Fighting Melanoma's Resistance To Chemotherapy

Blocking the action of a particular protein in our skin could improve the treatment of skin cancers, according to a study published in Oncogene by Philippe Roux, a researcher at the University of Montreal's Institute for Research in Immunology and Cancer (IRIC). "Our findings reveal part of the mechanisms responsible for the resistance of melanoma to anti-cancer treatments, and suggest that a particular protein in our bodies called RSK may be targeted in combination therapies to overcome drug resistance," Roux explained.

Although melanoma accounts for only 4% of all skin cancers, it is responsible for 80% of skin cancer-related deaths worldwide as it is highly invasive and resistant to conventional chemotherapies. Melanoma originates from pigment-producing cells, called melanocytes, located in the skin. The incidence of malignant melanoma is growing rapidly worldwide and there is still no effective therapy to treat it. Approximately 160,000 new cases of the disease are diagnosed each year.

Roux and his team focused their research on a signaling pathway called Ras/MAPK, which is often deregulated in melanoma, but also in lung, colon and pancreatic cancers. A signaling pathway is a chemical chain reaction that causes the cells in our bodies to act in a certain way. In this study, Roux and his team found that a protein in the Ras/MAPK pathway, RSK, contributes to chemoresistance by altering the response of cancer cells to chemotherapeutic agents.

This is the second Oncogene publication for Philippe Roux this year. In a paper published in July, Roux and his colleagues, IRIC Principal Investigators Katherine Borden and Sylvain Meloche, demonstrated that the same protein involved in chemoresistance contributes to melanoma growth, making the protein RSK a promising therapeutic target for treating the disease.

Fighting Melanoma's Resistance To Chemotherapy

Blocking the action of a particular protein in our skin could improve the treatment of skin cancers, according to a study published in Oncogene by Philippe Roux, a researcher at the University of Montreal's Institute for Research in Immunology and Cancer (IRIC). "Our findings reveal part of the mechanisms responsible for the resistance of melanoma to anti-cancer treatments, and suggest that a particular protein in our bodies called RSK may be targeted in combination therapies to overcome drug resistance," Roux explained.

Although melanoma accounts for only 4% of all skin cancers, it is responsible for 80% of skin cancer-related deaths worldwide as it is highly invasive and resistant to conventional chemotherapies. Melanoma originates from pigment-producing cells, called melanocytes, located in the skin. The incidence of malignant melanoma is growing rapidly worldwide and there is still no effective therapy to treat it. Approximately 160,000 new cases of the disease are diagnosed each year.

Roux and his team focused their research on a signaling pathway called Ras/MAPK, which is often deregulated in melanoma, but also in lung, colon and pancreatic cancers. A signaling pathway is a chemical chain reaction that causes the cells in our bodies to act in a certain way. In this study, Roux and his team found that a protein in the Ras/MAPK pathway, RSK, contributes to chemoresistance by altering the response of cancer cells to chemotherapeutic agents.

This is the second Oncogene publication for Philippe Roux this year. In a paper published in July, Roux and his colleagues, IRIC Principal Investigators Katherine Borden and Sylvain Meloche, demonstrated that the same protein involved in chemoresistance contributes to melanoma growth, making the protein RSK a promising therapeutic target for treating the disease.

View the Original article

Resistance In Melanoma Patients Delayed By Combination Of Targeted Treatment Drugs

Combined treatment with two drugs targeting different points in the same growth-factor pathway delayed the development of treatment resistance in patients with BRAF-positive metastatic malignant melanoma. The results of a phase I/II study of treatment with the kinase inhibitors dabrafenib and trametinib were published in the New England Journal of Medicine and released online to coincide with a presentation at the European Society for Medical Oncology meeting in Vienna.

"We investigated this combination because of research we and others have conducted into the molecular underpinnings of resistance to BRAF inhibitor therapy," says Keith Flaherty, MD, of the Massachustts General Hospital (MGH) Cancer Center, lead author of the NEJM report and principal investigator of the study. "We found that adding the MEK inhibitor trametinib to BRAF inhibitor dabrafenib clearly delays the emergence of resistance. In fact, the combination was at least twice as effective as BRAF inhibition alone."

In around half of patients with metastatic melanoma, tumor growth is driven by mutations that keep the BRAF protein - part of the MAPK cell growth pathway - constantly activated. In recent years, drugs that inhibit BRAF activity have rapidly halted and reversed tumor growth in about 90 percent of treated patients, but most patients' response is temporary, with tumor growth resuming in six or seven months. Investigations into how this resistance emerges have suggested that the MAPK pathway gets turned back on through activation of MEK, another protein further down the pathway. Based on promising results of animal studies, the current investigation was designed to test whether inhibiting both the BRAF and MEK proteins could delay treatment resistance.

Sponsored by GlaxoSmithKline, the study by researchers at 14 sites in the U.S. and Australia tested two of the company's drugs - BRAF inhibitor dabrafenib and MEK inhibitor trametinib, both oral medications currently being evaluated by the FDA as single-agent therapeutics - in adult patients with BRAF-expressing malignant melanoma. Phase I testing confirmed that there were no drug-to-drug interactions between the two agents and evaluated the safety of different dose combinations. In the open-label phase II portion of the study, 162 patients were randomized into three groups that received different dose combinations: two daily 150 mg doses of dabrafenib plus one 2 mg trametinib dose, the same dabrafenib dose with a 1 mg dose of trametinib, or treatment with dabrafenib alone. Participants receiving dabrafenib alone were able to cross over to the full-dose combination treatment if their cancer resumed progression.

Treatment with both combination regimens led to a significant delay - about four months longer than with dabrafenib alone - in the emergence of resistance. After one year of treatment, 41 percent of those receiving full-dose combination treatment had no progression of their cancer, compared with only 9 percent of those receiving one drug. The occurrence of side effects such as skin rash and the development of squamous cell carcinoma, a less malignant skin cancer, was similar to that typically seen when only one of the two drugs is used, and some side effects were less frequent with the combination therapy.

Noting that the tested combination, now being tested in a larger Phase III study, delayed but did not prevent resistance in most participants, Flaherty says, "We need to continue focusing on resistance mechnisms occuring with this combination approach so we can better understand how to treat patients once resistance emerges or to develop other combination regimens to further prevent relapse. We also need to see if this approach could serve as an effective adjuvant therapy used following surgery to prevent recurrence. That might have the biggest impact on patients." Flaherty is an associate professor of Medicine at Harvard Medical School.

View the Original article

Researchers Find Cause Of Chemotherapy Resistance In Melanoma

Researchers with UC Irvine's Chao Family Comprehensive Cancer Center have identified a major reason why melanoma is largely resistant to chemotherapy.

UCI dermatologist Dr. Anand Ganesan and colleagues found a genetic pathway in melanoma cells that inhibits the cellular mechanism for detecting DNA damage wrought by chemotherapy, thereby building up tolerance to cancer-killing drugs.

Targeting this pathway, comprising the genes RhoJ and Pak1, heralds a new approach to treating the deadly skin cancer, which claims nearly 10,000 U.S. lives each year. Study results appear online in Cancer Research, a journal of the American Association for Cancer Research.

"If we can find a way to turn off the pathway responsible for this resistance, melanoma tumors would suddenly become sensitive to therapies we've been using for the last 20 years," said Ganesan, assistant professor of dermatology and biological chemistry at UCI.

In pursuit of a cause for the chemo tolerance, he and his colleagues performed a genome-wide scan for genes controlling drug resistance in melanoma cells. Their search identified RhoJ, a gene normally involved in blood vessel growth. They saw that in response to drug-induced DNA damage in a melanoma cell, RhoJ activated another gene, Pak1, which initiated a molecular cascade suppressing the cell's ability to sense this damage - and blocking the apoptosis process.

"Normally, such drug-induced DNA damage would result in cell death," Ganesan said. "But this blunting of DNA damage response allows melanoma cells to mutate and proliferate. Being capable of rapid adaptation and change is a hallmark feature of this challenging form of cancer and makes it very difficult to treat."

On the heels of this discovery, he and colleagues have begun exploring methods to inhibit the genes responsible for this DNA damage tolerance. What they come up with could one day supplement chemotherapy treatments for melanoma, Ganesan added.

View the Original article

Resistance In Melanoma Patients Delayed By Combination Of Targeted Treatment Drugs

Combined treatment with two drugs targeting different points in the same growth-factor pathway delayed the development of treatment resistance in patients with BRAF-positive metastatic malignant melanoma .

Share