New Immunotherapy Is Promising in Early Trial

Blocking a protein that protects tumor cells may shrink melanomas, according to results from an ongoing trial that were presented at the 10th International Congress of the Society for Melanoma Research in Philadelphia, Pennsylvania. Called PD-L1, the protein shields tumor cells from the immune system and it can be blocked by a drug called MPDL3280A. The phase I trial included 45 people with melanoma who were treated with the PD-L1 blocker, and tumors shrank in one-third of them. This PD-L1 blocker is also being tested in a phase I trial in combination with the BRAF inhibitor drug vemurafenib, as well as in several phase II trials against renal cell carcinoma and non-small-cell lung cancer (NSCLC). In addition, two drugs similar to this PD-L1 blocker (nivolumab and MK-3475) are being tested in phase III trials against melanoma.

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…

Phenformin Enhances the Therapeutic Benefit of BRAFV600E Inhibition in Melanoma

“Inhibitors of BRAF protein kinase, such as Vemurafenib and Dabrafenib, have shown remarkable antitumor activity in patients with BRAF mutant melanoma. However, most of the patients developed drug resistance during the course of treatment, leading to resumed tumor growth. This drug resistance challenge underscores the need to improve on current BRAF-targeted therapy. In this study, we have shown that phenformin, a biguanide used for treating type 2 diabetes, enhances the antitumor activities of BRAF inhibitors in both cultured melanoma cells and a genetically engineered BRAFV600E-driven mouse model of melanoma. Our preclinical findings suggest that combining phenformin with a BRAF inhibitor may be a more effective treatment than a single-agent BRAF inhibitor for treating patients with melanoma whose tumor harbor BRAF mutations.”

The Promising Landscape of New Treatments for Metastatic Melanoma

In the last few years, patients with the grim diagnosis of metastatic melanoma have gained reasons to feel more hopeful about their chances of beating the disease. Melanoma has become a poster child for new cancer treatment options, with several targeted and immune therapies approved by the U.S. Food and Drug Administration (FDA) and many more in clinical development. Continue reading…

Hypoxia Induces Phenotypic Plasticity and Therapy Resistance in Melanoma via the Tyrosine Kinase Receptors ROR1 and ROR2

“An emerging concept in melanoma biology is that of dynamic, adaptive phenotype switching, where cells switch from a highly proliferative, poorly invasive phenotype to a highly invasive, less proliferative one. This switch may hold significant implications not just for metastasis, but also for therapy resistance. We demonstrate that phenotype switching and subsequent resistance can be guided by changes in expression of receptors involved in the non-canonical Wnt5A signaling pathway, ROR1 and ROR2. ROR1 and ROR2 are inversely expressed in melanomas and negatively regulate each other. Further, hypoxia initiates a shift of ROR1-positive melanomas to a more invasive, ROR2-positive phenotype. Notably, this receptor switch induces a 10-fold decrease in sensitivity to BRAF inhibitors. In melanoma patients treated with the BRAF inhibitor, Vemurafenib, Wnt5A expression correlates with clinical response and therapy resistance. These data highlight the fact that mechanisms that guide metastatic progression may be linked to those that mediate therapy resistance.”

Adoptive T-cell Transfer Therapy and Oncogene-Targeted Therapy for Melanoma: The Search for Synergy

“The clinical strengths of immunotherapy and small-molecule inhibitors targeting the mitogen-activated protein kinase (MAPK) pathway appear to be largely complementary for the treatment of advanced melanoma. In current practice, most patients with BRAF V600 mutant melanomas will see both modalities. Several in vitro and in vivo studies suggest that combining immunotherapy with MAPK inhibition may have synergistic effects. First, mouse models show that adoptive cell therapy (ACT) can be enhanced by vaccination. Rapid tumor destruction by vemurafenib could provide a vaccine-like stimulus to adoptively transferred T cells. Second, both in mice and in early clinical trials, melanoma metastases treated with MAPK inhibitors seem to display increased T-cell infiltrates. Third, MAPK inhibition upregulates the expression of some melanoma antigens and, therefore, may enhance T-cell recognition of vemurafenib-treated melanomas. Fourth, vemurafenib may sensitize tumor cells to immune destruction. Finally, some investigators have found that an optimal antitumor effect from MAPK inhibition is dependent on an intact host immune response. Currently, the Surgery Branch of the National Cancer Institute has initiated a phase II trial combining the BRAF inhibitor vemurafenib with ACT using tumor-infiltrating lymphocytes in patients with BRAF-mutant tumors to investigate the safety and efficacy of this combination. The proposed mechanisms for synergy between these two modalities can be complex, and their optimal combination may require testing a variety of sequences and schedules.”

New Combo-Targeted Treatment for Melanoma Wows in Early Trial

Results are encouraging in an ongoing clinical trial of a BRAF inhibitor combined with a MEK inhibitor, according to a presentation at the 2013 European Cancer Congress in Amsterdam, Netherlands. The BRAF inhibitor is vemurafenib, which is approved by the U.S. Food and Drug Administration (FDA), and the MEK inhibitor is cobimetinib (GDC-0973/XL518), which is experimental. The phase I trial has 128 people with melanomas that have BRAFV600 mutations; about half had been treated with BRAF inhibitors previously, while the other half had not. Tumors shrank in 15% of participants and didn’t grow in 43% of those who had been previously treated with BRAF inhibitors. Even better, tumors disappeared in 10%, shrank in 75%, and didn’t grow in 13% of those who had not been previously treated with BRAF inhibitors.

Identification of Multiple Mechanisms of Resistance to Vemurafenib in a Patient with BRAFV600E-Mutated Cutaneous Melanoma Successfully Rechallenged After Progression

“Purpose: To investigate the mechanism(s) of resistance to the RAF-inhibitor vemurafenib, we performed a comprehensive analysis of the genetic alterations occurring in metastatic lesions from a patient with a BRAFV600E-mutant cutaneous melanoma who, after a first response, underwent subsequent rechallenge with this drug. Experimental Design: We obtained blood and tissue samples from a patient diagnosed with a BRAFV600E-mutant cutaneous melanoma that was treated with vemurafenib and achieved a near-complete response. At progression, he received additional lines of chemo/immunotherapy and was successfully re-challenged with vemurafenib. Exome and RNA sequencing were performed on a pre-treatment tumor and two subcutaneous resistant metastases, one that was present at baseline and previously responded to vemurafenib (PV1), and one that appeared de novo after reintroduction of the drug (PV2). A culture established from PV1 was also analyzed…Conclusions: This work describes the co-existence within the same patient of different molecular mechanisms of resistance to vemurafenib affecting different metastatic sites. These findings have direct implications for the clinical management of BRAF-mutant melanoma.”

Targeting the BRAF V600E Mutation in Multiple Myeloma

“In multiple myeloma, there has been little progress in the specific therapeutic targeting of oncogenic mutations. Whole-genome sequencing data have recently revealed that a subset of patients carry an activating mutation (V600E) in the BRAF kinase. To uncover the clinical relevance of this mutation in multiple myeloma, we correlated the mutation status in primary tumor samples from 379 patients with myeloma with disease outcome. We found a significantly higher incidence of extramedullary disease and a shorter overall survival in mutation carriers when compared with controls. Most importantly, we report on a patient with confirmed BRAF V600E mutation and relapsed myeloma with extensive extramedullary disease, refractory to all approved therapeutic options, who has rapidly and durably responded to low doses of the mutation-specific BRAF inhibitor vermurafenib. Collectively, we provide evidence for the development of the BRAF V600E mutation in the context of clonal evolution and describe the prognostic and therapeutic relevance of this targetable mutation.”