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Melanoma: HELP
Articles by Scott E. Woodman
Based on 38 articles published since 2008
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Between 2008 and 2019, S. Woodman wrote the following 38 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Uveal Melanoma: Identifying Immunological and Chemotherapeutic Targets to Treat Metastases. 2017

Jager, Martine J / Dogrusöz, Mehmet / Woodman, Scott E. ·Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. ·Asia Pac J Ophthalmol (Phila) · Pubmed #28399339.

ABSTRACT: Uveal melanoma is an intraocular malignancy that, depending on its size and genetic make-up, may lead to metastases in up to 50% of cases. Currently, no therapy has been proven to improve survival. However, new therapies exploiting immune responses against metastases are being developed. The primary tumor is well characterized: tumors at high risk of developing metastases often contain macrophages and lymphocytes. However, these lymphocytes are often regulatory T cells that may suppress immune response. Currently, immune checkpoint inhibitors have shown marked efficacy in multiple cancers (eg, cutaneous melanoma) but do not yet improve survival in uveal melanoma patients. More knowledge needs to be acquired regarding the function of T cells in uveal melanoma. Other therapeutic options are related to the biochemical pathways. Targeting the RAF-MEK-ERK pathway with small molecule MEK inhibitors abrogates the growth of UM cells harboring GNAQ/GNA11 Q209 mutations, suggesting that these aberrant G-protein oncogenes mediate, at least in part, their effect through this hallmark proliferation pathway. Other pathways are also implicated, such as those involving c-Jun and YAP. Further studies may show how interference in the different pathways may affect survival.

2 Review Uveal melanoma: From diagnosis to treatment and the science in between. 2016

Chattopadhyay, Chandrani / Kim, Dae Won / Gombos, Dan S / Oba, Junna / Qin, Yong / Williams, Michelle D / Esmaeli, Bita / Grimm, Elizabeth A / Wargo, Jennifer A / Woodman, Scott E / Patel, Sapna P. ·Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Hematology / Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida. · Department of Head and Neck Surgery, Section of Ophthalmology, The University of Texas MD Anderson Cancer Center. · Department of Pathology, The University of Texas MD Anderson Cancer Center. · Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center. · Department of Systems Biology, The University of Texas MD Anderson Cancer Center. ·Cancer · Pubmed #26991400.

ABSTRACT: Melanomas of the choroid, ciliary body, and iris of the eye are collectively known as uveal melanomas. These cancers represent 5% of all melanoma diagnoses in the United States, and their age-adjusted risk is 5 per 1 million population. These less frequent melanomas are dissimilar to their more common cutaneous melanoma relative, with differing risk factors, primary treatment, anatomic spread, molecular changes, and responses to systemic therapy. Once uveal melanoma becomes metastatic, therapy options are limited and are often extrapolated from cutaneous melanoma therapies despite the routine exclusion of patients with uveal melanoma from clinical trials. Clinical trials directed at uveal melanoma have been completed or are in progress, and data from these well designed investigations will help guide future directions in this orphan disease. Cancer 2016;122:2299-2312. © 2016 American Cancer Society.

3 Review Metastatic uveal melanoma: biology and emerging treatments. 2012

Woodman, Scott E. ·Department of Melanoma Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX 77054, USA. swoodman@mdanderson.org ·Cancer J · Pubmed #22453016.

ABSTRACT: Uveal melanoma is the most common primary intraocular cancer in adults. Nearly half of primary uveal melanoma tumors metastasize, but there are currently no effective therapies for metastatic uveal melanoma. The recent discovery of mutations that underlie uveal melanoma metastasis, growth, and survival provide a key to the molecular understanding of this disease. Much work is now underway to leverage this knowledge to develop effective therapies. This review summarizes recently discovered molecular features of uveal melanoma and therapies being explored to capitalize on this knowledge.

4 Review New strategies in melanoma: molecular testing in advanced disease. 2012

Woodman, Scott E / Lazar, Alexander J / Aldape, Kenneth D / Davies, Michael A. ·Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ·Clin Cancer Res · Pubmed #22275506.

ABSTRACT: Melanoma is one of the most aggressive forms of skin cancer. The management of melanoma is evolving rapidly due to an improved understanding of the molecular heterogeneity of this disease and the development of effective, personalized, targeted therapy strategies. Although previous classification systems were based predominantly on clinical and histologic criteria, there is now a strong rationale for adding molecular markers to the diagnostic evaluation of these tumors. Research has shown that the types and prevalence of genetic alterations vary among melanoma subtypes. Thus, rational molecular testing should be based on an understanding of the events that are likely to occur in a given tumor and the clinical implications of test results. This review summarizes the existing data that support the rationale for molecular testing in clinically defined melanoma subtypes. Emerging challenges and controversies regarding the use of various molecular testing platforms, and their implications for clinical testing, are also discussed.

5 Review Profile of ipilimumab and its role in the treatment of metastatic melanoma. 2011

Patel, Sapna P / Woodman, Scott E. ·Melanoma Medical Oncology, Department, University of Texas, MD Anderson Cancer Center, Houston, TX 77054, USA. ·Drug Des Devel Ther · Pubmed #22267918.

ABSTRACT: Melanoma is an immunogenic cancer. However, the ability of the immune system to eradicate melanoma tumors is affected by intrinsic negative regulatory mechanisms. Multiple immune-modulatory therapies are currently being developed to optimize the immune response to melanoma tumors. Two recent Phase III studies using the monoclonal antibody ipilimumab, which targets the cytotoxic T-lymphocyte antigen (CTLA-4), a negative regulator of T-cell activation, have demonstrated improvement in overall survival of metastatic melanoma patients. This review highlights the clinical trial data that supports the efficacy of ipilimumab, the immune-related response criteria used to evaluate clinical response, and side-effect profile associated with ipilimumab treatment.

6 Review Targeting KIT in melanoma: a paradigm of molecular medicine and targeted therapeutics. 2010

Woodman, Scott E / Davies, Michael A. ·Departments of Melanoma Medical Oncology and Systems Biology, University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA. swoodman@mdanderson.org ·Biochem Pharmacol · Pubmed #20457136.

ABSTRACT: Despite multiple clinical trials utilizing a spectrum of therapeutic modalities, melanoma remains a disease with dismal outcomes in patients with advanced disease. However, it is now clear that melanoma is not a single entity, but can be molecularly divided into subtypes that generally correspond to the anatomical location of the primary melanoma. Melanomas from acral lentiginous, mucosal, and chronic sun-damaged sites frequently harbor activating mutations and/or increased copy number in the KIT tyrosine kinase receptor gene, which are very rare in the more common cutaneous tumors. Multiple case reports and early observations from clinical trials suggest that targeting mutant KIT with tyrosine kinase inhibitors is efficacious in KIT mutant melanoma. This review recounts what is known about the role of KIT in melanocyte maturation, our current understanding of KIT genetic aberrations in melanoma, and how this knowledge is being translated into clinical oncology.

7 Clinical Trial Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. 2018

Amaria, Rodabe N / Reddy, Sangeetha M / Tawbi, Hussein A / Davies, Michael A / Ross, Merrick I / Glitza, Isabella C / Cormier, Janice N / Lewis, Carol / Hwu, Wen-Jen / Hanna, Ehab / Diab, Adi / Wong, Michael K / Royal, Richard / Gross, Neil / Weber, Randal / Lai, Stephen Y / Ehlers, Richard / Blando, Jorge / Milton, Denái R / Woodman, Scott / Kageyama, Robin / Wells, Daniel K / Hwu, Patrick / Patel, Sapna P / Lucci, Anthony / Hessel, Amy / Lee, Jeffrey E / Gershenwald, Jeffrey / Simpson, Lauren / Burton, Elizabeth M / Posada, Liberty / Haydu, Lauren / Wang, Linghua / Zhang, Shaojun / Lazar, Alexander J / Hudgens, Courtney W / Gopalakrishnan, Vancheswaran / Reuben, Alexandre / Andrews, Miles C / Spencer, Christine N / Prieto, Victor / Sharma, Padmanee / Allison, James / Tetzlaff, Michael T / Wargo, Jennifer A. ·Department of Melanoma Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA. · Department of Breast Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA. · Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX, USA. · Department of Head and Neck Surgery, MD Anderson Cancer Center, Houston, TX, USA. · Department of Immunology, MD Anderson Cancer Center, Houston, TX, USA. · Department of Biostatistics, MD Anderson Cancer Center, Houston, TX, USA. · Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. · Department of Genomic Medicine, MD Anderson Cancer Center, Houston, TX, USA. · Department of Pathology, MD Anderson Cancer Center, Houston, TX, USA. · Department of Genitourinary Cancers, MD Anderson Cancer Center, Houston, TX, USA. · Department of Translational and Molecular Pathology, MD Anderson Cancer Center, Houston, TX, USA. · Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX, USA. jwargo@mdanderson.org. · Department of Genomic Medicine, MD Anderson Cancer Center, Houston, TX, USA. jwargo@mdanderson.org. ·Nat Med · Pubmed #30297909.

ABSTRACT: Preclinical studies suggest that treatment with neoadjuvant immune checkpoint blockade is associated with enhanced survival and antigen-specific T cell responses compared with adjuvant treatment

8 Clinical Trial Neoadjuvant plus adjuvant dabrafenib and trametinib versus standard of care in patients with high-risk, surgically resectable melanoma: a single-centre, open-label, randomised, phase 2 trial. 2018

Amaria, Rodabe N / Prieto, Peter A / Tetzlaff, Michael T / Reuben, Alexandre / Andrews, Miles C / Ross, Merrick I / Glitza, Isabella C / Cormier, Janice / Hwu, Wen-Jen / Tawbi, Hussein A / Patel, Sapna P / Lee, Jeffrey E / Gershenwald, Jeffrey E / Spencer, Christine N / Gopalakrishnan, Vancheswaran / Bassett, Roland / Simpson, Lauren / Mouton, Rosalind / Hudgens, Courtney W / Zhao, Li / Zhu, Haifeng / Cooper, Zachary A / Wani, Khalida / Lazar, Alexander / Hwu, Patrick / Diab, Adi / Wong, Michael K / McQuade, Jennifer L / Royal, Richard / Lucci, Anthony / Burton, Elizabeth M / Reddy, Sangeetha / Sharma, Padmanee / Allison, James / Futreal, Phillip A / Woodman, Scott E / Davies, Michael A / Wargo, Jennifer A. ·Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: jwargo@mdanderson.org. ·Lancet Oncol · Pubmed #29361468.

ABSTRACT: BACKGROUND: Dual BRAF and MEK inhibition produces a response in a large number of patients with stage IV BRAF-mutant melanoma. The existing standard of care for patients with clinical stage III melanoma is upfront surgery and consideration for adjuvant therapy, which is insufficient to cure most patients. Neoadjuvant targeted therapy with BRAF and MEK inhibitors (such as dabrafenib and trametinib) might provide clinical benefit in this high-risk p opulation. METHODS: We undertook this single-centre, open-label, randomised phase 2 trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Eligible participants were adult patients (aged ≥18 years) with histologically or cytologically confirmed surgically resectable clinical stage III or oligometastatic stage IV BRAF FINDINGS: Between Oct 23, 2014, and April 13, 2016, we randomly assigned seven patients to standard of care, and 14 to neoadjuvant plus adjuvant dabrafenib and trametinib. The trial was stopped early after a prespecified interim safety analysis that occurred after a quarter of the participants had been accrued revealed significantly longer event-free survival with neoadjuvant plus adjuvant dabrafenib and trametinib than with standard of care. After a median follow-up of 18·6 months (IQR 14·6-23·1), significantly more patients receiving neoadjuvant plus adjuvant dabrafenib and trametinib were alive without disease progression than those receiving standard of care (ten [71%] of 14 patients vs none of seven in the standard of care group; median event-free survival was 19·7 months [16·2-not estimable] vs 2·9 months [95% CI 1·7-not estimable]; hazard ratio 0·016, 95% CI 0·00012-0·14, p<0·0001). Neoadjuvant plus adjuvant dabrafenib and trametinib were well tolerated with no occurrence of grade 4 adverse events or treatment-related deaths. The most common adverse events in the neoadjuvant plus adjuvant dabrafenib and trametinib group were expected grade 1-2 toxicities including chills (12 patients [92%]), headache (12 [92%]), and pyrexia (ten [77%]). The most common grade 3 adverse event was diarrhoea (two patients [15%]). INTERPRETATION: Neoadjuvant plus adjuvant dabrafenib and trametinib significantly improved event-free survival versus standard of care in patients with high-risk, surgically resectable, clinical stage III-IV melanoma. Although the trial finished early, limiting generalisability of the results, the findings provide proof-of-concept and support the rationale for further investigation of neoadjuvant approaches in this disease. This trial is currently continuing accrual as a single-arm study of neoadjuvant plus adjuvant dabrafenib and trametinib. FUNDING: Novartis Pharmaceuticals Corporation.

9 Clinical Trial Copy Number Changes Are Associated with Response to Treatment with Carboplatin, Paclitaxel, and Sorafenib in Melanoma. 2016

Wilson, Melissa A / Zhao, Fengmin / Khare, Sanika / Roszik, Jason / Woodman, Scott E / D'Andrea, Kurt / Wubbenhorst, Bradley / Rimm, David L / Kirkwood, John M / Kluger, Harriet M / Schuchter, Lynn M / Lee, Sandra J / Flaherty, Keith T / Nathanson, Katherine L. ·Hematology/Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. · Dana Farber Cancer Institute, Boston, Massachusetts. · Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. · Departments of Melanoma Medical Oncology and Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Pathology, Yale University School of Medicine, New Haven, Connecticut. · University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. · Section of Medical Oncology, Yale Cancer Center, New Haven, Connecticut. · Hematology/Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. · Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts. · Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. knathans@exchange.upenn.edu. ·Clin Cancer Res · Pubmed #26307133.

ABSTRACT: PURPOSE: Copy number alterations have been shown to be involved in melanoma pathogenesis. The randomized phase III clinical trial E2603: carboplatin, paclitaxel, ± sorafenib (CP vs. CPS) offers a large collection of tumor samples to evaluate association of somatic mutations, genomic alterations, and clinical outcomes, prior to current FDA-approved therapies. EXPERIMENTAL DESIGN: Copy number and mutational analysis on 119 pretreatment samples was performed. RESULTS: CPS therapy was associated with improved progression-free survival (PFS) compared with CP in patients with tumors with RAF1 (cRAF) gene copy gains (HR, 0.372; P = 0.025) or CCND1 gene copy gains (HR, 0.45; P = 0.035). CPS therapy was associated with improved overall survival (OS) compared with CP in patients with tumors with KRAS gene copy gains (HR, 0.25; P = 0.035). BRAF gene copy gain and MET amplification were more common in samples with V600K versus V600E mutations (P < 0.001), which was validated in The Cancer Genome Atlas (TCGA) dataset. CONCLUSIONS: We observed improved treatment response with CPS in patients with melanoma whose tumors have RAF1 (cRAF), KRAS, or CCND1 amplification, all of which can be attributed to sorafenib targeting CRAF. These genomic alterations should be incorporated in future studies for evaluation as biomarkers.

10 Clinical Trial Phase I trial of biochemotherapy with cisplatin, temozolomide, and dose escalation of nab-paclitaxel combined with interleukin-2 and interferon-α in patients with metastatic melanoma. 2014

Alrwas, Anas / Papadopoulos, Nicholas E / Cain, Suzanne / Patel, Sapna P / Kim, Kevin B / Deburr, Tawania L / Bassett, Roland / Hwu, Wen-Jen / Bedikian, Agop Y / Davies, Michael A / Woodman, Scott E / Hwu, Patrick. ·aHealth Science Center, University of Oklahoma, Oklahoma City, Oklahoma Departments of bMelanoma Medical Oncology cPalliative Care and Rehabilitative Medicine dBiostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. ·Melanoma Res · Pubmed #24743052.

ABSTRACT: The primary objective of this study was to determine the safety, toxicity, and maximum tolerated dose of nanoparticle albumin-bound (nab)-paclitaxel as part of biochemotherapy for metastatic melanoma and to determine whether substituting nab-paclitaxel for less potent agents could increase response rates and duration. Treatment consisted of intravenous cisplatin (20 mg/m) on days 1-4, oral temozolomide (250 mg/m) on days 1-3, subcutaneous interferon-α (5×10 IU/m) on days 1-5, and continuous intravenous interleukin-2 (9×10 IU/m) for 96 h on days 1-4. A standard 3+3 dose escalation method was used; the nab-paclitaxel starting dose was 100 mg/m on day 1 and 70 mg/m on day 5. The treatment cycle was repeated every 3 weeks and toxicity was assessed weekly. Ten patients were enrolled. Dose-limiting toxicities included diarrhea, transaminasemia, and neutropenia. The maximum tolerated dose was not identified because the nab-paclitaxel dose on day 1 at the lowest planned dose (80 mg/m) caused dose-limiting toxicity in two of five patients. Of the nine patients who were evaluable for response, five had a partial response. The median time to disease progression was 5.30 months and the median overall survival was 8.73 months. Six patients developed central nervous system metastasis at a median of 5.33 months after treatment initiation. Biochemotherapy including nab-paclitaxel according to the doses and schedule regimen used in the present study has significant toxicity. Substituting dacarbazine with temozolomide did not prevent central nervous system metastasis in patients with metastatic melanoma.

11 Clinical Trial BRAF, NRAS and KIT sequencing analysis of spindle cell melanoma. 2012

Kim, Jinhyun / Lazar, Alexander J / Davies, Michael A / Homsi, Jade / Papadopoulos, Nicholas E / Hwu, Wen-Jen / Bedikian, Agop Y / Woodman, Scott E / Patel, Sapna P / Hwu, Patrick / Kim, Kevin B. ·Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. ·J Cutan Pathol · Pubmed #22809251.

ABSTRACT: BACKGROUND: Spindle cell melanoma represents a rare but distinct subset of melanoma, and its genomic spectrum has not been fully defined. METHODS: We searched our institutional database for patients with a diagnosis of pure spindle cell-type melanoma whose tumors had been analyzed for BRAF, NRAS, and KIT mutations using pyrosequencing technique. RESULTS: We identified 24 patients with spindle cell melanoma, including 10 patients with desmoplastic melanoma, whose tumors had been analyzed for at least one of the three genes. The median Breslow thickness was 2.6 mm, and the most common site of the primary melanoma was the trunk, followed by the head and neck region. BRAF, NRAS and KIT genomic sequencing was performed successfully in 20, 18 and 14 patients, respectively. Among the 20 melanomas with completed BRAF-sequencing analysis, 6 (30%) harbored a mutation, of which 5 (83%) had a V600E mutation and 1 (17%) had a V600R mutation. None of the melanomas harbored NRAS or KIT mutations. CONCLUSION: As has been reported in other common types of melanoma, V600 BRAF mutation is the most common mutation of those tested in spindle cell melanoma. NRAS or KIT mutation appears to be rare, if not completely absent.

12 Article Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. 2018

Gopalakrishnan, V / Spencer, C N / Nezi, L / Reuben, A / Andrews, M C / Karpinets, T V / Prieto, P A / Vicente, D / Hoffman, K / Wei, S C / Cogdill, A P / Zhao, L / Hudgens, C W / Hutchinson, D S / Manzo, T / Petaccia de Macedo, M / Cotechini, T / Kumar, T / Chen, W S / Reddy, S M / Szczepaniak Sloane, R / Galloway-Pena, J / Jiang, H / Chen, P L / Shpall, E J / Rezvani, K / Alousi, A M / Chemaly, R F / Shelburne, S / Vence, L M / Okhuysen, P C / Jensen, V B / Swennes, A G / McAllister, F / Marcelo Riquelme Sanchez, E / Zhang, Y / Le Chatelier, E / Zitvogel, L / Pons, N / Austin-Breneman, J L / Haydu, L E / Burton, E M / Gardner, J M / Sirmans, E / Hu, J / Lazar, A J / Tsujikawa, T / Diab, A / Tawbi, H / Glitza, I C / Hwu, W J / Patel, S P / Woodman, S E / Amaria, R N / Davies, M A / Gershenwald, J E / Hwu, P / Lee, J E / Zhang, J / Coussens, L M / Cooper, Z A / Futreal, P A / Daniel, C R / Ajami, N J / Petrosino, J F / Tetzlaff, M T / Sharma, P / Allison, J P / Jenq, R R / Wargo, J A. ·Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston, TX 77030, USA. · Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA. · Department of Cell, Developmental and Cell Biology, Oregon Health and Sciences University, Portland, OR 97239, USA. · Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Infectious Diseases, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Centre de Recherche de Jouy-en-Josas, Institut National de la Recherche Agronomique, 78352 Jouy-en-Josas, France. · Centre d'Investigation Clinique Biothérapie, Institut Gustave-Roussy, 94805 Villejuif Cedex, France. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. jwargo@mdanderson.org. ·Science · Pubmed #29097493.

ABSTRACT: Preclinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we examined the oral and gut microbiome of melanoma patients undergoing anti-programmed cell death 1 protein (PD-1) immunotherapy (

13 Article Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma. 2017

Robertson, A Gordon / Shih, Juliann / Yau, Christina / Gibb, Ewan A / Oba, Junna / Mungall, Karen L / Hess, Julian M / Uzunangelov, Vladislav / Walter, Vonn / Danilova, Ludmila / Lichtenberg, Tara M / Kucherlapati, Melanie / Kimes, Patrick K / Tang, Ming / Penson, Alexander / Babur, Ozgun / Akbani, Rehan / Bristow, Christopher A / Hoadley, Katherine A / Iype, Lisa / Chang, Matthew T / Anonymous1031111 / Cherniack, Andrew D / Benz, Christopher / Mills, Gordon B / Verhaak, Roel G W / Griewank, Klaus G / Felau, Ina / Zenklusen, Jean C / Gershenwald, Jeffrey E / Schoenfield, Lynn / Lazar, Alexander J / Abdel-Rahman, Mohamed H / Roman-Roman, Sergio / Stern, Marc-Henri / Cebulla, Colleen M / Williams, Michelle D / Jager, Martine J / Coupland, Sarah E / Esmaeli, Bita / Kandoth, Cyriac / Woodman, Scott E. ·Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada. · The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. · Buck Institute for Research on Aging, Novato, CA 94945, USA. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA. · Department of Biomolecular Engineering, Center for Biomolecular Sciences and Engineering, University of California, Santa Cruz, CA 95064, USA. · Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Public Health Sciences, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA. · The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD 21287, USA. · The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA. · Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA. · Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. · Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Human Oncology and Pathogenesis Program, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA. · Molecular and Medical Genetics, Computational Biology, Oregon Health and Science University, Portland, OR 97239, USA. · Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Institute for Applied Cancer Science, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. · Institute for Systems Biology, Seattle, WA 98109, USA. · Human Oncology and Pathogenesis Program, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA; Departments of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94122, USA. · Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Dermatology, University Hospital Essen, 45157 Essen, Germany. · Center for Cancer Genomics, National Cancer Institute, Bethesda, MD 20892, USA. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Pathology, The Ohio State University, Wexner Medical Center, Columbus, OH 43210, USA. · Department of Pathology, Dermatology and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Departments of Ophthalmology and Internal Medicine, Division of Human Genetics, The Ohio State University, Columbus, OH 43210, USA. · Department of Translational Research, Institut Curie, PSL Research University, Paris 75248, France. · Havener Eye Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43212, USA. · Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands. · Department of Molecular & Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool L7 8TX, UK; Department of Cellular Pathology, Royal Liverpool University Hospital, Liverpool, L69 3GA, UK. · Orbital Oncology & Ophthalmic Plastic Surgery, Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: besmaeli@mdanderson.org. · Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA. Electronic address: kandothc@mskcc.org. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: swoodman@mdanderson.org. ·Cancer Cell · Pubmed #28810145.

ABSTRACT: Comprehensive multiplatform analysis of 80 uveal melanomas (UM) identifies four molecularly distinct, clinically relevant subtypes: two associated with poor-prognosis monosomy 3 (M3) and two with better-prognosis disomy 3 (D3). We show that BAP1 loss follows M3 occurrence and correlates with a global DNA methylation state that is distinct from D3-UM. Poor-prognosis M3-UM divide into subsets with divergent genomic aberrations, transcriptional features, and clinical outcomes. We report change-of-function SRSF2 mutations. Within D3-UM, EIF1AX- and SRSF2/SF3B1-mutant tumors have distinct somatic copy number alterations and DNA methylation profiles, providing insight into the biology of these low- versus intermediate-risk clinical mutation subtypes.

14 Article SLC45A2: A Melanoma Antigen with High Tumor Selectivity and Reduced Potential for Autoimmune Toxicity. 2017

Park, Jungsun / Talukder, Amjad H / Lim, Seon A / Kim, Kwanghee / Pan, Ke / Melendez, Brenda / Bradley, Sherille D / Jackson, Kyle R / Khalili, Jahan S / Wang, Junmei / Creasy, Caitlin / Pan, Bih-Fang / Woodman, Scott E / Bernatchez, Chantale / Hawke, David / Hwu, Patrick / Lee, Kyung-Mi / Roszik, Jason / Lizée, Gregory / Yee, Cassian. ·Center for Cancer Immunology Research, Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Republic of Korea. · Department of Systems Biology, MD Anderson Cancer Center, Houston, Texas. · Center for Cancer Immunology Research, Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. glizee@mdanderson.org cyee@mdanderson.org. · Departments of Melanoma Medical Oncology and Immunology, MD Anderson Cancer Center, Houston, Texas. ·Cancer Immunol Res · Pubmed #28630054.

ABSTRACT: Cytotoxic T lymphocyte (CTL)-based immunotherapies have had remarkable success at generating objective clinical responses in patients with advanced metastatic melanoma. Although the melanocyte differentiation antigens (MDA) MART-1, PMEL, and tyrosinase were among the first melanoma tumor-associated antigens identified and targeted with immunotherapy, expression within normal melanocytes of the eye and inner ear can elicit serious autoimmune side effects, thus limiting their clinical potential as CTL targets. Using a tandem mass spectrometry (MS) approach to analyze the immunopeptidomes of 55 melanoma patient-derived cell lines, we identified a number of shared HLA class I-bound peptides derived from the melanocyte-specific transporter protein SLC45A2. Antigen-specific CTLs generated against HLA-A*0201- and HLA-A*2402-restricted SLC45A2 peptides effectively killed a majority of HLA-matched cutaneous, uveal, and mucosal melanoma cell lines tested (18/25). CTLs specific for SLC45A2 showed significantly reduced recognition of HLA-matched primary melanocytes that were, conversely, robustly killed by MART1- and PMEL-specific T cells. Transcriptome analysis revealed that SLC45A2 mRNA expression in normal melanocytes was less than 2% that of other MDAs, therefore providing a more favorable melanoma-to-melanocyte expression ratio. Expression of SLC45A2 and CTL sensitivity could be further upregulated in BRAF(V600E)-mutant melanoma cells upon treatment with BRAF or MEK inhibitors, similarly to other MDAs. Taken together, our study demonstrates the feasibility of using tandem MS as a means of discovering shared immunogenic tumor-associated epitopes and identifies SLC45A2 as a promising immunotherapeutic target for melanoma with high tumor selectivity and reduced potential for autoimmune toxicity.

15 Article Systematic genomic and translational efficiency studies of uveal melanoma. 2017

Johnson, Chelsea Place / Kim, Ivana K / Esmaeli, Bita / Amin-Mansour, Ali / Treacy, Daniel J / Carter, Scott L / Hodis, Eran / Wagle, Nikhil / Seepo, Sara / Yu, Xiaoxing / Lane, Anne Marie / Gragoudas, Evangelos S / Vazquez, Francisca / Nickerson, Elizabeth / Cibulskis, Kristian / McKenna, Aaron / Gabriel, Stacey B / Getz, Gad / Van Allen, Eliezer M / 't Hoen, Peter A C / Garraway, Levi A / Woodman, Scott E. ·Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America. · The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America. · Ocular Melanoma Center and Retina Service, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States of America. · Orbital Oncology and Ophthalmic Plastic Surgery Program, Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America. · Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America. · Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America. · Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. ·PLoS One · Pubmed #28594900.

ABSTRACT: To further our understanding of the somatic genetic basis of uveal melanoma, we sequenced the protein-coding regions of 52 primary tumors and 3 liver metastases together with paired normal DNA. Known recurrent mutations were identified in GNAQ, GNA11, BAP1, EIF1AX, and SF3B1. The role of mutated EIF1AX was tested using loss of function approaches including viability and translational efficiency assays. Knockdown of both wild type and mutant EIF1AX was lethal to uveal melanoma cells. We probed the function of N-terminal tail EIF1AX mutations by performing RNA sequencing of polysome-associated transcripts in cells expressing endogenous wild type or mutant EIF1AX. Ribosome occupancy of the global translational apparatus was sensitive to suppression of wild type but not mutant EIF1AX. Together, these studies suggest that cells expressing mutant EIF1AX may exhibit aberrant translational regulation, which may provide clonal selective advantage in the subset of uveal melanoma that harbors this mutation.

16 Article Clinicopathological features and clinical outcomes associated with TP53 and BRAF 2017

Kim, Dae Won / Haydu, Lauren E / Joon, Aron Y / Bassett, Roland L / Siroy, Alan E / Tetzlaff, Michael T / Routbort, Mark J / Amaria, Rodabe N / Wargo, Jennifer A / McQuade, Jennifer L / Kemnade, Jan / Hwu, Patrick / Woodman, Scott E / Roszik, Jason / Kim, Kevin B / Gershenwald, Jeffrey E / Lazar, Alexander J / Davies, Michael A. ·Department of Medical Oncology, Moffitt Cancer Center, Tampa, Florida. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Internal Medicine, Baylor College of Medicine, Houston, Texas. · Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Melanoma Clinical Research Program, California Pacific Medical Center, San Francisco, California. · Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. ·Cancer · Pubmed #27911979.

ABSTRACT: BACKGROUND: BRAF METHODS: This study analyzed the patient demographics, primary tumor features, and clinical outcomes of a large cohort of non-acral cutaneous melanoma patients who had undergone clinically indicated molecular testing (n = 926). RESULTS: The prevalence of BRAF CONCLUSIONS: These results add to the understanding of the clinical features associated with TP53 and BRAF

17 Article Novel algorithmic approach predicts tumor mutation load and correlates with immunotherapy clinical outcomes using a defined gene mutation set. 2016

Roszik, Jason / Haydu, Lauren E / Hess, Kenneth R / Oba, Junna / Joon, Aron Y / Siroy, Alan E / Karpinets, Tatiana V / Stingo, Francesco C / Baladandayuthapani, Veera / Tetzlaff, Michael T / Wargo, Jennifer A / Chen, Ken / Forget, Marie-Andrée / Haymaker, Cara L / Chen, Jie Qing / Meric-Bernstam, Funda / Eterovic, Agda K / Shaw, Kenna R / Mills, Gordon B / Gershenwald, Jeffrey E / Radvanyi, Laszlo G / Hwu, Patrick / Futreal, P Andrew / Gibbons, Don L / Lazar, Alexander J / Bernatchez, Chantale / Davies, Michael A / Woodman, Scott E. ·Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 904, Houston, TX, 77030, USA. jroszik@mdanderson.org. · Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. jroszik@mdanderson.org. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. · Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 904, Houston, TX, 77030, USA. · Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. · Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. · Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. · Lion Biotechnologies, Woodland Hills, CA, 91637, USA. · Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. · Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, 770393, USA. · Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. · Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. · EMD Serono, Rockland, MA, 02370, USA. · Department of Thoracic Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 904, Houston, TX, 77030, USA. swoodman@mdanderson.org. · Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. swoodman@mdanderson.org. ·BMC Med · Pubmed #27776519.

ABSTRACT: BACKGROUND: While clinical outcomes following immunotherapy have shown an association with tumor mutation load using whole exome sequencing (WES), its clinical applicability is currently limited by cost and bioinformatics requirements. METHODS: We developed a method to accurately derive the predicted total mutation load (PTML) within individual tumors from a small set of genes that can be used in clinical next generation sequencing (NGS) panels. PTML was derived from the actual total mutation load (ATML) of 575 distinct melanoma and lung cancer samples and validated using independent melanoma (n = 312) and lung cancer (n = 217) cohorts. The correlation of PTML status with clinical outcome, following distinct immunotherapies, was assessed using the Kaplan-Meier method. RESULTS: PTML (derived from 170 genes) was highly correlated with ATML in cutaneous melanoma and lung adenocarcinoma validation cohorts (R CONCLUSIONS: The approach of using small NGS gene panels, already applied to guide employment of targeted therapies, may have utility in the personalized use of immunotherapy in cancer.

18 Article Loss of IFN-γ Pathway Genes in Tumor Cells as a Mechanism of Resistance to Anti-CTLA-4 Therapy. 2016

Gao, Jianjun / Shi, Lewis Zhichang / Zhao, Hao / Chen, Jianfeng / Xiong, Liangwen / He, Qiuming / Chen, Tenghui / Roszik, Jason / Bernatchez, Chantale / Woodman, Scott E / Chen, Pei-Ling / Hwu, Patrick / Allison, James P / Futreal, Andrew / Wargo, Jennifer A / Sharma, Padmanee. ·Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Melanoma Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: padsharma@mdanderson.org. ·Cell · Pubmed #27667683.

ABSTRACT: Antibody blockade of the inhibitory CTLA-4 pathway has led to clinical benefit in a subset of patients with metastatic melanoma. Anti-CTLA-4 enhances T cell responses, including production of IFN-γ, which is a critical cytokine for host immune responses. However, the role of IFN-γ signaling in tumor cells in the setting of anti-CTLA-4 therapy remains unknown. Here, we demonstrate that patients identified as non-responders to anti-CTLA-4 (ipilimumab) have tumors with genomic defects in IFN-γ pathway genes. Furthermore, mice bearing melanoma tumors with knockdown of IFN-γ receptor 1 (IFNGR1) have impaired tumor rejection upon anti-CTLA-4 therapy. These data highlight that loss of the IFN-γ signaling pathway is associated with primary resistance to anti-CTLA-4 therapy. Our findings demonstrate the importance of tumor genomic data, especially IFN-γ related genes, as prognostic information for patients selected to receive treatment with immune checkpoint therapy.

19 Article Analysis of Immune Signatures in Longitudinal Tumor Samples Yields Insight into Biomarkers of Response and Mechanisms of Resistance to Immune Checkpoint Blockade. 2016

Chen, Pei-Ling / Roh, Whijae / Reuben, Alexandre / Cooper, Zachary A / Spencer, Christine N / Prieto, Peter A / Miller, John P / Bassett, Roland L / Gopalakrishnan, Vancheswaran / Wani, Khalida / De Macedo, Mariana Petaccia / Austin-Breneman, Jacob L / Jiang, Hong / Chang, Qing / Reddy, Sangeetha M / Chen, Wei-Shen / Tetzlaff, Michael T / Broaddus, Russell J / Davies, Michael A / Gershenwald, Jeffrey E / Haydu, Lauren / Lazar, Alexander J / Patel, Sapna P / Hwu, Patrick / Hwu, Wen-Jen / Diab, Adi / Glitza, Isabella C / Woodman, Scott E / Vence, Luis M / Wistuba, Ignacio I / Amaria, Rodabe N / Kwong, Lawrence N / Prieto, Victor / Davis, R Eric / Ma, Wencai / Overwijk, Willem W / Sharpe, Arlene H / Hu, Jianhua / Futreal, P Andrew / Blando, Jorge / Sharma, Padmanee / Allison, James P / Chin, Lynda / Wargo, Jennifer A. ·Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts. · Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. JWargo@mdanderson.org. ·Cancer Discov · Pubmed #27301722.

ABSTRACT: SIGNIFICANCE: These studies demonstrate that adaptive immune signatures in early on-treatment tumor biopsies are predictive of response to checkpoint blockade and yield insight into mechanisms of therapeutic resistance. These concepts have far-reaching implications in this age of precision medicine and should be explored in immune checkpoint blockade treatment across cancer types. Cancer Discov; 6(8); 827-37. ©2016 AACR.See related commentary by Teng et al., p. 818This article is highlighted in the In This Issue feature, p. 803.

20 Article ARF6 Is an Actionable Node that Orchestrates Oncogenic GNAQ Signaling in Uveal Melanoma. 2016

Yoo, Jae Hyuk / Shi, Dallas S / Grossmann, Allie H / Sorensen, Lise K / Tong, ZongZhong / Mleynek, Tara M / Rogers, Aaron / Zhu, Weiquan / Richards, Jackson R / Winter, Jacob M / Zhu, Jie / Dunn, Christine / Bajji, Ashok / Shenderovich, Mark / Mueller, Alan L / Woodman, Scott E / Harbour, J William / Thomas, Kirk R / Odelberg, Shannon J / Ostanin, Kirill / Li, Dean Y. ·Department of Medicine, Program in Molecular Medicine, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112, USA; Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA. · Department of Medicine, Program in Molecular Medicine, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112, USA; Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA. · Department of Medicine, Program in Molecular Medicine, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112, USA; Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA; ARUP Laboratories, University of Utah, Salt Lake City, UT 84112, USA. · Department of Medicine, Program in Molecular Medicine, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112, USA. · Navigen Inc., 383 Colorow Drive, Salt Lake City, UT 84108, USA; Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu 610072, China. · Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA. · Department of Medicine, Program in Molecular Medicine, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112, USA; Division of Cardiovascular Medicine, Department of Medicine, University of Utah, Salt Lake City, UT 84112, USA. · Department of Ophthalmology and Shiley Eye Institute, University of California, San Diego, La Jolla, CA 92093, USA. · Navigen Inc., 383 Colorow Drive, Salt Lake City, UT 84108, USA. · Navigen Inc., 383 Colorow Drive, Salt Lake City, UT 84108, USA; VioGen Biosciences LLC, Salt Lake City, UT 84119, USA. · Navigen Inc., 383 Colorow Drive, Salt Lake City, UT 84108, USA; Mol3D Research LLC, Salt Lake City, UT 84124, USA. · Department of Melanoma Medical Oncology, Department of Systems Biology, University of Texas, MD Anderson Cancer Center, Houston, TX 77054, USA. · Ocular Oncology Service, Bascom Palmer Eye Institute and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA. · Department of Medicine, Program in Molecular Medicine, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112, USA; Division of Hematology, Department of Medicine, University of Utah, Salt Lake City, UT 84112, USA. · Department of Medicine, Program in Molecular Medicine, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112, USA; Division of Cardiovascular Medicine, Department of Medicine, University of Utah, Salt Lake City, UT 84112, USA; Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84112, USA. · Navigen Inc., 383 Colorow Drive, Salt Lake City, UT 84108, USA. Electronic address: kostanin@nvgn.com. · Department of Medicine, Program in Molecular Medicine, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112, USA; Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA; Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA; ARUP Laboratories, University of Utah, Salt Lake City, UT 84112, USA; Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu 610072, China; Division of Cardiovascular Medicine, Department of Medicine, University of Utah, Salt Lake City, UT 84112, USA; Department of Cardiology, VA Salt Lake City Health Care System, Salt Lake City, UT 84112, USA. Electronic address: dean.li@u2m2.utah.edu. ·Cancer Cell · Pubmed #27265506.

ABSTRACT: Activating mutations in Gαq proteins, which form the α subunit of certain heterotrimeric G proteins, drive uveal melanoma oncogenesis by triggering multiple downstream signaling pathways, including PLC/PKC, Rho/Rac, and YAP. Here we show that the small GTPase ARF6 acts as a proximal node of oncogenic Gαq signaling to induce all of these downstream pathways as well as β-catenin signaling. ARF6 activates these diverse pathways through a common mechanism: the trafficking of GNAQ and β-catenin from the plasma membrane to cytoplasmic vesicles and the nucleus, respectively. Blocking ARF6 with a small-molecule inhibitor reduces uveal melanoma cell proliferation and tumorigenesis in a mouse model, confirming the functional relevance of this pathway and suggesting a therapeutic strategy for Gα-mediated diseases.

21 Article Comparative analysis of the GNAQ, GNA11, SF3B1, and EIF1AX driver mutations in melanoma and across the cancer spectrum. 2016

Johnson, Douglas B / Roszik, Jason / Shoushtari, Alexander N / Eroglu, Zeynep / Balko, Justin M / Higham, Catherine / Puzanov, Igor / Patel, Sapna P / Sosman, Jeffrey A / Woodman, Scott E. ·Department of Medicine, Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, USA. · Department of Melanoma Medical Oncology, MD Anderson Cancer Center, University of Texas, Houston, TX, USA. · Department of Systems Biology, MD Anderson Cancer Center, University of Texas, Houston, TX, USA. · Melanoma and Immunotherapeutics Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA. · Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA. · School of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. ·Pigment Cell Melanoma Res · Pubmed #27089234.

ABSTRACT: -- No abstract --

22 Article Inflammatory Marker Testing Identifies CD74 Expression in Melanoma Tumor Cells, and Its Expression Associates with Favorable Survival for Stage III Melanoma. 2016

Ekmekcioglu, Suhendan / Davies, Michael A / Tanese, Keiji / Roszik, Jason / Shin-Sim, Myung / Bassett, Roland L / Milton, Denái R / Woodman, Scott E / Prieto, Victor G / Gershenwald, Jeffrey E / Morton, Donald L / Hoon, Dave S / Grimm, Elizabeth A. ·Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. sekmekcioglu@mdanderson.org egrimm@mdanderson.org. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Dermatology, School of Medicine, Keio University, Tokyo, Japan. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Molecular Oncology, John Wayne Cancer Institute, Saint John's Health Center, Santa Monica, California. · Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Pathology and Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. ·Clin Cancer Res · Pubmed #26783288.

ABSTRACT: PURPOSE: Inflammatory marker expression in stage III melanoma tumors was evaluated for association with outcome, using two independent cohorts of stage III melanoma patients' tumor tissues. EXPERIMENTAL DESIGN: Fifteen markers of interest were selected for analysis, and their expression in melanoma tissues was determined by immunohistochemistry. Proteins associating with either overall survival (OS) or recurrence-free survival (RFS) in the retrospective discovery tissue microarray (TMA; n = 158) were subsequently evaluated in an independent validation TMA (n = 114). Cox proportional hazards regression models were used to assess the association between survival parameters and covariates, the Kaplan-Meier method to estimate the distribution of survival, and the log-rank test to compare distributions. RESULTS: Expression of CD74 on melanoma cells was unique, and in the discovery TMA, it associated with favorable patient outcome (OS: HR, 0.53; P = 0.01 and RFS: HR, 0.56; P = 0.01). The validation data set confirmed the CD74 prognostic significance and revealed that the absence of macrophage migration inhibitory factor (MIF) and inducible nitric oxide synthase (iNOS) was also associated with poor survival parameters. Consistent with the protein observation, tumor CD74 mRNA expression also correlated positively (P = 0.003) with OS in the melanoma TCGA data set. CONCLUSIONS: Our data validate CD74 as a useful prognostic tumor cell protein marker associated with favorable RFS and OS in stage III melanoma. Low or negative expression of MIF in both TMAs and of iNOS in the validation set also provided useful prognostic data. A disease-specific investigation of CD74's functional significance is warranted, and other markers appear intriguing to pursue. Clin Cancer Res; 22(12); 3016-24. ©2016 AACR.

23 Article Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy. 2016

Peng, Weiyi / Chen, Jie Qing / Liu, Chengwen / Malu, Shruti / Creasy, Caitlin / Tetzlaff, Michael T / Xu, Chunyu / McKenzie, Jodi A / Zhang, Chunlei / Liang, Xiaoxuan / Williams, Leila J / Deng, Wanleng / Chen, Guo / Mbofung, Rina / Lazar, Alexander J / Torres-Cabala, Carlos A / Cooper, Zachary A / Chen, Pei-Ling / Tieu, Trang N / Spranger, Stefani / Yu, Xiaoxing / Bernatchez, Chantale / Forget, Marie-Andree / Haymaker, Cara / Amaria, Rodabe / McQuade, Jennifer L / Glitza, Isabella C / Cascone, Tina / Li, Haiyan S / Kwong, Lawrence N / Heffernan, Timothy P / Hu, Jianhua / Bassett, Roland L / Bosenberg, Marcus W / Woodman, Scott E / Overwijk, Willem W / Lizée, Gregory / Roszik, Jason / Gajewski, Thomas F / Wargo, Jennifer A / Gershenwald, Jeffrey E / Radvanyi, Laszlo / Davies, Michael A / Hwu, Patrick. ·Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Pathology, University of Chicago, Chicago, Illinois. · Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Pathology, Yale University School of Medicine, New Haven, Connecticut. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. phwu@mdanderson.org mdavies@mdanderson.org. ·Cancer Discov · Pubmed #26645196.

ABSTRACT: SIGNIFICANCE: This study adds to the growing evidence that oncogenic pathways in tumors can promote resistance to the antitumor immune response. As PTEN loss and PI3K-AKT pathway activation occur in multiple tumor types, the results support the rationale to further evaluate combinatorial strategies targeting the PI3K-AKT pathway to increase the efficacy of immunotherapy.

24 Article Intrathecal Administration of Tumor-Infiltrating Lymphocytes Is Well Tolerated in a Patient with Leptomeningeal Disease from Metastatic Melanoma: A Case Report. 2015

Glitza, Isabella C / Haymaker, Cara / Bernatchez, Chantale / Vence, Luis / Rohlfs, Michelle / Richard, Jessie / Lacey, Carol / Mansaray, Rahmatu / Fulbright, Orenthial J / Ramachandran, Renjith / Toth, Christopher / Wardell, Seth / Patel, Sapna P / Woodman, Scott E / Hwu, Wen-Jen / Radvanyi, Laszlo G / Davies, Michael A / Papadopoulos, Nicholas E / Hwu, Patrick. ·Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. icglitza@mdanderson.org. · Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas. ·Cancer Immunol Res · Pubmed #26216417.

ABSTRACT: TREATMENTS: Subsequent imaging demonstrated disease stabilization, and neurological deficits also remained stable. The patient expired 5 months after the initiation of i.t. TIL therapy with disease progression in the brain, liver, lung, and peritoneal and retroperitoneal lymph nodes, but without LMD progression. These results demonstrate the safety of i.t. administration of TIL in melanoma patients with LMD and support the feasibility of conducting a prospective clinical trial to determine this therapy's clinical benefit among these patients.

25 Article ErbB3-ErbB2 Complexes as a Therapeutic Target in a Subset of Wild-type BRAF/NRAS Cutaneous Melanomas. 2015

Capparelli, Claudia / Rosenbaum, Sheera / Berman-Booty, Lisa D / Salhi, Amel / Gaborit, Nadège / Zhan, Tingting / Chervoneva, Inna / Roszik, Jason / Woodman, Scott E / Davies, Michael A / Setiady, Yulius Y / Osman, Iman / Yarden, Yosef / Aplin, Andrew E. ·Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. · The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York. · Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel. · Division of Biostatistics, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · ImmunoGen, Inc., Waltham, Massachusetts. · The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York. The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, New York. · Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. aea004@jefferson.edu. ·Cancer Res · Pubmed #26206558.

ABSTRACT: The treatment options remain limited for patients with melanoma who are wild-type for both BRAF and NRAS (WT/WT). We demonstrate that a subgroup of WT/WT melanomas display high basal phosphorylation of ErbB3 that is associated with autocrine production of the ErbB3 ligand neuregulin-1 (NRG1). In WT/WT melanoma cells displaying high levels of phospho-ErbB3, knockdown of NRG1 reduced cell viability and was associated with decreased phosphorylation of ErbB3, its coreceptor ErbB2, and its downstream target, AKT. Similar effects were observed by targeting ErbB3 with either siRNAs or the neutralizing ErbB3 monoclonal antibodies huHER3-8 and NG33. In addition, pertuzumab-mediated inhibition of ErbB2 heterodimerization decreased AKT phosphorylation, cell growth in vitro, and xenograft growth in vivo. Pertuzumab also potentiated the effects of MEK inhibitor on WT/WT melanoma growth in vitro and in vivo. These findings demonstrate that targeting ErbB3-ErbB2 signaling in a cohort of WT/WT melanomas leads to tumor growth reduction. Together, these studies support the rationale to target the NRG1-ErbB3-ErbB2 axis as a novel treatment strategy in a subset of cutaneous melanomas.

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