BreakThrough Digest Medical News |
- Stopping and starting cancer cell cycle weakens and defeats multiple myeloma
- McGill researchers discover the cause of an inherited form of epilepsy
- New delivery method improves efficacy of 2 common Parkinson’s disease medications
| Stopping and starting cancer cell cycle weakens and defeats multiple myeloma Posted: 20 Jun 2012 09:00 PM PDT
Weill Cornell Medical College researchers have devised an innovative boxer-like strategy, based on the serial use of two anti-cancer drugs, to deliver a one-two punch to first weaken the defenses of multiple myeloma and then deliver the final knock-out punch to win the fight.
The study, published online by the journal Blood, is the first to show that precise timing of therapies that target a cancer cell’s cycle ? the life phases leading to its division and replication ? disables key survival genes, resulting in cell death. The drug that delivers the weakening jab at the cell cycle is the experimental agent PD 0332991, which allows bortezomib, a proteasome inhibitor already approved for use in myeloma and lymphoma, to land the final defeating blow at lower than normal doses. While this is potentially good news for patients with multiple myeloma, a cancer of blood plasma cells that is currently incurable, the study suggests that using this therapeutic strategy could also work for other tumor types, says the study’s senior investigator, Dr. Selina Chen-Kiang, professor of Pathology and Laboratory Medicine and of Microbiology and Immunology at Weill Cornell Medical College. “Because robust functioning of the cell cycle is crucial to cancer growth and survival, this mechanism-based strategy could theoretically be used against many kinds of cancers,” she says. “Based on the genetics of a patient’s tumor, we could pair PD 0332991 with the right cytotoxic partner drug to both inhibit cancer cell division and sensitize the cells for that knock-out punch,” says Dr. Chen-Kiang. “We are very excited about the promise of this approach.” In fact, physicians at Weill Cornell have opened two new human clinical trials, one in multiple myeloma and one in mantle cell lymphoma, based on the findings of this study in a mouse model as well as on a previous phase I clinical trial led by Weill Cornell investigators that tested PD 0332991 in patients with mantle cell lymphoma. Playing Havoc with the Cancer Cell Cycle
Dr. Chen-Kiang and her laboratory colleagues have long studied genes and proteins that control the cell cycle and cell suicide (apoptosis) in cancer. Cancer is fundamentally a disease of uncontrolled cell proliferation, where cells are able to continuously divide. In contrast, cell division in a healthy individual is regulated by the cell cycle, an orderly sequence of programmed gene expression in which the cell is driven through various checkpoints by a highly regulated network of proteins. Cyclin-dependent kinases (CDKs) are molecules that power the progression of the cell cycle through its four phases. For example, CDK4 and CDK6 help move cells through the first G1 “gap” phase to later phases where the cell splits in two. In many cancers, these two enzymes are over-expressed, ensuring continual growth. Therefore, targeting CDK4 and CDK6 to shut them down has long been a goal of cancer drug discovery, but clinical success, so far, has been disappointing because of lack of effectiveness as well as drug toxicity, says Dr. Chen-Kiang. PD 0332991, a small molecule synthesized by Pfizer, is different because it is exceptionally selective for CDK4 and CDK6, she says. The drug initially did not receive much attention because it is also reversible, meaning that it needs to be used continuously to inhibit CDK4 and CDK6; withdrawing it would reactivate these enzymes, stimulating growth. But Dr. Chen-Kiang had been searching for a drug that she could use for her selective cell cycle-based therapy ? the idea being that playing havoc with a cancer cell’s cycle would fatally weaken it when more traditional anti-cancer drugs are used sequentially. “Given that the gene expression program is coupled to the cell cycle, we hypothesize that inhibition of CDK4/CDK6 maintains gene expression programmed for early G1, while preventing the expression of genes scheduled for other cell cycle phases,” she explains. “And because metabolic needs in tumor cells differ from normal cells, this prolonged arrest in G1 would create an imbalance in gene expression that preferentially sensitizes tumor cells to cytotoxic drugs, allowing for low-dosage treatments.” “Because PD 0332991 is also reversible, we further hypothesize that release from G1 by removal of the inhibitor would synchronize the cell cycles, but may not synchronize gene expression schedules,” Dr. Chen-Kiang adds. “This tension between cell cycle synchronization and differential gene expression synchronization further weakens the tumor cells during their progression, as does the heightened metabolic load and demand for energy to replicate DNA.” Loss of Survival Protein
This is exactly what the researchers found. By using PD 0332991 several times to induce a prolonged arrest of G1, and then a release from that arrest, the cells were sensitized to killing by bortezomib. They found this to be the case in laboratory studies of primary myeloma tumor cells and in mice, which were left with healthy bone marrow cells. “We found bortezomib, even when used in a low dose, was significantly more effective when the cancer cells were sensitized by our strategy,” says the study’s first author, Dr. Xiangao Huang, assistant research professor of Pathology and Laboratory Medicine at Weill Cornell Medical College. In exploring the underpinning mechanism, the researchers discovered that prolonged arrest in G1 markedly enhances cell suicide, induced by bortezomib. They discovered that during this phase, the cell loses a protein called IRF4, an essential survival factor for myeloma cells, and gains several pro-apoptotic proteins. “These findings demonstrate for the first time that key survival and apoptotic genes are regulated by the cell cycle in cancer cells, and suggest new molecular targets for intervention,” Dr. Chen-Kiang says. “This work represents the seamless integration of basic biological research on the cell cycle and direct medical application in clinical trials,” she adds. “Both the tools available to us, and our unique location at NewYork-Presbyterian/Weill Cornell Medical Center, allow us to move biological research forward while rapidly translating our findings to therapy.” ### The National Cancer Institute, a Leukemia and Lymphoma Society Translational Research Program grant, and a Starr Cancer Consortium grant supported the study. Other study co-authors include Dr. Maurizio Di Liberto, Dr. David Jayabalan, Dr. Jun Liang, Dr. Scott Ely, Dr. Jamieson Bretz, Tracey Louie, and Dr. Ruben Niesvizky from Weill Cornell Medical College; Dr. Arthur L. Shaffer and Dr. Louis M. Staudt from the National Institutes of Health; Dr. Isan Chen and Dr. Sophia Randolph from Pfizer Oncology in San Diego; Dr. William Hahn from the Broad Institute of MIT and Harvard; and Dr. Malcolm A.S. Moore from Memorial Sloan-Kettering Cancer Center. Weill Cornell Medical College
Weill Cornell Medical College, Cornell University’s medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances ? including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson’s disease, and most recently, the world’s first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with the Methodist Hospital in Houston. For more information, visit weill.cornell.edu. Contact: Lauren Woods |
| McGill researchers discover the cause of an inherited form of epilepsy Posted: 20 Jun 2012 09:00 PM PDT
Researchers at McGill University have discovered the cause of an inherited form of epilepsy. The disease, known as double-cortex syndrome, primarily affects females and arises from mutations on a gene located on the X chromosome. Drs. Susanne Bechstedt and Gary Brouhard of the Department of Biology have used a highly advanced microscope to discover how these mutations cause a malformation of the human brain. The results of their study are published in the journal Developmental Cell.
When the brain develops in the uterus, new brain cells are born deep within the brain, near the center. These newborn brain cells then crawl out of the so-called “niche” where they were born and migrate outward to the edges of the brain. This outermost layer of the brain is known as the cerebral cortex and is the seat of all higher-level thinking and cognition. In girls with a mutation on their X chromosome, the outward migration of brain cells unfortunately fails. Instead of making it all the way to the edges of the brain, some of the brain cells pile up on top of one another and form a secondary or “double-cortex.” The activity of these abnormally placed brain cells gives rise to seizures and also, in some cases, mental retardation. Drs. Bechstedt and Brouhard were able to purify the product of the mutated gene, a protein known as doublecortin, and to watch the protein in action under a microscope. This protein helps brain cells to build a scaffold inside themselves, much like the scaffolds at construction sites, built of “poles” called microtubules; these form a “skeleton” for the brain cells, known as the cytoskeleton. Brain cells require this internal skeleton to crawl and to migrate, much as humans need their skeletons to walk and run. The McGill researchers discovered that, in order for doublecortin proteins to help build this scaffold, many doublecortin proteins must work together as a team. They found that disease-causing mutations cause a breakdown in this teamwork. This loss of teamwork is sufficient to prevent the brain cells from constructing a proper “skeleton.” This discovery has implications for treatments for a range of conditions, from other forms of epilepsy to spinal cord injuries. In each case, therapies are increasingly directed at triggering brain cells to extend their skeletons — for example when re-growing a nerve ending past the site of a wound in the spinal cord. Understanding how brain cells construct their skeletons will open avenues for doctors to target the brain cell skeleton to extend and re-grow when needed. ### This research was funded by the Canadian Institutes of Health Research. Contact: Chris Chipello |
| New delivery method improves efficacy of 2 common Parkinson’s disease medications Posted: 19 Jun 2012 09:00 PM PDT
A new delivery method for levodopa/carbidopa, a common dual-drug Parkinson’s disease (PD) regimen, significantly improved the duration of the drugs’ effectiveness in people with advanced PD, according to research by Mount Sinai School of Medicine. The new method is continuous delivery of an intestinal gel formulation of the therapies, which are traditionally taken orally. The study found that the continuous gel delivery reduced “off” time?when the medicine’s effectiveness wears off?by an average of nearly two extra hours per day. The gel also improved “on” time without involuntary movements when patients enjoyed a good response, compared to people taking standard levodopa/carbidopa.
The researchers are presenting their findings at the Movement Disorder Society’s 16th International Congress of Parkinson’s Disease and Movement Disorders being held from June 17-21 in Dublin. Levodopa is the most effective drug for treating PD, reducing tremors, slowness, stiffness, and walking difficulty, and carbidopa helps prevent nausea and vomiting associated with levodopa. After five to 10 years, however, the duration of its treatment benefits wears off and PD-related symptoms return, representing a major source of disability for patients despite the benefits of the drug. This period of ineffectiveness, which can last six hours or more per day, is known as “off” time. Researchers led by C. Warren Olanow, MD, Henry P. and Georgette Professor and Chairman Emeritus, Department of Neurology and Director of the Bendheim Parkinson Center at The Mount Sinai Medical Center, performed a double-blind study to explore whether continuous delivery of an intestinal gel form of levodopa/carbidopa could reduce “off” time in people with advanced PD. They found that the levodopa/carbidopa intestinal gel (LCIG) reduced “off” time by nearly four hours, two hours more than standard oral formulations of levodopa. “Maintaining a response to oral therapy is a challenge in Parkinson’s disease patients, and there is a significant unmet need for a treatment that provides the benefits of the drug without off time or dyskinesia,” said Dr. Olanow. “Since it is administered continuously through a pump, LCIG is a promising development that improves outcomes and quality of life in patients with advanced disease.” The research team conducted a 12-week randomized, double-blind trial in 71 PD patients. At the start of the study, the average person had PD for about 11 years and experienced 6.6 hours of “off” time per day. Patients were randomized to receive a continuous infusion of LCIG, delivered through a portable pump connected to a tube implanted in the intestine, plus placebo pills; or placebo gel plus oral levodopa/carbidopa. Treatment with LCIG was not associated with an increase in troublesome dyskinesia. The most common side effects associated with LCIG treatment involved complications due to inserting the device, abdominal pain, pain during the procedure and nausea. ### Dr. Olanow has served as a consultant to Abbott, who manufactures LCIG and supports the study. About The Mount Sinai Medical Center
The Mount Sinai Medical Center encompasses both The Mount Sinai Hospital and Mount Sinai School of Medicine. Established in 1968, Mount Sinai School of Medicine is one of the leading medical schools in the United States. The Medical School is noted for innovation in education, biomedical research, clinical care delivery, and local and global community service. It has more than 3,400 faculty in 32 departments and 14 research institutes, and ranks among the top 20 medical schools both in National Institutes of Health (NIH) funding and by U.S. News & World Report. The Mount Sinai Hospital, founded in 1852, is a 1,171-bed tertiary- and quaternary-care teaching facility and one of the nation’s oldest, largest and most-respected voluntary hospitals. In 2011, U.S. News & World Report ranked The Mount Sinai Hospital 16th on its elite Honor Roll of the nation’s top hospitals based on reputation, safety, and other patient-care factors. Of the top 20 hospitals in the United States, Mount Sinai is one of 12 integrated academic medical centers whose medical school ranks among the top 20 in NIH funding and U.S. News & World Report and whose hospital is on the U.S. News & World Report Honor Roll. Nearly 60,000 people were treated at Mount Sinai as inpatients last year, and approximately 560,000 outpatient visits took place. For more information, visit http://www.mountsinai.org/. |
| You are subscribed to email updates from BreakThrough Digest Medical News To stop receiving these emails, you may unsubscribe now. | Email delivery powered by Google |
| Google Inc., 20 West Kinzie, Chicago IL USA 60610 | |
