Editor’s note: Targeted therapies that fight tumors with specific genetic mutations opened up a new era in cancer treatment, but many patients become resistant to these treatments, and their cancer grows back. A new type of treatment called immunotherapy boosts a patient’s own immune system to fight cancer. Researchers are hopeful that combining targeted drugs with immunotherapy drugs could be highly effective. This article discusses the idea of combining immunotherapy with targeted drugs developed to treat melanomas with mutations in the GRAF gene. It is a scientific article, but may interest some patients and caregivers dealing with BRAF-mutant melanoma.
“Hu–Lieskovan S, et al. – In this review,the authors present the concept and potential mechanisms of combinatorial activity of targeted therapy and immunotherapy, review the literature for evidence to support the combination, and discuss the potential challenges and future directions for rational conduct of clinical trials.
“Recent breakthroughs in the treatment of advanced melanoma are based on scientific advances in understanding oncogenic signaling and the immunobiology of this cancer.
“Targeted therapy can successfully block oncogenic signaling in BRAFV600-mutant melanoma with high initial clinical responses, but relapse rates are also high.
“Activation of an immune response by releasing inhibitory check points can induce durable responses in a subset of patients with melanoma.
“These advances have driven interest in combining both modes of therapy with the goal of achieving high response rates with prolonged duration.
“Combining BRAF inhibitors and immunotherapy can specifically target the BRAFV600 driver mutation in the tumor cells and potentially sensitize the immune system to target tumors.
“However, it is becoming evident that the effects of paradoxical mitogen-activated protein kinase pathway activation by BRAF inhibitors in non–BRAF-mutant cells needs to be taken into account, which may be implicated in the problems encountered in the first clinical trial testing a combination of the BRAF inhibitor vemurafenib with ipilimumab (anti-CTLA4), with significant liver toxicities.”
Among melanomas, BRAF-mutated disease gets the vast majority of attention. Fifty percent of melanomas harbor BRAF mutations, which can be targeted with BRAF inhibitors. However, despite its notoriety, BRAF is not the only important melanoma mutation.
Another melanoma-linked mutation can be found in the NRAS gene. Like BRAF mutations, NRAS mutations are ‘driver mutations’—a tumor with an NRAS mutation is dependent on the mutation for its growth and survival. Continue reading…
Reuveni H, Flashner-Abramson E, Steiner L, Makedonski L, et al. Cancer Research. May 7, 2013.
“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.”
While melanomas with BRAF mutations can be targeted with a combination of BRAF inhibitors and MEK inhibitors, the treatment can have side effects such as fever, light sensitivity, and rashes. But early results of a phase I clinical trial suggest that BRAF-mutant melanomas could be treated safely and effectively with a new combination: LGX818, a BRAF inhibitor developed by Novartis and MEK162, a MEK inhibitor developed by Array BioPharma. Moreover, using these drugs together may decrease common side effects of targeted BRAF treatments, including skin toxicities and muscle and joint pain. A phase III trial of this new combination treatment is expected to begin later in 2013.
van Akkooi AC, Nijsten T. Br J Dermatol. Mar 2013.
“Dabrafenib, an inhibitor of mutated BRAF, has clinical activity with a manageable safety profile in phase I and II studies in patients with BRAF (V600)–mutated metastatic melanoma. The study aims to assess the efficacy of dabrafenib in a phase III trial of patients with BRAF (V600)–mutated metastatic melanoma. Dabrafenib significantly improved PFS compared with dacarbazine.” – from http://www.mdlinx.com/oncology/news-article.cfm/4484415/?xml
Knight DA, Ngiow SF ... McArthur GA, Smyth MJ. J Clin Invest. Mar 1, 2013.
“The BRAF mutant, BRAFV600E, is expressed in nearly half of melanomas, and oral BRAF inhibitors induce substantial tumor regression in patients with BRAFV600E metastatic melanoma. The inhibitors are believed to work primarily by inhibiting BRAFV600E-induced oncogenic MAPK signaling; however, some patients treated with BRAF inhibitors exhibit increased tumor immune infiltration, suggesting that a combination of BRAF inhibitors and immunotherapy may be beneficial. We used two relatively resistant variants of BrafV600E-driven mouse melanoma (SM1 and SM1WT1) and melanoma-prone mice to determine the role of host immunity in type I BRAF inhibitor PLX4720 antitumor activity.”
A clinical trial found that dabrafenib, a BRAF inhibitor, was far more effective in treating melanomas that have BRAF mutations than the chemotherapy drug dacarbazine, according to a report at an American Society of Clinical Oncology meeting. Patients treated with this drug lived without getting worse for 70% longer than those treated with dacarbazine (5.1 vs. 2.7 months, respectively). Moreover, compared to those treated with vemurafenib in other studies, dabrafenib-treated patients had less risk of another kind of skin cancer called squamous cell carcinoma. This suggests that dabrafenib, which is experimental, could be safer than vemurafenib, which is FDA approved.
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.
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.