the Proceedings of the National Academy of Sciences Online Early Edition.

“Targeting Trim24 may offer a therapeutic approach to restoring p53 and killing tumor cells,” said senior author Michelle Barton, Ph.D., professor in M. D. Anderson’s Department of Biochemistry and Molecular Biology.

The discovery is based on an unusual approach to studying p53, which normally forces potentially cancerous cells to kill themselves and is shut down or depleted in most human cancers. Studies of the p53 protein and gene tend to focus on cancer cell lines or tumors, where the dysfunction already is established, Barton said. “We wanted to purify p53 from normal cells to better understand the mechanisms that regulate it.”

The team developed a strain of mice with a biochemical tag attached to every p53 protein expressed. After first assuring that the tagged p53 behaved like normal p53, the team then used the tag, or hook, to extract the protein. “We could then identify proteins that were attached to p53, interacting with it, through mass spectrometry,” Barton said.

They found Trim24, a protein previously unassociated with p53 that is highly expressed in tumors and is a target of two known oncogenes in distinct forms of leukemia and thyroid cancer.

Subsequent experiments showed that decreased levels of Trim24 led to increased levels of p53 expression in the cell nucleus, and increasing Trim24 expression reduced p53 levels. Loss of Trim24 expression in a breast cancer cell line caused spontaneous programmed cell death apoptosis. A similar response was confirmed in human lung, colon and prostate cancer cells.

Treating cells with a proteasome inhibitor also led to increased p53 expression. Removing an important binding domain of Trim24 or depleting it completely both led to greatly reduced ubiquitin targeting of p53.

An analogous system in fruit flies showed that a simpler version of Trim24 in the flies plays a similar role regulating p53, demonstrating that the relationship is evolutionarily conserved.

Co-authors with Barton are first author Kendra Allton, Abhinav Jain, Ph.D., Hans-Martin Herz, Ph.D., Wen-Wei Tsai, Ph.D., Andres Bergmann, Ph.D., and Randy Johnson, Ph.D., all of M. D. Anderson’s Department of Biochemistry and Molecular Biology; and Sung Yun Jung, Ph.D., and Jun Qin, Ph.D., of the Department of Molecular and Cellular Biology at Baylor College of Medicine. Allton completed the paper as her master’s degree thesis for The University of Texas Graduate School of Biomedical Sciences, a joint program of M. D. Anderson and The University of Texas Health Science Center at Houston. Allton, Jain, Tsai, Johnson and Barton also are with M. D. Anderson’s Center for Stem Cell and Developmental Biology.

Funding for the project was provided by M. D. Anderson’s Kleberg Fund for Innovative Research, grants from the National Institutes of Health, CellCentric, Ltd., the Kadoorie Foundation, the Welch Foundation, the National Cancer Institute and the Laura and John Arnold Foundation Odyssey Fellowship (for Abhinav Jain).

About M. D. Anderson

The University of Texas M. D. Anderson Cancer Center in Houston ranks as one of the world’s most respected centers focused on cancer patient care, research, education and prevention. M. D. Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For four of the past six years, including 2008, M. D. Anderson has ranked No. 1 in cancer care in “America’s Best Hospitals,” a survey published annually in U.S. News & World Report.

Source: University of Texas M. D. Anderson Cancer Center

Laboratoires Pierre Fabre announce that the Committee for Medicinal Products for Human Use (CHMP), the scientific advisory committee of the European Medicines Agency (EMEA), has issued a positive opinion supporting approval and is recommending to grant marketing authorisation for JAVLOR(R) as monotherapy in metastatic treatment of bladder cancer (advanced or metastatic transitional cell carcinoma of the urothelial tract after failure of a prior platinum-containing regimen).

CHMP has issued a positive opinion based on two phase II study results and on the only phase III randomized study ever conducted in the indication of metastatic treatment of bladder cancer after failure of a prior platinum-containing regimen.

When the EMEA will grant the marketing authorization, JAVLOR(R) will become the first monotherapy approved in Europe for the treatment of adult patients with advanced or metastatic transitional cell carcinoma of the urothelial tract after failure of a prior platinum-containing regimen, where the expectation is important for both oncologists and patients. In Europe the burden of bladder cancer is significative with an estimated 100.000 new cases and 50.000 deaths annually; most of cases are related to the use of tobacco products.

Jean-Pierre Garnier, Chief Executive Officer of Pierre Fabre SA, stated: “The favourable opinion of the CHMP for JAVLOR(R) confirms the therapeutic interest of our anticancer product, strengthened by the clinical data of our file. Again, it rewards the quality of work done by our colleagues dedicated to R&D. JAVLOR(R) will introduce innovative therapy to physicians and patients in an area considered as an unmet medical need”.

This approval is a significant milestone for Laboratoires Pierre Fabre as JAVLOR(R) represents one of the leading products of their pipeline and these positive results reward their important efforts in oncology research.

About JAVLOR(R) (vinflunine):

Discovered by scientists at the Pierre Fabre Research Center, vinflunine is a new bi-fluorinated MTI (Microtubule inhibitor) obtained by chemistry exploiting the reactivity of Vinca scaffold in superacidic media. Such strategy, finalized in collaboration with experts at the University of Poitiers (France), enabled the selective introduction of two fluorine atoms in a part of that structure previously inaccessible by classic chemistry, thereby leading to the first bi-fluorinated vinca alkaloid.

Besides its original structure, JAVLOR(R) exhibits unique pharmacological properties and is also devoid of any unpredictable major toxicity and does not induce cumulative toxicity.

Its every 3 weeks administration enables convenient hospital treatment on an out patient basis (a 20 minutes infusion without any IV premedication).

JAVLOR(R) 25 mg/ml solution for infusion has been approved as monotherapy for the treatment of adult patients with advanced or metastatic transitional cell carcinoma of the urothelial tract after failure of a prior platinum-containing regimen.

About Laboratoires Pierre Fabre

Pierre Fabre group, France’s second biggest independent pharmaceutical laboratory, achieved a turnover of 1.75 billion euros in 2008. Approximatively 10,000 people including 1,400 in the research sector, are employed.

Its therapeutical areas are ethical products, healthcare products and dermocosmetics with the brands Avene, Ducray, A Derma, Galenic, Klorane and Rene Furterer. In 2008, Pierre Fabre Medicament dedicated 33% of its annual turnover to R&D in five main therapeutic directions: oncology, the Central Nervous System, cardiology, internal medicine /urology and dermatology.

Source: Pierre Fabre SA

The AGA Foundation for Digestive Health and Nutrition (FDHN) has named Michael Y. Choi , MD, the first recipient of the Mary Terese Hartzheim Award for Neuroendocrine Tumor Research. This new research award was created for young investigators interested in researching carcinoid or neuroendocrine tumors. Dr. Choi is an investigator at Massachusetts General Hospital and an instructor of medicine at Harvard Medical School, Boston. He was previously named an AGA Foundation Research Scholar Award recipient in 2005.

“We are pleased to be working with the Mary Terese Hartzheim (MTH) Foundation and Caring for Carcinoid Foundation (CFCF) to fund this grant for individuals who show promise in researching the development, diagnosis and treatment of carcinoid and neuroendocrine tumors,” said Sidney Cohen, MD, AGAF, chairman of the Foundation for Digestive Health and Nutrition. “The AGA Foundation for Digestive Health and Nutrition helps fund gifted scholars to enable them to begin and/or maintain their research programs. We are especially pleased when previous grant recipients continue their work and qualify for additional funding to further their research.”

The five-year survival rate for intestinal carcinoids in the U.S. between 1973 and 2002 has remained at 60 percent. This lack of improvement in treatment success is largely due to incomplete understanding of the biology behind both neuroendocrine tumors and the corresponding neuroendocrine cells. Carcinoid tumors are rare, slow-growing cancers that usually start in the lining of the digestive tract or in the lungs. Because they grow slowly and often do not produce symptoms in the early stages, the average age of people diagnosed with digestive or lung carcinoids is about 60. Surgery is the main treatment for carcinoid tumors; if they haven’t spread to other parts of the body, surgery can cure the cancer.

The Mary Terese Hartzheim Award for Neuroendocrine Tumor Research provides $75,000 per year for two years (total $150,000) to a junior investigator who will make meaningful contributions to understanding the biology of carcinoid and neuroendocrine tumors and/or the development of novel therapeutic approaches to this group of diseases. The award’s objective is to expand interest and expertise in this specific field of research at academic medical institutions, and to attract new scientists who may not have previously worked in this area.

This award is funded by the Mary Terese Hartzheim (MTH) Foundation and Caring for Carcinoid Foundation (CFCF).

Source:
Aimee Frank
American Gastroenterological Association