Points better than the new model of drug resistance in breast cancer treatment

In model of human breast cancer tumors metastatic carcinoma transplanted in mice, from the Washington University School of medicine Alvin j. Siteman Cancer Center (home) and provides insights into how to attack breast cancer unresponsive to medications used to treat them in the St. Louis and San Antonio Breast Cancer Symposium according to survey released 12/12.

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Cutting off all points of escape for melanoma cells

Sep. 19, 2013 — Despite the success of recent approved therapeutics to treat advanced melanoma, metastatic cancer cells inevitably evolve resistance to drugs. In the journal Cell Reports, a team of researchers based at The Wistar Institute, report on the mechanics by which melanoma can evolve resistance to a powerful combination of drugs -- BRAF and MEK inhibitors.

They found that resistant melanomas acquired a mutation in the MEK2 gene and multiple copies of the mutant BRAF oncogene, simultaneously decreasing the sensitivity to both drug targets. Their findings also uncovered a new potential target for melanoma therapy, a protein called S6K. Additionally, early studies in a laboratory model for melanoma show that a triple combination of drug inhibitors halted the growth of resistant tumors.

"Melanoma tumors are particularly adept at rewiring themselves so that anticancer drugs lose their effectiveness, and we must continue to outthink the disease in order to block off all points at which it can evade therapy," said Jessie Villanueva, Ph.D., assistant professor in Wistar's NCI-designated Cancer Center and member of The Wistar Institute Melanoma Research Center. "There are currently therapeutics available that can block the pathway that leads to S6K, but we are also interested in developing inhibitors to S6K itself."

Melanoma is the deadliest, most aggressive form of skin cancer. While surgical treatment of early-stage melanoma leads to 90 percent cure rates, advanced melanoma is notoriously resistant to chemotherapy and has a tendency to metastasize, or spread, throughout the body. According to the World Health Organization, cases of the disease continue to rise internationally, which has helped spur research into therapies such as BRAF and MEK inhibitors.

BRAF inhibitors were developed in response to discoveries that a specific mutation in the BRAF gene was responsible for nearly 50 percent of melanoma cases. The BRAF protein is part of the MAP kinase pathway, a chain of enzymatic reactions -- including the enzyme MEK -- that is commonly over-activated in cancers.

"Combining BRAF and MEK inhibitors was conceived as a one-two punch against the MAP kinase pathway," Villanueva said, "and while it is considered successful in the clinic, some tumors do not respond and others develop resistance, underscoring the need for new therapeutic strategies."

As cancer clinicians began to see patients develop resistance to BRAF and MEK inhibitors, the Wistar team began to explore the mechanisms by which tumors develop resistance. They found that melanoma cells used different tactics for each enzyme. Mutations in MEK2, for example, would render anti-MEK therapies ineffective. To defeat BRAF inhibitors, surviving melanoma cells exhibited numerous copies of the mutant BRAF gene, enough to overpower anti-BRAF drugs.

"There were simply too many copies of BRAF to block, it became a numbers game and the mutation was winning," Villanueva said. "Increasing the dosage of BRAF inhibitors could be one solution, but that cannot be done in patients without causing serious toxic effects."

A possible answer, they reasoned, was in the PI3K/mTOR pathway, a network of signaling enzymes often active within melanoma cells. However, they could find no sign that any of the "usual suspects" -- points along the pathway commonly known to be involved in cancers -- had any evident part in BRAF/MEK resistance. It was not until they examined farther "downstream" that they found persistent activation of S6K, an enzyme that appears to be at the point where P13K/mTOR and MAP kinase pathways merge.

So the researchers tried combinations of inhibitors against BRAF, MEK and PI3K/mTOR (as there are currently no effective S6K inhibitors) in a mouse model of melanoma. "With a triple combination of drugs, the tumors slow down and just stop growing," Villanueva explained.

Although a cocktail of two drugs (a combination of BRAF and PI3K/mTOR inhibitors, for example) might work, they postulated that using three drugs could be more potent and counter intuitively less toxic at the same time. "We followed these mice with melanoma for three weeks, tumors remain stable, and mice did not show any evident signs of toxicity, " Villanueva said

"For patients, it is not a simple matter of introducing triple combination therapies into use," Villanueva said, " but now we have a mechanism and a rational approach to develop both new drugs and more effective combinations aimed at solving drug resistance in melanoma. Our findings might also offer important lessons for other forms of metastatic cancer."

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Research points to promising treatment for macular degeneration

Sep. 13, 2013 — Researchers at the University of North Carolina School of Medicine have published new findings in the hunt for a better treatment for macular degeneration. In studies using mice, a class of drugs known as MDM2 inhibitors proved highly effective at regressing the abnormal blood vessels responsible for the vision loss associated with the disease.

"We believe we may have found an optimized treatment for macular degeneration," said senior study author Sai Chavala, MD, director of the Laboratory for Retinal Rehabilitation and assistant professor of Ophthalmology and Cell Biology & Physiology at the UNC School of Medicine. "Our hope is that MDM2 inhibitors would reduce the treatment burden on both patients and physicians."

The research appeared Sept. 9, 2013 in the Journal of Clinical Investigation.

As many as 11 million Americans have some form of macular degeneration, which is the most common cause of central vision loss in the western world. Those with the disease find many daily activities such as driving, reading and watching TV increasingly difficult.

Currently, the best available treatment for macular degeneration is an antibody called anti-VEGF that is injected into the eye. Patients must visit their doctor for a new injection every 4-8 weeks, adding up to significant time and cost.

"The idea is we'd like to have a long-lasting treatment so patients wouldn't have to receive as many injections," said Chavala. "That would reduce their overall risk of eye infections, and also potentially lower the economic burden of this condition by reducing treatment costs." Chavala practices at the Kittner Eye Center at UNC Health Care in Chapel Hill and New Bern.

All patients with age-related macular degeneration start out with the "dry" form of the disease, which can cause blurred vision or blind spots. In about 20 percent of patients, the disease progresses to its "wet" form, in which abnormal blood vessels form in the eye and begin to leak fluid or blood, causing vision loss.

While anti-VEGF works by targeting the growth factors that lead to leaky blood vessels, MDM2 inhibitors target the abnormal blood vessels themselves causing them to regress -- potentially leading to a lasting effect.

Chavala and his colleagues investigated the effects of MDM2 inhibitors in cell culture and in a mouse model of macular degeneration. They found that the drug abolishes the problematic blood vessels associated with wet macular degeneration by activating a protein known as p53. "p53 is a master regulator that determines if a cell lives or dies. By activating p53, we can initiate the cell death process in these abnormal blood vessels," said Chavala.

MDM2 inhibitors also have conceivable advantages over another treatment that is currently being investigated in several clinical trials: the use of low-dose radiation for wet macular degeneration. Radiation works by causing DNA damage in cells leading to an increase in p53 and cell death. MDM2 inhibitors activate p53 without causing DNA damage. Also, MDM2 inhibitors can be given by eye injection, which is advantageous over some forms of radiation treatment that require surgery to administer.

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