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Two Array-Invented MEK Inhibitors Showcased At ASCO

"Two Array BioPharma-invented MEK inhibitors, binimetinib (MEK162) and selumetinib, were showcased at the 50th annual meeting of the American Society of Clinical Oncology (ASCO).  At the meeting, preliminary data for the combination of binimetinib and CDK4/6 inhibitor LEE011 (discovered by Novartis Institutes for BioMedical Research in collaboration with Astex Pharmaceuticals) from a Phase 1b/2 dose-escalation study conducted by Novartis in NRAS-mutant melanoma indicates the combination demonstrated an acceptable safety profile for most patients with promising preliminary antitumor activity.  Additionally, preliminary data for selumetinib showed favorable clinical activity in pediatric patients with neurofibromatosis type 1 (NF1) and plexiform neurofibromas (PNs)."


Editor's note: This article discusses a melanoma treatment that combines two durgs: binimetinib (aka MEK162) and selumetinib. A clinical trial recently found that the combo shows promise for melanoma patients whose tumors have mutations in the NRAS gene, as detected by molecular testing. Binimetinib is also being tested as a potential treatment for patients whose tumors have mutations in the BRAF gene.

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Array BioPharma  |  Jun 2, 2014

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10 Issues to Consider During National Skin Cancer Awareness Month

10 Issues to Consider During National Skin Cancer Awareness Month | Melanoma Dispatch | Scoop.it

"Accounting for approximately half of all cancers in the United States, skin cancer is widely recognized as the most common cause of cancer nationwide. More than 3.5 million cases of skin cancer are diagnosed each year, and according to the Skin Cancer Foundation, incidences of skin cancer outnumber all combined cases of breast, colon, lung and prostate cancers.


"With the month of May designated as National Skin Cancer Awareness Month, HemOnc Today highlights 10 issues for oncologists and dermatologists to consider for their patients, as well as the new guideline revisions and research regarding the identification, treatment and management of patients with melanoma and skin cancer."

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Healio  |  May 15, 2014

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UPDATE 1-EU Agency Backs Approval of New GlaxoSmithKline Melanoma Drug

"GlaxoSmithKline's melanoma drug Mekinist - one of several drugs being sold to Novartis under an asset swap deal - has been recommended for approval by European regulators.


"The European Medicines Agency (EMA) said on Friday its experts had backed the drug, also known as trametinib, as a treatment for unresectable or metastatic melanoma in patients with a mutation of a gene known as BRAF."

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Reuters  |  Apr 25, 2014

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A Bad Penny: Cancer's Thirst for Copper Can be Targeted

A Bad Penny: Cancer's Thirst for Copper Can be Targeted | Melanoma Dispatch | Scoop.it

"Drugs used to block copper absorption for a rare genetic condition may find an additional use as a treatment for certain types of cancer, researchers at Duke Medicine report.


"The researchers found that cancers with a mutation in the BRAF gene require copper to promote tumor growth. These tumors include melanoma, the most dangerous form of skin cancer that kills an estimated 10,000 people in the United States a year, according to the National Cancer Institute...


"Already, a clinical trial has been approved at Duke to test the copper-reducing drugs in patients with melanoma, although enrollment has not yet begun."


Editor's note: The scientists hypothesize that copper-reducing drugs might help fight melanoma tumors with BRAF mutations, as detected by molecular testing.

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Medical Xpress  |  Apr 9, 2014

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New Treatments for Advanced Melanoma Presented at AAD

New Treatments for Advanced Melanoma Presented at AAD | Melanoma Dispatch | Scoop.it

"In recent years, the FDA has approved new drugs for the treatment of advanced melanoma, which has presented new ways to treat the disease, according to a presentation at the American Academy of Dermatology annual meeting.


“ 'In the last four years there have been four new drugs that have been FDA-approved for melanoma and what’s even more exciting is that they really speak to two new ways to treating melanoma,' Allan C. Halpern, MD, MSc, chief of dermatology service at Memorial Sloan-Kettering Cancer Center, told Healio.com.


"The most recent FDA approval, in January, was the combination of a BRAF inhibitor and a MEK inhibitor for treating advanced melanoma."

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Healio  |  Mar 23, 2014

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‘Real World’ Safety Study of Vemurafenib in BRAF V600–Mutated Metastatic Melanoma Shows Similar Safety Profile as Pivotal Trials

‘Real World’ Safety Study of Vemurafenib in BRAF V600–Mutated Metastatic Melanoma Shows Similar Safety Profile as Pivotal Trials | Melanoma Dispatch | Scoop.it

"As reported in The Lancet Oncology by Larkin et al, interim results of a safety study designed to reflect the spectrum of patients encountered in routine practice suggest that vemurafenib (Zelboraf) has a safety profile in patients with BRAF V600–mutated metastatic melanoma similar to that observed in the more select patient population included in registration trials. The study included patients with limited treatment options and sizable proportions with brain metastases, elevated lactate dehydrogenase (LDH), poor performance status, and age ≥ 75 years."


Editor's Note: The important takeaway from this story is that the drug vemurafenib can be used safely and effectively in some melanoma patients with poor prognoses, who may not fit the profile of patients typically enrolled in clinical trials to test the drug. To learn more about clinical trials and "targeted therapies" like vemurafenib, visit our Melanoma Basics.

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The ASCO Post  |  Mar 5, 2014

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Extended Follow-up in BRIM-3 Shows Prolonged Survival With Vemurafenib in BRAF V600E/K Mutation–Positive Melanoma

Extended Follow-up in BRIM-3 Shows Prolonged Survival With Vemurafenib in BRAF V600E/K Mutation–Positive Melanoma | Melanoma Dispatch | Scoop.it

"In the BRIM-3 trial, vemurafenib (Zelboraf) was associated with improved progression-free and overall survival vs dacarbazine in patients with advanced BRAF V600 mutation–positive melanoma. In an extended follow-up reported in The Lancet Oncology, McArthur et al found that superior survival outcomes were maintained and were present in both theBRAF V600E and BRAF V600K mutation subgroups."


Editor's note: Read more about vemurafenib here: http://www.nlm.nih.gov/medlineplus/druginfo/meds/a612009.html

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The ASCO Post  |  Feb 12, 2014

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US FDA OKs Combo Treatment for Melanomas with BRAF Mutations

US FDA OKs Combo Treatment for Melanomas with BRAF Mutations | Melanoma Dispatch | Scoop.it

Good news for people with melanomas that have BRAF mutations — the US Food and Drug administration just greenlighted using two targeted treatments at the same time. The two targeted treatments are the BRAF inhibitor Tafinlar (dabrafenib) and the MEK inhibitor Mekinist (trametinib), and both were previously FDA-approved for separate use. Melanomas often become resistant to BRAF inhibitors, and adding the MEK inhibitor could prevent or stave off this resistance.

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Reuters  |  Jan 9, 2014

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Overcoming Resistance to BRAF Inhibitors May Take Two More Drugs

Overcoming Resistance to BRAF Inhibitors May Take Two More Drugs | Melanoma Dispatch | Scoop.it

We already knew that melanomas can resist BRAF inhibitor drugs by activating a particular cancer pathway (a group of proteins in a cell that work together to control cell multiplication, which can lead to tumor growth)—but new research shows that this resistance can also be caused by activating a second cancer pathway. The first pathway is called MAPK and the second is called PI3K-PTEN-AKT. The researchers studied 100 melanomas that resisted the BRAF inhibitors vemurafenib or dabrafenib, and found that 70% had mutations in the first pathway, while 22% had mutations in the second pathway. Moreover, mutations in both pathways could occur in the same tumor, suggesting that thwarting resistance to BRAF inhibitors may require targeting both pathways with a combination treatment.

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Cancer Discovery│Nov 21, 2013

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New Test May Show When BRAF Inhibitors Work

New Test May Show When BRAF Inhibitors Work | Melanoma Dispatch | Scoop.it

Even though about half of melanomas have BRAF mutations, some of these still fail to respond to BRAF inhibitors. Now, there may be a way to tell whether BRAF inhibitors are working, according to findings presented at the 2013 International Conference on Molecular Targets and Cancer Therapeutics. The researchers found that a BRAF inhibitor kept tumors from growing in six out of nine people with BRAF-mutant melanomas, and that those who benefitted from the treatment also had less activation of a protein called S6 at 2 weeks. If this link is verified in large clinical trials, S6 activation levels could predict BRAF inhibitor effectiveness during the early stages of treatment.

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American Association for Cancer Research | Oct 22, 2013

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New Drug May Overcome Cancer Treatment Resistance

An experimental drug could keep melanomas and breast cancer from resisting targeted therapies, according to findings reported at the 2013 International Conference on Molecular Targets and Cancer Therapeutics. Called LEE011, the new drug inhibits proteins called cyclin-dependent kinases (CDKs), which make cells divide. The targeted CDKs are abnormally active in many cancers, including melanomas with BRAF mutations and breast cancers with PIK3CA mutations. The researchers found that LEE011 keeps cultured tumor cells from dividing and that combining the drug with targeted treatments prevents resistance in melanomas and breast cancer in mice. Now, these combination treatments are being tested in several phase I clinical trials on a variety of cancers in adults, as well as in children.

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American Association for Cancer Research │Oct 20, 2013

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How to Control Other Cancers Caused by Targeted Treatments for Melanoma

While effective against melanomas with BRAF mutations, BRAF inhibitors can also cause other cancers such as squamous cell carcinoma and RAS-mutant leukemia. In an overview of the field, researchers say that people treated with BRAF inhibitors may need long-term follow-ups. The researchers also suggest combining BRAF inhibitors with treatments that target the other cancers. These include MEK inhibitors, which control some but not all of the other cancers. In addition, people treated with BRAF inhibitors may need more aggressive screening if they have a family history of colorectal cancer.


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Nature Reviews Clinical Oncology│Aug 14, 2013

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Viral Drug Helps Shrink Melanomas in Early Trial

Initial results of a phase II trial suggest that melanoma tumors shrink when treated with both chemotherapy and an experimental drug called Reolysin. Developed by the pharmaceutical firm Oncolytics Biotech, Reolysin is a virus that that doesn't harm healthy cells, but kills cancer cells with RAS mutations, which have defective antiviral defenses. The researchers treated 14 melanoma patients with the drug combination and found that tumors shrank in 3 of them and did not get bigger in 7 more. Next, the researchers will test Reolysin combined with drugs that target melanomas with BRAF mutations.

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Oncolytics Biotech│May 22, 2013

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Combination Dabrafenib/Trametinib Increased PFS in BRAF-Positive Melanoma

Combination Dabrafenib/Trametinib Increased PFS in BRAF-Positive Melanoma | Melanoma Dispatch | Scoop.it

"Data from a phase 3 trial demonstrate combination dabrafenib and trametinib was superior to dabrafenib plus placebo for improved PFS in patients with BRAFV600-positive metastatic melanoma, according to data presented here at the ASCO Annual Meeting.


“ 'This is the first melanoma trial, phase 3, to have an active control arm,' researcher Georgina V. Long, BSc, PhD, MBBS, FRCP, oncologist at Melanoma Institute Australia at the University of Sydney, said of the COMBI-D trial."


Editor's note: This story describes the results of a clinical trial, in which volunteer patients are help test a new treatment. The treatment consists of a combination of the targeted therapy drugs dabrafenib and trametinib. Patients treated with the combination lived longer without progression of their cancer than patients who received dabrafenib plus a non-active placebo. Importantly, these results are specific to patients whose tumors have "BRAF V600E" mutations, which doctors can detect via molecular testing.

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Healio  |  Jun 2, 2014

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Dabrafenib Improved Quality of Life in Patients with Metastatic Melanoma

Dabrafenib Improved Quality of Life in Patients with Metastatic Melanoma | Melanoma Dispatch | Scoop.it

"Patients with metastatic melanoma treated with dabrafenib demonstrated improved quality of life compared with those who received dacarbazine, according to phase 3 study results.


"Initial analyses of the BREAK-3 trial indicated dabrafenib (Tafinlar; GlaxoSmithKline) prolonged median PFS compared with dacarbazine (DTIC) in patients with BRAFV600E-mutant metastatic melanoma (5.1 months vs. 2.7 months; HR=0.30; 95% CI, 0.18-0.53)."

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Healio  |  May 2, 2014

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Binimetinib Continues To Advance In Clinical Development

Binimetinib Continues To Advance In Clinical Development | Melanoma Dispatch | Scoop.it

"Three Phase 3 trials with binimetinib continue to enroll in advanced cancer patients:  NRAS-mutant melanoma (NEMO / NCT01763164), low-grade serous ovarian cancer (MILO / NCT01849874) and BRAF-mutant melanoma (COLUMBUS / NCT01909453).  NRAS-mutant melanoma represents the first potential indication for binimetinib, with a projected regulatory filing from the NRAS-mutant melanoma study estimated to be in 2015."


Editor's note: This is a press release from a company that is testing a new potential treatment for melanoma called binimetinib, or "MEK162." The drug is being tested in clinical trials (learn more about clinical trials). One of the trials is enrolling melanoma patients whose tumors have mutations in the NRAS gene, as detected by molecular testing. Another is enrolling patients with BRAF mutations.

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Array Biopharma  |  Apr 23, 2014

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Conference Abstract - MAP Kinase Pathway Alterations in BRAF-Mutant Melanoma Patients With Acquired Resistance to Combined RAF/MEK Inhibition

Conference Abstract - MAP Kinase Pathway Alterations in BRAF-Mutant Melanoma Patients With Acquired Resistance to Combined RAF/MEK Inhibition | Melanoma Dispatch | Scoop.it

"Treatment of BRAF-mutant melanoma with combined dabrafenib and trametinib, which target RAF and the downstream MAP–ERK kinase (MEK)1 and MEK2 kinases, respectively, improves progression-free survival and response rates compared with dabrafenib monotherapy. Mechanisms of clinical resistance to combined RAF/MEK inhibition are unknown. This study represents an initial clinical genomic study of acquired resistance to combined RAF/MEK inhibition in BRAF-mutant melanoma, using WES and RNA-seq. The presence of diverse resistance mechanisms suggests that serial biopsies and genomic/molecular profiling at the time of resistance may ultimately improve the care of patients with resistant BRAF-mutant melanoma by specifying tailored targeted combinations to overcome specific resistance mechanisms."


Editor's note: We previously covered the benefits of a dabrafenib/trametinib combo for advanced-stage melanoma. However, some patients' tumors become resistant to this drug combination and new treatment routes need to be considered. This study is exploring how molecular testing of specific genetic mutations in patients' tumors might be used to help guide treatment decisions after they become resistant to the dabrafenib/trametinib combo.

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MDLinx  |  Apr 8, 2014

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Immunotherapy, BRAF Inhibitor Sequence Affected Outcomes in Metastatic Melanoma

Immunotherapy, BRAF Inhibitor Sequence Affected Outcomes in Metastatic Melanoma | Melanoma Dispatch | Scoop.it

"Prior treatment with immunotherapy did not limit response to BRAF inhibitors among patients with metastatic melanoma, according to results of a retrospective study.


"However, patients who underwent initial treatment with BRAF inhibitors and subsequently received immunotherapy with ipilimumab (Yervoy, Bristol-Myers Squibb) demonstrated poorer outcomes, results showed.


"Patients with BRAF-positive metastatic melanoma have several treatment options, including BRAF inhibitors vemurafenib (Zelboraf, Hoffmann-La Roche) and dabrafenib  (Taflinar, GlaxoSmithKline), the MEK inhibitor trametinib (Mekinist, GlaxoSmithKline), and the immunotherapy agents ipilimumab and interleukin-2. Yet, there are limited data with regard to optimal sequencing, according to researchers."

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Healio  |  Mar 14, 2014

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Krishan Maggon 's curator insight, March 15, 2014 4:19 AM

Prior treatment with BRAF inhibitors reduced subsequent response to immunotherapy. Prior treatment with ipilimumab had no effect on response to BRAF inhibitors.

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Blocking Autophagy with Malaria Drug May Help Overcome Resistance to Melanoma BRAF Drugs

Blocking Autophagy with Malaria Drug May Help Overcome Resistance to Melanoma BRAF Drugs | Melanoma Dispatch | Scoop.it

"Half of melanoma patients with the BRAF mutation have a positive response to treatment with BRAF inhibitors, but nearly all of those patients develop resistance to the drugs and experience disease progression.


"Now, a new preclinical study published online ahead of print in the Journal of Clinical Investigation from Penn Medicine researchers found that in many cases the root of the resistance may lie in a never-before-seen autophagy mechanism induced by the BRAF inhibitors vermurafenib and dabrafenib. Autophagy is a process by which cancer cells recycle essential building blocks to fuel further growth. Block this pathway with the antimalarial drug hydroxycholoroquine [sic] (HCQ), the authors found, and the BRAF inhibitors will be able to do their job better...


"Based on these promising preclinical results, Dr. Amaravadi and his team have already launched a clinical trial for patients with advanced BRAF mutant melanoma to see how well-tolerated HCQ is with the BRAF inhibitor vemurafenib. 'So far,' he said, 'we are seeing a benefit to patients and low toxicity.' "

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Medical Xpress  |  Feb 24, 2014

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Trial Supports Recent US FDA Approval of New Melanoma Combo Treatment

Trial Supports Recent US FDA Approval of New Melanoma Combo Treatment | Melanoma Dispatch | Scoop.it

The US Food and Drug Administration just granted accelerated approval for a treatment that combines two drugs that target melanomas with BRAF mutations — but this was contingent results of an ongoing phase III clinical trial. The drugs are the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist). Now the latest results of the trial are in and they look good. This combination treatment is not approved elsewhere in the world, and the trial included 423 people from Australia, Europe, and North and South America. Final results are expected later this year and will be presented at a scientific meeting. In addition, another trial is comparing this combination treatment to the BRAF inhibitor vemurafenib (Zelboraf), which is also FDA-approved.

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GlaxoSmithKline │ Jan 24, 2014

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New Targetable Genetic Abnormalities Found in Melanomas

New Targetable Genetic Abnormalities Found in Melanomas | Melanoma Dispatch | Scoop.it

More than one-third of melanomas are 'pan-negative,' meaning they lack known mutations that can be targeted for treatment. But now researchers have identified two new genetic abnormalities in pan-negative melanomas. These abnormalities consist of the BRAF gene joined with another gene (PAPSS1 or TRIM24), and so are called BRAF fusions. The new study showed that about 8% of pan-negative melanomas have BRAF fusions. Next, the researchers grew melanoma cells with these BRAF fusions in the lab and tested known targeted treatments on them. While these cultured cells were not sensitive to the BRAF inhibitor vemurafenib, they were sensitive to the MEK inhibitor trametinib, suggesting that MEK inhibitors could be used to target melanomas with these BRAF fusions.

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Clinical Cancer Research │Dec 15, 2013

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New Test May Reveal When Melanomas Resist Targeted Therapies

New Test May Reveal When Melanomas Resist Targeted Therapies | Melanoma Dispatch | Scoop.it

Melanomas with BRAF mutations often become drug-resistant, but now researchers think they know how to tell who will benefit from continued treatments. The researchers studied BRAF-mutant melanomas in nine people before and after targeted treatment, and found that tumors were less likely to grow when a protein called S6 was not activated. Next, the researchers developed a way to monitor S6 — and so tumor response —in treated melanomas in real-time. Their method entails fine-needle aspiration, which is far less invasive than conventional biopsies and could potentially replace the serial biopsies currently done to test for tumor resistance.

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HemOnc Today │ Nov 11, 2013

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Better Way to Detect BRAF Mutations

Better Way to Detect BRAF Mutations | Melanoma Dispatch | Scoop.it

A new test for BRAF mutations outshines the standard method, according to results reported at the 2013 International Conference on Molecular Targets and Cancer Therapeutics. There are more than 30 known different versions of BRAF mutations, which occur mostly in melanomas but are also found in other types of cancer. The standard test for BRAF mutations requires a lot of sample preparation and usually takes 3 to 4 weeks. In contrast, the new test—called MDx—skips sample preparation and gives accurate results in as little as 90 minutes. Ultimately, the researchers plan to extend this approach to other cancer mutations with U.S. Food and Drug Administration (FDA)-approved targeted therapies.

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American Association for Cancer Research│Oct 22, 2013

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Why Melanoma Strikes Redheads

Why Melanoma Strikes Redheads | Melanoma Dispatch | Scoop.it

People with red hair and very fair skin are 10 to 100 times more likely to get melanoma—and new research pins this on a mutated protein. The normal protein, called MC1R, helps suppress tumors. But, in a lab, cells with the mutant protein divided abnormally fast after exposure to ultraviolet (UV) radiation, which is a risk factor for melanoma. This abnormal cell division is driven by a known cancer pathway, opening the way to developing targeted treatments for redheads with melanomas. Underscoring the urgency, the researchers found that this cancer pathway was even more active in cells with both the mutant 'redhead' protein and the BRAF mutation found in nearly 70% of melanomas.

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Medical Xpress│Aug 22, 2013

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New Combination Treatment May Target Melanomas with BRAF Mutations Safely

New Combination Treatment May Target Melanomas with BRAF Mutations Safely | Melanoma Dispatch | Scoop.it

While melanomas with BRAF mutations can be targeted with a combination of BRAF inhibitors and MEK inhibitors, the treatment can have side effects such as fever, light sensitivity, and rashes. But early results of a phase I clinical trial suggest that BRAF-mutant melanomas could be treated safely and effectively with a new combination: LGX818, a BRAF inhibitor developed by Novartis and MEK162, a MEK inhibitor developed by Array BioPharma. Moreover, using these drugs together may decrease common side effects of targeted BRAF treatments, including skin toxicities and muscle and joint pain. A phase III trial of this new combination treatment is expected to begin later in 2013.

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Array Biopharma│Jun 3, 2013

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