Diabetes drug points the way to overcoming drug resistance in melanoma

Despite success with BRAFV600E inhibitors, therapeutic responses in patients with metastatic melanoma are short-lived because of the acquisition of drug resistance. Researchers  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. Proteome-profiling revealed an upregulation in enzymes of mitochondrial oxidative-ATP-synthesis (oxidative phosphorylation) in this subpopulation. Inhibition of mitochondrial respiration blocked the emergence of the JARID1B^high subpopulation and sensitized melanoma cells to therapy, independent of their genotype. Our findings support a two-tiered approach combining anticancer agents that eliminate rapidly proliferating melanoma cells with inhibitors of the drug-resistant slow-cycling subpopulation.

Ref: http://www.cell.com/cancer-cell/retrieve/pii/S1535610813001967 

Diabetes drug points the way to overcoming drug resistance in melanoma

Adult cancer drugs show promise against an aggressive childhood brain tumor

Researchers relied on mice with group 3 medulloblastoma grown from patient tumors. The mice were developed in Roussel’s laboratory and are a powerful tool for testing the effectiveness of drugs against human tumors. Researchers used the mice to show that pemetrexed and gemcitabine worked against human group 3 tumors and that the drugs could be used in combination with existing chemotherapy agents to boost treatment effectiveness without undue risk. Cisplatin and cyclophosphamide were the other drugs used in this study.

“The finding provides a strong rationale for combination therapy with pemetrexed and gemcitabine for treatment of group 3 medulloblastoma,” Roussel said. Researchers found no evidence that mouse tumor cells develop resistance to the drugs.

Pemetrexed works by disrupting the ability of cancer cells to proliferate. Gemcitabine kills cells by triggering their suicide pathway. Researchers also found evidence the drugs work specifically against group 3 medulloblastoma. The drugs did not extend survival of mice with a different medulloblastoma subtype.

The study builds on previous St. Jude research that has helped to revolutionize understanding of the origins of medulloblastoma and laid the foundation for a new era of risk-based therapy. The goal is to maximize the likelihood of a cure and minimize long-term side effects. The approach combines clinical factors and the molecular markers associated with the different medulloblastoma subtypes to guide how radiation and chemotherapy are combined with surgery.

Adult cancer drugs show promise against an aggressive childhood brain tumor  

Varubi (rolapitant) approved to prevent delayed phase chemotherapy-induced nausea and vomiting

The U.S. Food and Drug Administration approved Varubi (rolapitant) to prevent delayed phase chemotherapy-induced nausea and vomiting (emesis). Varubi is approved in adults in combination with other drugs (antiemetic agents) that prevent nausea and vomiting associated with initial and repeat courses of vomit-inducing (emetogenic and highly emetogenic) cancer chemotherapy.

Nausea and vomiting are common side effects experienced by cancer patients undergoing chemotherapy. Symptoms can persist for days after the chemotherapy drugs are administered. Nausea and vomiting that occurs from 24 hours to up to 120 hours after the start of chemotherapy is referred to as delayed phase nausea and vomiting, and it can result in serious health complications. Prolonged nausea and vomiting can lead to weight loss, dehydration and malnutrition in cancer patients leading to hospitalization.

"Chemotherapy-induced nausea and vomiting remains a major issue that can disrupt patients' lives and sometimes their therapy," said Amy Egan, M.D., M.P.H., deputy director of the Office of Drug Evaluation III in the FDA's Center for Drug Evaluation and Research. "Today's approval provides cancer patients with another treatment option for the prevention of the delayed phase of nausea and vomiting caused by chemotherapy."

Varubi is a substance P/neurokinin-1 (NK-1) receptor antagonist. Activation of NK-1 receptors plays a central role in nausea and vomiting induced by certain cancer chemotherapies, particularly in the delayed phase. Varubi is provided to patients in tablet form.

The safety and efficacy of Varubi were established in three randomized, double-blind, controlled clinical trials where Varubi in combination with granisetron and dexamethasone was compared with a control therapy (placebo, granisetron and dexamethasone) in 2,800 patients receiving a chemotherapy regimen that included highly emetogenic (such as cisplatin and the combination of anthracycline and cyclophosphamide) and moderately emetogenic chemotherapy drugs. Those patients treated with Varubi had a greater reduction in vomiting and use of rescue medication for nausea and vomiting during the delayed phase compared to those receiving the control therapy.

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Varubi (rolapitant) approved to prevent delayed phase chemotherapy-induced nausea and vomiting