Medicine In Melanoma Research Articles

1H and 31P Magnetic Resonance Spectroscopic Metabolomic Imaging: Assessing Mitogen-Activated Protein Kinase Inhibition in Melanoma.

The MAPK signaling pathway with BRAF mutations has been shown to drive the pathogenesis of 40-60% of melanomas. Inhibitors of this pathway's BRAF and MEK components are currently used to treat these malignancies. However, responses to these treatments are not always successful. Therefore, identifying noninvasive biomarkers to predict treatment responses is essential for personalized medicine in melanoma. Using noninvasive 1H magnetic resonance spectroscopy (1H MRS), we previously showed that BRAF inhibition reduces lactate and alanine tumor levels in the early stages of effective therapy and could be considered as metabolic imaging biomarkers for drug response. The present work demonstrates that these metabolic changes observed by 1H MRS and those assessed by 31P MRS are also found in preclinical human melanoma models treated with MEK inhibitors. Apart from 1H and 31P MRS, additional supporting in vitro biochemical analyses are described. Our results indicate significant early metabolic correlations with response levels to MEK inhibition in the melanoma models and are consistent with our previous study of BRAF inhibition. Given these results, our study supports the potential clinical utility of noninvasive MRS to objectively image metabolic biomarkers for the early prediction of melanoma's response to MEK inhibition.

Towards Personalized Medicine in Melanoma: Implementation of a Clinical Next-Generation Sequencing Panel

Molecular diagnostics are increasingly performed routinely in the diagnosis and management of patients with melanoma due to the development of novel therapies that target specific genetic mutations. The development of next-generation sequencing (NGS) technologies has enabled to sequence multiple cancer-driving genes in a single assay, with improved sensitivity in mutation detection. The main objective of this study was the design and implementation of a melanoma-specific sequencing panel, and the identification of the spectrum of somatic mutations in a series of primary melanoma samples. A custom panel was designed to cover the coding regions of 35 melanoma-related genes. Panel average coverage was 2,575.5 reads per amplicon, with 92,8% of targeted bases covered ≥500×. Deep coverage enabled sensitive discovery of mutations in as low as 0.5% mutant allele frequency. Eighty-five percent (85/100) of the melanomas had at least one somatic mutation. The most prevalent mutated genes were BRAF (50%;50/199), NRAS (15%;15/100), PREX2 (14%;14/100), GRIN2A (13%;13/100), and ERBB4 (12%;12/100). Turn-around-time and costs for NGS-based analysis was reduced in comparison to conventional molecular approaches. The results of this study demonstrate the cost-effectiveness and feasibility of a custom-designed targeted NGS panel, and suggest the implementation of targeted NGS into daily routine practice.

Abstract 470: Application of sequencing, liquid biopsies and patient derived xenografts for personalized medicine in melanoma

Abstract BRAF/MEK inhibitors and immunotherapies have revolutionized care for patients with advanced melanoma, improving expected median survival from 9 months to 25-30 months, but the majority of patients still die of their disease. Personalized medicine strives to individualize and improve patient care. To individualize treatment decisions in advanced melanoma we analyzed 364 samples from 214 patients. We performed whole exome sequencing (WES) and circulating tumor DNA (ctDNA) analysis, and we developed patient derived xenografts (PDX). WES and targeted sequencing of ctDNA allowed us to predict responses to therapy and to identify and monitor mechanisms of resistance. WES of tumors revealed new therapeutic strategies in BRAF V600 wild-type and BRAF inhibitor-resistant melanoma and we validated these in patient derived xenografts (PDX). Thus, we describe a powerful combination of techniques for personalized medicine to improve the management of melanoma patients. Citation Format: Maria R. Girotti, Gabriela Gremel, Rebecca Lee, Elena Galvani, Dominic Rothwell, Amaya Viros, Amit Kumar Mandal, Kok Haw Jonathan Lim, Grazia Saturno, Simon J Furney, Franziska Baenke, Malin Pedersen, Jane Rogan, Jacqueline Swan, Matthew Smith, Alberto Fusi, Deemesh Oudit, Nathalie Dhomen, Ged Brady, Caroline Dive, Richard Marais. Application of sequencing, liquid biopsies and patient derived xenografts for personalized medicine in melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 470.

836 - Application of sequencing, liquid biopsies and patient-derived xenografts for personalized medicine in melanoma

836 - Application of sequencing, liquid biopsies and patient-derived xenografts for personalized medicine in melanoma

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Application of Sequencing, Liquid Biopsies, and Patient-Derived Xenografts for Personalized Medicine in Melanoma.

Targeted therapies and immunotherapies have transformed melanoma care, extending median survival from ∼9 to over 25 months, but nevertheless most patients still die of their disease. The aim of precision medicine is to tailor care for individual patients and improve outcomes. To this end, we developed protocols to facilitate individualized treatment decisions for patients with advanced melanoma, analyzing 364 samples from 214 patients. Whole exome sequencing (WES) and targeted sequencing of circulating tumor DNA (ctDNA) allowed us to monitor responses to therapy and to identify and then follow mechanisms of resistance. WES of tumors revealed potential hypothesis-driven therapeutic strategies for BRAF wild-type and inhibitor-resistant BRAF-mutant tumors, which were then validated in patient-derived xenografts (PDX). We also developed circulating tumor cell-derived xenografts (CDX) as an alternative to PDXs when tumors were inaccessible or difficult to biopsy. Thus, we describe a powerful technology platform for precision medicine in patients with melanoma. Although recent developments have revolutionized melanoma care, most patients still die of their disease. To improve melanoma outcomes further, we developed a powerful precision medicine platform to monitor patient responses and to identify and validate hypothesis-driven therapies for patients who do not respond, or who develop resistance to current treatments.

Abstract 2432: A technology platform for personalized medicine in melanoma

Abstract We developed patient derived xenografts (PDX), performed whole exome sequencing (WES) and analyzed circulating tumor DNA (ctDNA) to complement clinical management of four melanoma patients. Synchronous treatment of patients and mice showed that PDX responses mirrored those of the patients’ tumor to BRAF inhibitors. PDXs were used to test second-line treatments in relapsed patients and to validate WES-based therapies in tumors that did not have a BRAF mutation. Longitudinal analysis of ctDNA was predictive of responses to targeted and immunotherapies, and to determine mechanisms of resistance. Thus, we describe a powerful combination of techniques for personalized medicine in melanoma and discuss the challenges and limitations of implementing these novel technologies in patient management. Citation Format: Maria R. Girotti, Dominic Rothwell, Amaya Viros, Amit Kumar Mandal, Kok Haw J. Lim, Gabriela Gremel, Simon Furney, Malin Pedersen, Jane Rogan, Jacqueline Swan, Alberto Fusi, Ged Brady, Paul Lorigan, Caroline Dive, Richard Marais. A technology platform for personalized medicine in melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2432. doi:10.1158/1538-7445.AM2015-2432

Abstract 2842: Personalized pre-clinical trials in BRAF inhibitor resistant patient derived xenograft models of melanoma identify c-Met as an effective second line combination therapy target

Abstract Melanoma has seen a remarkable improvement in the treatment of advanced disease. However, the majority of patients still relapse with the emergence of resistant disease. This is especially true for BRAF inhibitors, were multiple mechanisms of resistance have been uncovered. However, the lack of dependable models to develop approaches to overcome resistance, poses a real challenge for clinical decisions on second line therapies. In addition, combination therapies necessary to achieve long term responses increase the number of possibilities to be assessed. In this study, we developed patient derived xenograft (PDX) models from BRAF inhibitor resistant patients and, after characterization, tested rational second line combination therapies in co-clinical trials.Fresh tumor tissue from 12 patients after progression on vemurafenib or dabrafenib was implanted into immune deficient NSG mice. Once the tumor grafts were established, mice were continually dosed with PLX4720 to approximate clinical plasma levels to preserve the resistant phenotype. Xenografts were then characterized for genomic alterations and pathway activation status using a targeted sequencing array and a reverse phase protein array, respectively. We found at least 2 and up to 9 known deleterious alterations in all samples, many of which have been described as conferring resistance. The protein array clustered into two major groups: MAPK pathway activated and PI3K pathway activated, again consistent with previous reports. Integrating these data allowed us to design rational combination therapies for in vivo testing. We treated a PDX model with MET amplification and high phospho c-Met with the BRAF inhibitor LGX818 20mg/kg QD, the MEK inhibitor MEK162 3mg/kg QD, and the c-Met inhibitor INC280 25mg/kg QD (all p.o.). Although INC280 alone led to significant decrease in tumor growth, only the LGX818/ MEK162/ INC280 triple combination led to complete and sustained tumor regression in all mice. Further, we tested a second PDX model with a MET amplification (albeit broader and lower) but baseline pMET on the protein level. In this model, INC280 did not show any antitumor effect confirming the specificity for c-Met and the importance of validating genomic data.In summary, using our BRAF inhibitor resistant PDX model pipeline we were not only able to identify actionable alterations in all models, but also to test rational second line combination therapies in pre-clinical in vivo trials. Genomic data alone might not be sufficient to accurately predict therapy responses and protein arrays were a valuable tool to validate deleterious alteration calls. This study represents an important step towards improving personalized medicine in melanoma, and highlights the potential use of c-Met inhibitors in melanoma combination therapy in a defined subset of patients. Citation Format: Clemens Krepler, Min Xiao, Katrin Sproesser, Patricia Brafford, Batool Shannan, Marilda Beqiri, Wei Xu, Bradley Garman, Katherine L. Nathanson, Xiaowei Xu, Giorgos Karakousis, Gordon B. Mills, Yiling Lu, Giordano Caponigro, Markus Boehm, Malte Peters, Lynn Schuchter, Meenhard Herlyn. Personalized pre-clinical trials in BRAF inhibitor resistant patient derived xenograft models of melanoma identify c-Met as an effective second line combination therapy target. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2842. doi:10.1158/1538-7445.AM2015-2842

Epigenetic mechanisms involved in melanoma pathogenesis and chemoresistance.

The discovery of highly recurrent mutations in melanoma, such as BRAF(V600E), completely changed the clinical management including therapy of melanoma patients. In the era of Personalized Medicine targeted melanoma therapies showed high response rates, currently evidenced by BRAF inhibitors or immune-stimulating therapies. In addition to genetic biomarkers, epigenetic knowledge in melanoma has undergone a major step forward in recent years. In particular, epigenetics is unveiling new perspectives to fight this disease, providing an encouraging number of DNA methylation based biomarkers that will likely improve patient stratification for prognosis and treatment. In this regard, putative targetable biomarkers or those with predictive value for the outcome of currently applied therapies are promising tools for future precision oncology strategies. In addition, the progress made in genetic and epigenetic profiling technologies and their reconfiguration to real-time clinical screening approaches makes personalized medicine in melanoma an achievable objective in upcoming years.

Genetic Alterations and Personalized Medicine in Melanoma: Progress and Future Prospects

High-throughput sequencing technologies are providing new insights into the genetic alterations involved in melanomagenesis. It appears likely that most genetic events important in the pathogenesis of melanoma will be discovered over the next few years. Genetic analysis is also increasingly being used to direct patient care. In parallel with the discovery of new genes and the elucidation of molecular pathways important in the development of melanoma, therapies targeting these pathways are becoming available. In other words, the age of personalized medicine has arrived, characterized by molecular profiling of melanoma to identify the relevant genetic alterations and the abnormal signaling mechanisms involved, followed by selection of optimal, individualized therapies. In this review, we summarize the key genetic alterations in melanoma and the development of targeted agents against melanomas bearing specific mutations. These developments in melanoma serve as a model for the implementation of personalized medicine for patients with all cancers.

Up Close and Personal: The Challenges of Precision Medicine in Melanoma

Up Close and Personal: The Challenges of Precision Medicine in Melanoma

Vemurafenib: The road to personalized medicine in melanoma

Advanced melanoma has a poor prognosis due to its resistance to traditional chemotherapeutics, leading to the search for alternative treatment approaches. With the finding that approximately 50% of melanomas harbor an activating mutation in the serine/threonine-protein kinase B-raf gene (BRAF), inhibition of mutated B-raf represented an attractive and innovative focus for the development of novel targeted therapy potentially benefiting a large proportion of melanoma patients. Impressive response rates with an overall survival benefit in addition to minimal treatment-related toxicity in phase I-III clinical studies led to the FDA's approval of vemurafenib for patients with locally advanced/unresectable or metastatic BRAFV600E-mutated malignant melanoma in August 2011. While the majority of patients with BRAF-mutated disease show favorable treatment responses shortly after initiation of vemurafenib therapy, the median progression-free survival is 6 months, making the search for resistance mechanisms a high priority. While vemurafenib represents an excellent model for successful targeted anticancer therapy, long-term safety data are needed and rational combination with other agents will be critical to prevent or circumvent the development of resistance.

Role of nuclear medicine in melanoma.

Melanoma is a malignant tumour of the melanocytes presenting characteristic metabolic and biological features, which remains a difficult and important issue in oncology. As a functional modality, nuclear medicine offers a variety of possibilities to assist in the clinical management of this disease. A brief survey of currently available techniques is presented for the diagnosis, staging and follow up, either by organ imaging or by using a great spectrum of tumour-seeking radiopharmaceuticals. The role of lymphoscintigraphy in melanoma is emphasized, as well as the supportive role of nuclear medicine in the surgical theater, enabling selective lymph node dissection by the sentinel node procedure and high dose regional chemotherapy by isolated limb perfusion. Although hardly used for metastatic melanoma so far, with all its tumour-seeking approaches nuclear medicine holds a therapeutic potential for this disease as well.