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Scientists Find New Way to Combat Drug Resistance in Skin Cancer

Scientists Find New Way to Combat Drug Resistance in Skin Cancer | Melanoma Dispatch | Scoop.it

"Rapid resistance to vemurafenib – a treatment for a type of advanced melanoma, the deadliest form of skin cancer – could be prevented by blocking a druggable family of proteins, according to research published in Nature Communications today.


"Scientists at the Cancer Research UK Manchester Institute, based at the University of Manchester, have revealed the MLK family of four enzymes 'undoes' the tumour-shrinking effects of vemurafenib."


Editor's note: This story describes a potential new way to treat melanoma that has become resistant to vemurafenib. While promising, the research is still in preliminary stages, so new treatments are not yet available for patients.

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Medical Xpress  |  May 22, 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 Melanoma Combo Treatment Is Promising in Early Trial

Because melanomas can quickly resist BRAF inhibitor drugs alone or in combination with MEK inhibitors, researchers are testing a new combination treatment: the BRAF inhibitor vemurafenib and PX-866, which inhibits a cancer pathway called PI3K. In a phase I/II clinical trial of 19 people with melanomas that have BRAF mutations, the vemurafenib/PX-866 combination shrank tumors in 10 of them. These findings were presented at the 10th International Congress of the Society for Melanoma Research in Philadelphia. However, while results so far are encouraging, it will take larger trials to see if this new combo treatment really overcomes drug resistance in melanomas. This ongoing trial is still accepting new participants.

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Cancer Network  |  Nov 25, 2013

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New Immunotherapy Is Promising in Early Trial

New Immunotherapy Is Promising in Early Trial | Melanoma Dispatch | Scoop.it

Blocking a protein that protects tumor cells may shrink melanomas, according to results from an ongoing trial that were presented at the 10th International Congress of the Society for Melanoma Research in Philadelphia, Pennsylvania. Called PD-L1, the protein shields tumor cells from the immune system and it can be blocked by a drug called MPDL3280A. The phase I trial included 45 people with melanoma who were treated with the PD-L1 blocker, and tumors shrank in one-third of them. This PD-L1 blocker is also being tested in a phase I trial in combination with the BRAF inhibitor drug vemurafenib, as well as in several phase II trials against renal cell carcinoma and non-small-cell lung cancer (NSCLC). In addition, two drugs similar to this PD-L1 blocker (nivolumab and MK-3475) are being tested in phase III trials against melanoma.

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Cancer Network│Nov 19, 2013

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New Clinical Trial Tests Combine Targeted Treatment and Immunotherapy for Melanoma

Pharmaceutical company Prometheus Laboratories has launched a phase IV clinical trial of interleukin, which boosts the immune system, combined with vemurafenib, an FDA-approved drug that targets melanomas that have BRAF V600 mutations. Vemurafenib shrinks tumors rapidly at first, but this is temporary, while interleukin can shrink tumors for years, but only in 16% of people with melanoma. The researchers hope that the combination treatment will both work in more people and be longer lasting. The trial will be done in about 25 sites in the U.S. and is currently accepting participants.

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Prometheus Laboratories Inc.│May 9, 2013

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Managing the Side Effects of Vemurafenib

Managing the Side Effects of Vemurafenib | Melanoma Dispatch | Scoop.it

The BRAF inhibitor vemurafenib increases survival in people with melanomas that have BRAFV600E mutations. But vemurafenib can also have side effects, including another kind of skin cancer called squamous cell carcinoma (SCC). A new Annals of Oncology study assessed the side effects of 42 people who were treated with vemurafenib and found that 26% had SCC. Other side effects included rashes, light sensitivity, and lesions on the hands and feet. The researchers recommend that doctors measure the symptoms of these adverse reactions and that patients avoid the sun.

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Annals of Oncology │ Feb 13, 2013

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Researchers Write New Guide to Optimal Treatments for Melanomas with BRAF Mutations

Based on current data, researchers have developed a new treatment guide for melanomas with the most common mutations (BRAF V600). While these melanomas can be targeted with vemurafenib and dabrafenib, challenges remain. Not all tumors respond, some become resistant, and side effects can include another type of skin cancer called squamous cell carcinoma. Other treatment options include trametinib, which targets a protein called MEK, as well as immunotherapies such as high-dose interleukin 2 and ipilimumab, both of which can control tumors completely.

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Lancet Oncology | Feb 1, 2013

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Cost-Benefit Analysis Questions Treating Medicaid Patients with Vemurafenib

The impressive, but still short-term, benefits of vemurafenib for melanoma patients may not justify the hefty cost to a Massachusetts Medicaid program, according to an analysis presented at an American Society of Health-System Pharmacists meeting. Vemurafenib targets the most common mutation of BRAF, which is one of the genes that is most often abnormal in melanomas. The analysis noted that vemurafenib boosted 6-month survival rates over those of the conventional chemotherapy drug dacarbazine (84% and 64%, respectively). However, vemurafenib is also more expensive than dacarbazine, with relative per patient costs estimated at $9,995 and $1,811 per month, respectively. 

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MedPage Today | Dec 7, 2012

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First Report that Vemurafenib Can Trigger Leukemia

A melanoma patient treated with vemurafenib also developed leukemia temporarily, according to a case report in The New England Journal of Medicine. This drug was already known to cause squamous cell skin cancers in some people with melanomas that have BRAF mutations. Vemurafenib activates proteins called extracellular-signal-regulated kinases (ERK), which are involved in cell division and can lead to cancer in cells that have RAS mutations. The leukemia in the vemurafenib-treated patient had a RAS mutation and disappeared after treatment ended. The patient’s melanoma tumors, which did not have a RAS mutation, shrank during treatment.

 

Primary source: http://www.nejm.org/doi/full/10.1056/NEJMoa1208958

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MedPage Today | Nov 8, 2012

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Vemurafenib Boosts Immunotherapy against Melanoma in Mice

Vemurafenib increases the effectiveness of a treatment that uses immune system cells modified to target cancer cells, according to a study in Cancer Research. When combined with vemurafenib, which targets melanomas with the most common BRAF mutations (V600), this immunotherapy treatment killed more melanoma cells in mice. The combination treatment was also more successful than vemurafenib alone. The researchers conclude that their work supports testing this combination treatment in people with melanomas that have BRAF V600 mutations.

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Cancer Research | Jun 12, 2012

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Dabrafenib May Shrink Melanomas in the Brain

An early stage clinical trial suggests that dabrafenib, a BRAF inhibitor, could treat melanomas that have spread to the brain. The study, reported in The Lancet, included 10 people with brain metastases of melanomas that had BRAF mutations. Tumors shrank in 9 patients and were not evident in 4 patients. This is a surprise because the drug had not been expected to cross the blood-brain barrier effectively. Indeed, melanoma patients with brain metastases have been routinely excluded from previous trials of vemurafenib (Zelboraf) and other BRAF inhibitors.

 

Primary source: http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2812%2970269-3/abstract

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MedPage Today | May 18, 2012

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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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‘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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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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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 Combo-Targeted Treatment for Melanoma Wows in Early Trial

New Combo-Targeted Treatment for Melanoma Wows in Early Trial | Melanoma Dispatch | Scoop.it

Results are encouraging in an ongoing clinical trial of a BRAF inhibitor combined with a MEK inhibitor, according to a presentation at the 2013 European Cancer Congress in Amsterdam, Netherlands. The BRAF inhibitor is vemurafenib, which is approved by the U.S. Food and Drug Administration (FDA), and the MEK inhibitor is cobimetinib (GDC-0973/XL518), which is experimental. The phase I trial has 128 people with melanomas that have BRAFV600 mutations; about half had been treated with BRAF inhibitors previously, while the other half had not. Tumors shrank in 15% of participants and didn't grow in 43% of those who had been previously treated with BRAF inhibitors. Even better, tumors disappeared in 10%, shrank in 75%, and didn't grow in 13% of those who had not been previously treated with BRAF inhibitors.

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Business Wire│Sep 28, 2013

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First Evidence That Taking Breaks from Treatment May Prevent Vemurafenib Resistance in People

The drug vemurafenib targets melanomas with BRAF mutations, but treatment usually stops working after just 6 to 8 months because tumors become drug-resistant. However, resistance could be avoided by giving people periodic breaks from treatment, suggests work presented at the 2013 meeting of the American Association for Cancer Research. The researchers found that stopping treatment slowed tumor growth in 14 out of 19 people with vemurafenib-resistant melanomas. They also found that intermittent treatment (4 weeks on and 2 weeks off) prevented vemurafenib resistance in human melanomas implanted in mice. This strengthens the researchers' previous work showing that vemurafenib-resistant melanomas actually depend on the drug to grow.

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American Association for Cancer Research │ Apr 7, 2013

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Genentech Adds MEK Inhibitor to Phase III BRAF Inhibitor Trial

Biotech company Genentech has added a MEK inhibitor to a phase III trial of vemurafenib, an FDA-approved BRAF inhibitor. MEK inhibitors have been shown to counteract resistance to BRAF inhibitors. The experimental MEK inhibitor is called GDC-0973 and is also known as XL-518 or RG7421. Vemurafenib (Zelboraf®) targets melanomas with BRAF V600 mutations, which are found in about half of these aggressive skin cancers. Genentech is part of the Roche Group and the two companies are conducting this combination treatment trial jointly.

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US Securities and Exchange Commission filing │ Jan 14, 2013

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Treatment Breaks May Delay or Prevent Vemurafenib Resistance

Giving melanoma patients a break from vemurafenib could make this treatment more effective. Research in Nature shows that vemurafenib-resistant tumors keep growing during treatment because they produce high levels of mutated BRAF proteins, which are involved in cell division. Moreover, these tumors actually depend on the drug to grow. In contrast, an on-and-off treatment schedule can help keep melanomas from becoming resistant to vemurafenib in mice.

 

Primary source: http://www.nature.com/nature/journal/vaop/ncurrent/full/nature11814.html

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CancerNetwork | Jan 9, 2013

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Vemurafenib Extends Life up to 3 Years in Melanoma Trial

An ongoing clinical trial found that 26% of melanoma patients treated with vemurafenib (Zelboraf®) were alive at 3 years—far longer than the average survival time of 9 months with conventional chemotherapy. Vemurafenib is a BRAF inhibitor and this trial includes 32 people with the most common BRAF mutation (V600E). In addition, 5 people survived at 3 years and 4 months; 3 of them had no evidence of disease. 

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Drugs.com | Nov 9, 2012

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UK Health Institute Approves Vemurafenib and Ipilimumab for Melanomas

UK Health Institute Approves Vemurafenib and Ipilimumab for Melanomas | Melanoma Dispatch | Scoop.it

The National Institute for Health and Clinical Excellence recommends giving people in England and Wales access to vemurafenib and ipilimumab via the National Health Service. The FDA has already approved these drugs for treating metastatic melanoma in the U.S. Initially, the cost of these treatments was a stumbling block in the UK and the watchdog institute’s recommendation comes with the caveat that manufacturers must provide a discount to the NHS. 

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The Independent | Nov 2, 2012

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Scans May Reveal Early Drug Resistance in Melanomas

Preliminary results suggest that an imaging technique can give early signs of drug resistance in melanomas. A Journal of Clinical Oncology study found that PET/CT scans correlated with standard measures of tumor response in seven melanoma patients treated with vemurafenib. The scans also showed that during the third and fourth weeks of treatment, tumors in three patients began to take up and metabolize more of a sugar. This is a sign of cell activity, suggesting that these tumors were starting to resist the drug.

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Journal of Clinical Oncology | May 2012

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