Melanoma: New Combination Therapy Targets Resistant Tumors

MedicalResearch.com Interview with:

Daniel S. Peeper, PhD Professor of Functional Oncogenomics (VUmc) Member of Oncode Institute Head, Division of Molecular Oncology & Immunology Chair, Scientific Faculty Council Chair, Translational Research Board The Netherlands Cancer Institute Amsterdam The Netherlands

Dr. Peeper

Daniel S. Peeper, PhD
Professor of Functional Oncogenomics (VUmc)
Member of Oncode Institute
Head, Division of Molecular Oncology & Immunology
Chair, Scientific Faculty Council
Chair, Translational Research Board
The Netherlands Cancer Institute
Amsterdam The Netherlands

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: BRAF mutant melanomas are now commonly treated with either immunotherapy or with the combination of BRAFi + MEKi. Recent clinical trials showed that combination checkpoint blockade gives 58% 3 year survival for advanced melanoma. For BRAF+MEKi these numbers are somewhat less impressive. Our study relates to the latter setting.

Clearly, most patients treated with this combination do not experience a durable clinical benefit. We showed previously that resistance to these inhibitors is commonly associated with a striking increase in the number of AXL+ cells; this is the rationale for the current study.  Continue reading

Model of RAF Inhibitor Action Provides Roadmap For Resistant Colon and Thyroid Cancer Treatment

MedicalResearch.com Interview with:

Poulikos I. Poulikakos, PhD Assistant Professor Department of Oncological Sciences Department of Dermatology The Tisch Cancer Institute Icahn School of Medicine at Mount Sinai

Dr. Poulikakos

Poulikos I. Poulikakos, PhD
Assistant Professor
Department of Oncological Sciences
Department of Dermatology
The Tisch Cancer Institute
Icahn School of Medicine at Mount Sinai

MedicalResearch.com: What is the background for this study?

Response: Mutations in the oncoprotein kinase BRAF are found in about 8% of human tumors, including more than 50% of melanomas. Small molecule RAF inhibitors prolonged survival of melanoma patients with mutant-BRAF tumors, but resistance limits their effectiveness. Further, RAF inhibitors showed only modest efficacy in patients with colorectal and thyroid mutant-BRAF tumors. Previous studies have suggested that the complex biochemical mechanisms of action of RAF inhibitors account for both sensitivity and major mechanisms of resistance to these drugs. Recently, a number of next generation RAF inhibitors have entered preclinical or clinical development, but the most appropriate clinical context for their use remained elusive.

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Melanoma: Targeting Macrophages Increases BRAF Inhibitors’ Effectiveness

Russel E. Kaufman, MD President Emeritus Professor, Molecular and Cellular Oncogenesis Program Molecular and Cellular Oncogenesis Program The Wistar InstituteMedicalResearch.com Interview with:
Russel E. Kaufman, MD President Emeritus
Professor, Molecular and Cellular Oncogenesis Program
Molecular and Cellular Oncogenesis Program
The Wistar Institute

Medical Research: What is the background for this study? What are the main findings?

Response: Targeted therapies in cancer were hailed as a “magic bullet” because of their ability to act upon the mutations responsible for cancer while leaving nearby healthy cells alone. Using an approach like this, it would make sense that therapies designed to target mutations of BRAFV600E/K could be effective for melanoma, since that gene is mutated in about half of all cases of the disease.

However, we’ve learned over time that these targeted therapies simply aren’t as effective as we had hoped they would be. In the case of these BRAF inhibitors, while patients do live slightly longer, they eventually relapse within months of treatment. We wanted to know why this was happening.

We decided to look at macrophages, which are the most abundant inflammatory cells in melanoma. The more macrophages present in a patient with melanoma, the worse his or her outcome will be. They’ve been linked to cancer progression, but before this study, no one had really looked at the role they may play in the resistance to treatment with BRAF inhibitors.

We found that BRAF inhibitors activate the mitogen-activated protein kinase (MAPK) pathway in macrophages. When this pathway is activated, it leads to the production of vascular endothelial growth factor (VEGF), a signaling protein closely associated with angiogenesis. The VEGF produced in the macrophages is able to activate the MAPK pathway in melanoma cells, thereby stimulating the growth of cancer cells.

Taking these findings one step further, we discovered that when we blocked the MAPK pathway or VEGF signaling, we appeared to reverse macrophage-mediated resistance. When we targeted macrophages, we were able to increase the antitumor activity of BRAF inhibitors in mouse and human models.

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Melanoma: BRAF Inhibition May Switch Cancer Cells To Become More Metastatic

Keiran Smalley, PhD. Scientific Director, The Comprehensive Melanoma Research Center Associate Professor The Moffitt Cancer Center & Research Institute, Tampa, FLMedicalResearch.com Interview with:
Keiran Smalley, PhD.

Scientific Director, The Comprehensive Melanoma Research Center
Associate Professor The Moffitt Cancer Center & Research Institute, Tampa, FL

 

Medical Research: What is the background for this study? What are the main findings?

Dr. Smalley: Although many patients with BRAF mutant melanoma respond very well to BRAF inhibitors and the BRAF/MEK inhibitor combination, resistance is commonplace and the majority of those treated ultimately fail therapy. Most studies to date have focused upon the genetic changes that are associated with acquired BRAF and BRAF/MEK inhibitor resistance. We decided to take a different approach and to use proteomics to comprehensively map all of the signaling changes associated with resistance. Our study showed that melanoma cells with resistance to BRAF and BRAF/MEK inhibition were highly invasive and aggressive. This aggressive phenotype was driven through a cell surface receptor called EphA2, and this became upregulated in both melanoma cell cultures and in patient tumors following BRAF inhibitor treatment. As this suggested that the resistant cells would be more metastatic, we then performed animal experiments and analyzed tumors from melanoma patients receiving BRAF inhibitor. These studies showed an increase in EphA2 expression in the metastatic tumors that was lacking in the primary tumors. When we looked at cohorts of melanoma patients who received either a BRAF inhibitor or an older chemotherapy drug, we found that more of the BRAF inhibitor treated patients seemed to develop disease at new sites. Together this suggested that BRAF inhibition may switch the cancer cells to being more metastatic.

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Melanoma: Combination BRAF and MEK Inhibitors Has Better Safety Profile

Martina Sanlorenzo, MD Department of Dermatology Mt. Zion Cancer Research Bldg. San Francisco, CA 94143-0808MedicalResearch.com Interview with:
Martina Sanlorenzo, MD
Department of Dermatology
Mt. Zion Cancer Research Bldg.
San Francisco, CA 94143-0808


Medical Research:
What are the main findings of the study?

Dr. Sanlorenzo: In the treatment of BRAF mutant melanoma, the combination of BRAF inhibitor and MEK inhibitor has a better cutaneous safety profile compared with BRAF inhibitor monotherapy. Combination regimen shows fewer cutaneous adverse events and longer cutaneous adverse event-free interval. In particular, the development of squamous cell carcinoma or keratoacanthoma was significantly less frequent.
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Melanoma: Combination BRAF and MEK Inhibition Improved Outcomes

Georgina Long BSc PhD MBBS FRACP Associate Professor of Melanoma Biology and Translational Research Melanoma Institute Australia and the University of Sydney MedicalResearch.com Interview with:
Georgina Long BSc PhD MBBS FRACP
Associate Professor of Melanoma Biology and Translational Research
Melanoma Institute Australia and the University of Sydney

Medical Research: Could you provide some background on this project? Why did you decide to do this research project? What prior work led up to this latest paper?

Dr. Long: Pre-clinically, we had data that showed that the combination of BRAF inhibitor + MEK inhibitor

  • Decreased skin proliferative toxicity seen with BRAF inhibitors alone (seen as hyperproliferative lesions in rats)
  • and delayed the emergence of resistance I.e. The tumours in the mice reduced in size more, and stayed reduced for longer.We then confirmed this concept in a randomised phase 2 study, although it was not powered for a definitive progression free survival (PFS_ difference like a phase 3 trial is, we saw a strong difference in response rate and in PFS, yet there were only 54 patients per arm.

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Thyroid Cancer: Increase in BRAF, RAS Mutations

Yuri E. Nikiforov, M.D., Ph.D. Professor of Pathology Vice Chair for Molecular Pathology Director, Division of Molecular & Genomic Pathology Department of Pathology University of Pittsburgh Pittsburgh, PA 15213MedicalResearch.com Interview
Yuri E. Nikiforov, M.D., Ph.D.
Professor of Pathology, Vice Chair for Molecular Pathology
Director, Division of Molecular & Genomic Pathology
Department of Pathology, University of Pittsburgh Pittsburgh, PA

MedicalResearch.com: What are the main findings of the study?

Dr. Nikiforov: This is examined temporal changes in mutational profiles and standardized histopathologic features of thyroid cancer in the U.S. over the last four decades. It showed a significant change in molecular profiles of thyroid cancer during the past 40 years as it determined two major trends in changing the mutational make-up of thyroid cancer: a rapid increase in the prevalence of RAS mutations, particularly for the last 10 years, and continuous decrease in frequency of RET/PTC rearrangement. The rising incidence of RAS mutations points to new and more recent etiologic factors, probably of a chemical or dietary nature. The decreasing incidence of RET/PTC rearrangements, a known marker of high-dose environmental and medical radiation, suggest that the impact of ionizing radiation, at least as related to high-dose environmental exposures and historical patterns of radiation treatment for benign conditions, is diminishing.
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