Drug combination against NRAS-mutant melanoma discovered

September 17, 2012 in Cancer

A new study published online in Nature Medicine, led by scientists at The University of Texas MD Anderson Cancer Center, describes the discovery of a novel drug combination aimed at a subset of melanoma patients who currently have no effective therapeutic options.

Melanoma patients have different responses to therapy, depending on what genes are mutated in their tumors. About half of melanomas have a mutation in the BRAF gene; while a quarter have a mutation in the NRAS gene.

New BRAF inhibitor drugs are effective against BRAF-mutant melanoma, but no comparable therapies are currently available against NRAS-mutant melanoma. For the first time, this study provides new hope for patients with NRAS-mutant melanoma that an effective targeted treatment might be developed in the coming years.

By analyzing a sophisticated, genetically engineered mouse model of NRAS-mutant melanoma with a novel systems biology approach, scientists discovered that combining two different classes of drugs shrinks these tumors.

The researchers, led by Lynda Chin, M.D., chair of the Department of Genomic Medicine and scientific director of the Institute for Applied Cancer Science, at MD Anderson – together with colleagues from the Dana-Farber Cancer Institute at Harvard Medical School and from Boston University – discovered that the two drugs, which inhibit proteins Mek and Cdk4, complement one another by targeting unique cancer features.

"The lack of a drug like the BRAF inhibitor that works against NRAS means that there is still no effective treatment option for NRAS-mutant patients to fall back on," said Chin. "Developing an effective combination using existing drugs or drugs already in clinical development is a path to address this unmet need for this population of melanoma patients."

A roadmap for effective drug combinations

Researchers must first know what an effective treatment actually looks like before they can identify and develop effective drug combinations. To accomplish this, Chin and her colleagues generated an inducible NRAS (iNRAS) mouse model. In the model, activating mutant NRAS caused melanomas to form, while turning it off caused the melanomas to shrink – exactly what an effective drug therapy should do.

"We had this great mouse model where the tumors disappear using a genetic trick, and we realized that it was essentially a model of 'the perfect targeted therapy'. So we decided to use it as 'road map' to guide us toward effective ." said lead author Lawrence Kwong, Ph.D., an instructor in MD Anderson's Department of Genomic Medicine.

The researchers speculated that comparing the molecular effects of a drug versus genetically switching off mutant NRAS would reveal what mechanism(s) the drug lacks to be effective. With this knowledge, a complementary secondary drug could be identified which, in combination with the first, would achieve a similar effect to shutting off mutant NRAS.

The researchers used Mek inhibitors as a starting point because these drugs are already in late stage clinical development in which they have been shown to slow tumor growth without shrinking them. The goal of this study was to identify additional inhibitors to combine with the Mek inhibitors to shrink NRAS mutant melanomas.

Using genomic technologies, including transcriptomic profiling, combined with a mathematical approach called Transcriptional Regulatory Associations in Pathways (TRAP), Kwong and colleagues identified Cdk4 as a target that is predicted to provide a synergistic effect when co-inhibited along with Mek. TRAP is a network model that evaluates complex biological interactions mathematically.

Cdk4, Cyclin-dependent kinase 4, is a major regulator of cell proliferation, the process of cells dividing to produce more cells. Cancer cells often hijack Cdk4 as a way to grow rapidly.

When researchers combined the Cdk4 and Mek inhibitors in four different model systems, the combination produced a synergistic effect and shrank tumors, validating the mathematical and experimental predictions.

"This is exciting because our study used a novel approach," said Kwong. "We combined a preclinical model – the iNRAS mouse – with powerful genomic and computational science to identify an effective combination of already-available drugs. This is a great proof-of-concept that preclinical studies in the mouse can inform the clinical development of drugs for patients."

A dimmer switch dialing down tumors

The molecular answer behind the synergistic effect can be explained like a dimmer switch on a household light bulb, where NRAS is not a simple on-off switch that either causes tumors to grow or to shrink. Using the Mek inhibitor by itself was like turning the dimmer switch only halfway down – it was able to coax many tumor cells to die, but the remaining cells kept growing. The addition of the Cdk4 inhibitor, which by itself would have little effect, directly inhibited the cell cycle machinery to halt cell growth. The net effect of driving cancer cells to die without the ability to grow is tumor shrinkage.

"This new way of thinking about RAS signaling opens new opportunities to target other important signaling pathways in cancer, and the approach we have taken can now inform similar efforts to develop non-obvious combination strategies for other RAS mutated cancers," said Chin.

Journal reference: Nature Medicine search and more info website

Provided by University of Texas M. D. Anderson Cancer Center search and more info website

5 /5 (1 vote)  

Rank 5 /5 (1 vote)
Relevant PhysicsForums posts

More news stories

Small cancer risk following CT scans in childhood and adolescence confirmed

The gap between life expectancy in patients with a mental illness and the general population has widened since 1985 and efforts to reduce this gap should focus on improving physical health, suggest researchers in a paper ...

Cancer created 6 hours ago | popularity not rated yet | comments 0

Changing cancer's environment to halt its spread

By studying the roles two proteins, thrombospondin-1 and prosaposin, play in discouraging cancer metastasis, a trans-Atlantic research team has identified a five-amino acid fragment of prosaposin that significantly reduces ...

Cancer created 7 hours ago | popularity not rated yet | comments 0

Novel RNA-based classification system for colorectal cancer

A novel transcriptome-based classification of colon cancer that improves the current disease stratification based on clinicopathological variables and common DNA markers is presented in a study published in PLOS Medicine this w ...

Cancer created 8 hours ago | popularity not rated yet | comments 0

Low radiation scans help identify cancer in earliest stages

A study of veterans at high risk for developing lung cancer shows that low-dose computed tomography (LDCT) can be highly effective in helping clinicians spot tiny lung nodules which, in a small number of patients, may indicate ...

Cancer created 9 hours ago | popularity not rated yet | comments 0

Poliovirus vaccine trial shows early promise for recurrent glioblastoma

An attack on glioblastoma brain tumor cells that uses a modified poliovirus is showing encouraging results in an early study to establish the proper dose level, researchers at Duke Cancer Institute report.

Cancer created 11 hours ago | popularity not rated yet | comments 0


If you can remember it, you can remember it wrong

(Medical Xpress)—Native peoples in regions where cameras are uncommon sometimes react with caution when their picture is taken. The fear that something must have been stolen from them to create the photo ...

B vitamins could delay dementia

(Medical Xpress)—Despite spending billions of dollars on research and development, drug companies have been unable to come up with effective treatments for dementia and Alzheimer's Disease (AD). Now, A. ...

New sleeping pill poised to hit US markets

An experimental sleeping pill from US drug company Merck is effective at helping people fall and stay asleep, according to reviewers at the US Food and Drug Administration, which could soon approve the new drug.

Reducing caloric intake delays nerve cell loss

Activating an enzyme known to play a role in the anti-aging benefits of calorie restriction delays the loss of brain cells and preserves cognitive function in mice, according to a study published in the May ...

Insight into the dazzling impact of insulin in cells

Australian scientists have charted the path of insulin action in cells in precise detail like never before. This provides a comprehensive blueprint for understanding what goes wrong in diabetes.

Antidepressant reduces stress-induced heart condition

A drug commonly used to treat depression and anxiety may improve a stress-related heart condition in people with stable coronary heart disease, according to researchers at Duke Medicine.