Melanoma: A 2013 ‘Progress Report’


The past year saw some remarkable advances in melanoma clinical research and treatment. This feature explores the most notable melanoma news of 2013: Continue reading…


Patient’s Perspective: Erin Youngerberg’s Take on Melanoma


Erin Youngerberg was diagnosed with melanoma in October, 2010, at age 32 years. Well-traveled and an avid photographer, she grew up in Minnesota, went to college and worked in Milwaukee, then made her way east, living in Ohio and North Carolina before ending up in Jersey City, just outside of New York City. After her diagnosis, she started a blog to keep folks back home updated. Called ‘Melanoma and the City,’ it tells the whole story: from appointments at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City to various city adventures; from treatment side effects to recipes for quinoa and tacos. Erin has also found herself dedicated to spreading the word about melanoma awareness. We asked her to take us through her melanoma story. Continue reading…


Therapeutic Destruction of Insulin Receptor Substrates for Cancer Treatment

“Insulin receptor substrates 1 and 2 (IRS1/2) mediate mitogenic and antiapoptotic signaling from insulin-like growth factor 1 receptor (IGF-IR), insulin receptor (IR), and other oncoproteins. IRS1 plays a central role in cancer cell proliferation, its expression is increased in many human malignancies, and its upregulation mediates resistance to anticancer drugs. IRS2 is associated with cancer cell motility and metastasis. Currently, there are no anticancer agents that target IRS1/2. We present new IGF-IR/IRS-targeted agents (NT compounds) that promote inhibitory Ser-phosphorylation and degradation of IRS1 and IRS2. Elimination of IRS1/2 results in long-term inhibition of IRS1/2-mediated signaling. The therapeutic significance of this inhibition in cancer cells was shown while unraveling a novel mechanism of resistance to B-RAFV600E/K inhibitors. We found that IRS1 is upregulated in PLX4032-resistant melanoma cells and in cell lines derived from patients whose tumors developed PLX4032 resistance. In both settings, NT compounds led to the elimination of IRS proteins and evoked cell death. Treatment with NT compounds in vivo significantly inhibited the growth of PLX4032-resistant tumors and displayed potent antitumor effects in ovarian and prostate cancers. Our findings offer preclinical proof-of-concept for IRS1/2 inhibitors as cancer therapeutics including PLX4032-resistant melanoma. By the elimination of IRS proteins, such agents should prevent acquisition of resistance to mutated-B-RAF inhibitors and possibly restore drug sensitivity in resistant tumors.”


Liver Toxicity Halts Melanoma Study

Unexpected liver toxicity derailed a phase I melanoma trial of concurrent treatment with the first two targeted agents approved for the disease, according to a brief communication from investigators.


Ipilimumab Could Treat Small Melanomas in the Brain

A study in The Lancet shows that the drug ipilimumab could treat melanomas that have spread to the brain, particularly in people who do yet not have neurological symptoms. Of 51 such patients treated with ipilimumab, 12 had tumors in the brain that shrank or did not get worse and 14 had tumors outside the brain that shrank or did not get worse. Ipilimumab (Yervoy) is an immune system booster that the FDA has approved for treating advanced melanomas.

Primary source: http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2812%2970090-6/abstract


Drug Targets Two Common Melanoma Mutations

An experimental drug could help control some melanomas that have BRAF or NRAS mutations, according to a report at an American Society of Clinical Oncology meeting. Tumors shrank or did not get worse in 8 out of 35 patients with the most common BRAF mutation (V600E), and in 6 out of 28 patients with NRAS mutations. This is the first targeted treatment for melanomas that have NRAS mutations. BRAF and NRAS mutations can activate a protein called MEK that is involved in cell division. The experimental drug, which is called MEK162, is a MEK inhibitor. The side effects of MEK162, which included diarrhea, rashes and swelling, were manageable.


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


Trametinib Outperforms Chemotherapy for Melanomas with BRAF Mutations

A New England Journal of Medicine study reports a promising new approach to treating melanomas with BRAF mutations, which often respond to BRAF inhibitors for just a short time. Melanoma patients treated with trametinib were stable (ie, did not get worse) for three times longer than those treated with dacarbazine, a conventional chemotherapy drug (4.8 vs. 1.5 months, respectively). Trametinib inhibits MEK, a protein that is activated by BRAF and is involved in cell division. The drug’s most common side effects were rash, diarrhea, and swelling in the legs, which could be controlled by periodically adjusting the dose.

Primary source: http://www.nejm.org/doi/full/10.1056/NEJMoa1203421


New Melanoma Mutation Frequent Enough for Routine Screening

Researchers identified a new mutation (BRAF L597) in a melanoma patient and then tested for it in 49 other melanomas that had no known cancer-linked mutations, which account for about half of all melanomas. They found that BRAF L597 occurred in 4% of the other melanomas tested. The study, which appeared in Cancer Discovery, also showed that tumors with this mutation respond to a MEK inhibitor called TAK-733. The existence of a targeted treatment, coupled with the new mutation’s relatively high incidence, lead the researchers to suggest routinely screening melanomas for BRAF L597.