Comprehensive Melanoma Research Center

Sun City Center, FL, United States

Comprehensive Melanoma Research Center

Sun City Center, FL, United States
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Rebecca V.W.,Comprehensive Melanoma Research Center | Sondak V.K.,Comprehensive Melanoma Research Center | Sondak V.K.,Moffitt Cancer Center | Smalley K.S.M.,Comprehensive Melanoma Research Center | Smalley K.S.M.,Moffitt Cancer Center
Melanoma Research | Year: 2012

In recent years, melanoma research has undergone a renaissance. What was once viewed, at least in the metastatic setting, as an intractable and untreatable disease is now revealing its molecular weaknesses. 2011 was a landmark year for melanoma therapy, with two new agents, the anti-CTLA4 antibody ipilimumab and the BRAF inhibitor vemurafenib, shown to confer a survival benefit in randomized phase III clinical trials. Overlooked in the recent flurry of interest that has accompanied the development of these drugs, melanoma is in fact an ancient disease that has long frustrated attempts at therapeutic interventions. In this article, we trace the history of melanoma: from the earliest known cases of melanoma in pre-Colombian South America, through the explorations of the Victorian anatomists right up to the molecular biology revolution of the 20th century that allowed for the identification of the key driving events required for melanomagenesis. We further outline how observations about melanoma heterogeneity, first made over 190 years ago, continue to drive our efforts to reduce melanoma to the level of a chronic, manageable disease and ultimately to cure it entirely. Melanoma Res 22:114-122 © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Flaherty K.T.,Massachusetts General Hospital | Infante J.R.,Sarah Cannon Research Institute Tennessee Oncology | Daud A.,University of California at San Francisco | Gonzalez R.,Aurora University | And 22 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: Resistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogen-activated protein kinase (MAPK) pathway. To address this problem, we conducted a phase 1 and 2 trial of combined treatment with dabrafenib, a selective BRAF inhibitor, and trametinib, a selective MAPK kinase (MEK) inhibitor. METHODS: In this open-label study involving 247 patients with metastatic melanoma and BRAF V600 mutations, we evaluated the pharmacokinetic activity and safety of oral dabrafenib (75 or 150 mg twice daily) and trametinib (1, 1.5, or 2 mg daily) in 85 patients and then randomly assigned 162 patients to receive combination therapy with dabrafenib (150 mg) plus trametinib (1 or 2 mg) or dabrafenib monotherapy. The primary end points were the incidence of cutaneous squamous-cell carcinoma, survival free of melanoma progression, and response. Secondary end points were overall survival and pharmacokinetic activity. RESULTS: Dose-limiting toxic effects were infrequently observed in patients receiving combination therapy with 150 mg of dabrafenib and 2 mg of trametinib (combination 150/2). Cutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination 150/2 and in 19% receiving monotherapy (P = 0.09), whereas pyrexia was more common in the combination 150/2 group than in the monotherapy group (71% vs. 26%). Median progression-free survival in the combination 150/2 group was 9.4 months, as compared with 5.8 months in the monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval, 0.25 to 0.62; P<0.001). The rate of complete or partial response with combination 150/2 therapy was 76%, as compared with 54% with monotherapy (P = 0.03). CONCLUSIONS: Dabrafenib and trametinib were safely combined at full monotherapy doses. The rate of pyrexia was increased with combination therapy, whereas the rate of proliferative skin lesions was nonsignificantly reduced. Progression-free survival was significantly improved. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01072175.). Copyright © 2012 Massachusetts Medical Society.


Tiago M.,University of Sao Paulo | De Oliveira E.M.,University of Sao Paulo | Brohem C.A.,University of Sao Paulo | Pennacchi P.C.,University of Sao Paulo | And 6 more authors.
Tissue Engineering - Part A | Year: 2014

Melanoma is the most aggressive form of skin cancer and until recently, it was extremely resistant to radio-, immuno-, and chemotherapy. Despite the latest success of BRAF V600E-targeted therapies, responses are typically short lived and relapse is all but certain. Furthermore, a percentage (40%) of melanoma cells is BRAF wild type. Emerging evidence suggests a role for normal host cells in the occurrence of drug resistance. In the current study, we compared a variety of cell culture models with an organotypic incomplete skin culture model (the "dermal equivalent") to investigate the role of the tissue microenvironment in the response of melanoma cells to the chemotherapeutic agent doxorubicin (Dox). In the dermal equivalent model, consisting of fibroblasts embedded in type I collagen matrix, melanoma cells showed a decreased cytotoxic response when compared with less complex culture conditions, such as seeding on plastic cell culture plate (as monolayers cultures) or on collagen gel. We further investigated the role of the microenvironment in p53 induction and caspase 3 and 9 cleavage. Melanoma cell lines cultured on dermal equivalent showed decreased expression of p53 after Dox treatment, and this outcome was accompanied by induction of interleukin IL-6, IL-8, and matrix metalloproteinases 2 and 9. Here, we show that the growth of melanoma cells in the dermal equivalent model inflects drug responses by recapitulating important pro-survival features of the tumor microenvironment. These studies indicate that the presence of stroma enhances the drug resistance of melanoma in vitro, more closely mirroring the in vivo phenotype. Our data, thus, demonstrate the utility of organotypic cell culture models in providing essential context-dependent information critical for the development of new therapeutic strategies for melanoma. We believe that the organotypic model represents an improved screening platform to investigate novel anti-cancer agents, as it provides important insights into tumor-stromal interactions, thus assisting in the elucidation of chemoresistance mechanisms. © Copyright 2014, Mary Ann Liebert, Inc.


Kudchadkar R.,H. Lee Moffitt Cancer Center and Research Institute | Paraiso K.H.T.,H. Lee Moffitt Cancer Center and Research Institute | Paraiso K.H.T.,Comprehensive Melanoma Research Center | Smalley K.S.M.,H. Lee Moffitt Cancer Center and Research Institute | Smalley K.S.M.,Comprehensive Melanoma Research Center
Cancer Journal | Year: 2012

The discovery of activating BRAF mutations in ∼50% of all melanomas has proved to be a turning point in the therapeutic management of the disseminated disease. In this commentary, we review the latest research delineating the role of mutant BRAF in melanoma initiation and progression and discuss the remarkable 10-year journey leading up to the recent U.S. Food and Drug Administration approval of the small-molecule BRAF inhibitor vemurafenib. We further outline the most recent findings on the mechanisms that underlie intrinsic and acquired BRAF inhibitor resistance and describe ongoing preclinical and clinical studies designed to delay or abrogate the onset of therapeutic escape. It is hoped that our evolving understanding of melanoma genetics and intracellular signaling coupled with a growing armamentarium of signal transduction inhibitors will lead to significant improvements in the level and durability of therapeutic response in metastatic melanoma. Copyright © 2012 by Lippincott Williams &Wilkins.


Fedorenko I.V.,Comprehensive Melanoma Research Center | Gibney G.T.,Comprehensive Melanoma Research Center | Smalley K.S.M.,Comprehensive Melanoma Research Center
Oncogene | Year: 2013

The recent years have seen a significant shift in the expectations for the therapeutic management of disseminated melanoma. The clinical success of BRAF targeted therapy suggests that long-term disease control may one day be a reality for genetically defined subgroups of melanoma patients. Despite this progress, few advances have been made in developing targeted therapeutic strategies for the 50% of patients whose melanomas are BRAF wild-type. The most well-characterized subgroup of BRAF wild-type tumors is the 15-20% of all melanomas that harbor activating NRAS (Neuroblastoma Rat Sarcoma Virus) mutations. Emerging preclinical and clinical evidence suggests that NRAS mutant melanomas have patterns of signal transduction and biological behavior that is distinct from BRAF mutant melanomas. This overview will discuss the unique clinical and prognostic behavior of NRAS mutant melanoma and will summarize the emerging data on how NRAS-driven signaling networks can be translated into novel therapeutic strategies. © 2013 Macmillan Publishers Limited. All rights reserved.


Smalley K.S.M.,Comprehensive Melanoma Research Center
Journal of Investigative Dermatology | Year: 2010

Despite years of research, there has been little improvement in survival for patients with disseminated melanoma. Recent work has identified mutations in BRAF and NRAS, leading to constitutive mitogen-activated protein kinase (MAPK) pathway as well as constitutive activity in the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway, as being critical events in melanoma growth and progression. In the current review, we discuss how these complex mutational and signaling profiles can be understood using a network biology approach, and suggest how an understanding of the key signaling nodes involved in progression and survival will lead to improvements in melanoma therapy. © 2010 The Society for Investigative Dermatology.


Sung H.,H. Lee Moffitt Cancer Center and Research Institute | Sung H.,Comprehensive Melanoma Research Center | Kanchi K.L.,Washington University in St. Louis | Wang X.,H. Lee Moffitt Cancer Center and Research Institute | And 23 more authors.
Oncotarget | Year: 2016

Inactivation of Ras GTPase activating proteins (RasGAPs) can activate Ras, increasing the risk for tumor development. Utilizing a melanoma whole genome sequencing (WGS) data from 13 patients, we identified two novel, clustered somatic missense mutations (Y472H and L481F) in RASA1 (RAS p21 protein activator 1, also called p120RasGAP). We have shown that wild type RASA1, but not identified mutants, suppresses soft agar colony formation and tumor growth of BRAF mutated melanoma cell lines via its RasGAP activity toward R-Ras (related RAS viral (r-ras) oncogene homolog) isoform. Moreover, R-Ras increased and RASA1 suppressed Ral-A activation among Ras downstream effectors. In addition to mutations, loss of RASA1 expression was frequently observed in metastatic melanoma samples on melanoma tissue microarray (TMA) and a low level of RASA1 mRNA expression was associated with decreased overall survival in melanoma patients with BRAF mutations. Thus, these data support that RASA1 is inactivated by mutation or by suppressed expression in melanoma and that RASA1 plays a tumor suppressive role by inhibiting R-Ras, a previously less appreciated member of the Ras small GTPases.


PubMed | Washington University in St. Louis, Comprehensive Melanoma Research Center, H. Lee Moffitt Cancer Center and Research Institute, NYU Langone Medical Center and University of New Mexico
Type: Journal Article | Journal: Oncotarget | Year: 2016

Inactivation of Ras GTPase activating proteins (RasGAPs) can activate Ras, increasing the risk for tumor development. Utilizing a melanoma whole genome sequencing (WGS) data from 13 patients, we identified two novel, clustered somatic missense mutations (Y472H and L481F) in RASA1 (RAS p21 protein activator 1, also called p120RasGAP). We have shown that wild type RASA1, but not identified mutants, suppresses soft agar colony formation and tumor growth of BRAF mutated melanoma cell lines via its RasGAP activity toward R-Ras (related RAS viral (r-ras) oncogene homolog) isoform. Moreover, R-Ras increased and RASA1 suppressed Ral-A activation among Ras downstream effectors. In addition to mutations, loss of RASA1 expression was frequently observed in metastatic melanoma samples on melanoma tissue microarray (TMA) and a low level of RASA1 mRNA expression was associated with decreased overall survival in melanoma patients with BRAF mutations. Thus, these data support that RASA1 is inactivated by mutation or by suppressed expression in melanoma and that RASA1 plays a tumor suppressive role by inhibiting R-Ras, a previously less appreciated member of the Ras small GTPases.

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