A new drug combination could treat melanomas that resist therapy with a single drug, suggests research that appeared in Cancer Discovery on melanoma cells grown in the laboratory. The researchers tested melanoma cells that had BRAF mutations and resisted treatment with the BRAF inhibitor vemurafenib, and that had NRAS mutations, which resist many treatments. The most effective combination treatment was statins, which are commonly used to treat high cholesterol, but can also kill melanoma cells, and drugs that inhibit proteins called cyclin-dependent kinases, which are involved in cell division.
Treatments that target a protein called MEK could work better when combined with drugs that inhibit a protein called SMURF2, according to research in the British Journal of the National Cancer Institute. MEK is involved in cell division and can be activated by BRAF and NRAS mutations. However, melanomas often resist MEK inhibitors. The researchers found that MEK inhibitors made melanoma cells grown in the laboratory produce too much of a protein called SMURF2. This in turn led to overproduction of another protein called MITF, which protects melanomas against MEK inhibitors. When treated with both a MEK inhibitor called selumetinib and a SMURF2 inhibitor, tumor growth was suppressed by 98% in mice.
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.
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.
A British Medical Journal report questions an invasive, expensive standard practice for melanoma patients in the U.S. Called sentinel node biopsy, the approach involves testing lymph nodes near tumors for cancer cells and removing nodes that test positive. The report cites a 2006 study showing that sentinel node biopsy did not increase 5-year survival rates and calls for further analysis of the practice’s effectiveness. Sentinel node biopsies are not standard in the UK.
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.
A JAMA Surgery study clarified when melanoma is likely to return in people determined to be cancer-free by sentinel lymph node biopsy. The researchers found that melanoma recurred in 16% of 515 such patients and that 4% of them had tumors in the lymph nodes that had been tested. Recurrence was more likely when the initial tumors were on the head or neck and were deeper (2.7 vs. 1.8 mm). Recurrence was less likely in women and in people who were younger when first diagnosed.