Researchers at the Wistar Institute in Philadelphia, Pennsylvania, recently developed a combination approach to target melanoma tumor cells that are particularly resistant to both chemotherapy and targeted therapies, such as vemurafenib. A combination of anti-melanoma drugs with an anti-diabetes drug was better able to target all of the cells in a tumor than the anti-melanoma drugs alone. The combination therapy even proved effective against cells that are usually resistant to therapy and are thought to be responsible for at least some of the resistance patients develop to melanoma treatment. Continue reading…
“Selective BRAF inhibitors have now been established as a standard of care option for patients diagnosed with metastatic melanoma whose tumors carry a BRAF mutation. Their successful development represents a milestone in the treatment of this disease, and has the potential to impact therapy for other malignancies as well. The use of these agents, however, has introduced a number of critical questions regarding the optimal use and selection of patients for BRAF inhibitor therapy. This review discusses the current status of BRAF inhibitor clinical development, the clinicopathologic features of BRAF mutated melanoma, as well as strategies for overcoming resistance.”
“Despite success with BRAFV600E inhibitors, therapeutic responses in patients with metastatic melanoma are short-lived because of the acquisition of drug resistance. We identified a mechanism of intrinsic multidrug resistance based on the survival of a tumor cell subpopulation. Treatment with various drugs, including cisplatin and vemurafenib, uniformly leads to enrichment of slow-cycling, long-term tumor-maintaining melanoma cells expressing the H3K4-demethylase JARID1B/KDM5B/PLU-1.“
“The clinical benefits of BRAF inhibition in patients with advanced-stage BRAF-mutant melanoma are now well established. Although the emergence of cutaneous squamous-cell carcinomas (SCCs) and secondary melanomas in patients on BRAF-inhibitor therapy have been well described, reports are emerging of additional secondary premalignant and malignant events, including RAS-mutant leukaemia, the metastatic recurrence of RAS-mutant colorectal cancer and the development of gastric and colonic polyps.”
Good news for people with melanomas that have spread—the U.S. Food and Drug Administration just approved two new drugs that target tumors with common mutations. The drugs are dabrafenib (Tafinlar), a BRAF inhibitor, and trametinib (Mekinist), an MEK inhibitor. Developed by the pharmaceutical firm GlaxoSmithKline, both drugs target BRAF V600E mutations, which occur in about half of melanoma tumors. In addition, trametinib also targets V600K mutations, which are the next most common BRAF abnormalities. While these drugs have been tested in combination, using them together is not yet approved. The FDA also okayed a new test for the BRAF V600E mutation that is made by diagnostics firm bioMerieux.
“Elevated activity of the mitogen-activated protein kinase (MAPK) signaling cascade is found in the majority of human melanomas and is known to regulate proliferation, survival and invasion. Current targeted therapies focus on decreasing the activity of this pathway; however, we do not fully understand how these therapies impact tumor biology, especially given that melanoma is a heterogeneous disease. Using a three-dimensional (3D), collagen-embedded spheroid melanoma model, we observed that MEK and BRAF inhibitors can increase the invasive potential of ∼20% of human melanoma cell lines…”
“Resistance to BRAF inhibitor therapy places priority on developing BRAF inhibitor-based combinations that will overcome de novo resistance and prevent the emergence of acquired mechanisms of resistance. The CRM1 receptor mediates the nuclear export of critical proteins required for melanoma proliferation, survival and drug resistance. We hypothesize that by inhibiting CRM1-mediated nuclear export, we will alter the function of these proteins resulting in decreased melanoma viability and enhanced BRAF inhibitor anti-tumoral effects…”