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Melanoma: HELP
Articles by Scott E. Woodman
Based on 44 articles published since 2010
(Why 44 articles?)
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Between 2010 and 2020, S. Woodman wrote the following 44 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 B cells and tertiary lymphoid structures promote immunotherapy response. 2020

Helmink, Beth A / Reddy, Sangeetha M / Gao, Jianjun / Zhang, Shaojun / Basar, Rafet / Thakur, Rohit / Yizhak, Keren / Sade-Feldman, Moshe / Blando, Jorge / Han, Guangchun / Gopalakrishnan, Vancheswaran / Xi, Yuanxin / Zhao, Hao / Amaria, Rodabe N / Tawbi, Hussein A / Cogdill, Alex P / Liu, Wenbin / LeBleu, Valerie S / Kugeratski, Fernanda G / Patel, Sapna / Davies, Michael A / Hwu, Patrick / Lee, Jeffrey E / Gershenwald, Jeffrey E / Lucci, Anthony / Arora, Reetakshi / Woodman, Scott / Keung, Emily Z / Gaudreau, Pierre-Olivier / Reuben, Alexandre / Spencer, Christine N / Burton, Elizabeth M / Haydu, Lauren E / Lazar, Alexander J / Zapassodi, Roberta / Hudgens, Courtney W / Ledesma, Deborah A / Ong, SuFey / Bailey, Michael / Warren, Sarah / Rao, Disha / Krijgsman, Oscar / Rozeman, Elisa A / Peeper, Daniel / Blank, Christian U / Schumacher, Ton N / Butterfield, Lisa H / Zelazowska, Monika A / McBride, Kevin M / Kalluri, Raghu / Allison, James / Petitprez, Florent / Fridman, Wolf Herman / Sautès-Fridman, Catherine / Hacohen, Nir / Rezvani, Katayoun / Sharma, Padmanee / Tetzlaff, Michael T / Wang, Linghua / Wargo, Jennifer A. ·Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. bhelmink@mdanderson.org. · Department of Breast Medical Oncology, 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 Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Stem Cell Transplantation and Cellular Therapy, 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 Medicine, Massachusetts General Hospital Cancer Center, Boston, MA, USA. · Broad Institute of the Massachusetts Institute of Technology, Boston, MA, USA. · Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Thoracic / Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. · Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Nanostring Technologies, Seattle, WA, USA. · Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. · Departments of Medicine, Surgery, Immunology and Clinical and Translational Science, University of Pittsburgh, Pittsburgh, PA, USA. · Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · INSERM, Cordeliers Research Center, Team Cancer, Immune Control and Escape, Paris, France. · University Paris Descartes Paris 5, Sorbonne Paris Cite, Centre de Recherche des Cordeliers, Paris, France. · Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. jwargo@mdanderson.org. · Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. jwargo@mdanderson.org. ·Nature · Pubmed #31942075.

ABSTRACT: Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers

13 Article Elevated Endogenous SDHA Drives Pathological Metabolism in Highly Metastatic Uveal Melanoma. 2019

Chattopadhyay, Chandrani / Oba, Junna / Roszik, Jason / Marszalek, Joseph R / Chen, Ken / Qi, Yuan / Eterovic, Karina / Robertson, A Gordon / Burks, Jared K / McCannel, Tara A / Grimm, Elizabeth A / Woodman, Scott E. ·Melanoma Medical Oncology, UT MD Anderson Cancer Center, Houston, Texas, United States. · Genomic Medicine, UT MD Anderson Cancer Center, Houston, Texas, United States. · Institute of Applied Cancer Science & Center for Co-Clinical Trials, UT MD Anderson Cancer Center, Houston, Texas, United States. · Bioinformatics & Computational Biology, UT MD Anderson Cancer Center, Houston, Texas, United States. · Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada. · Leukemia, UT MD Anderson Cancer Center, Houston, Texas, United States. · Stein Eye and Doheny Eye Institutes, University of California Los Angeles, Los Angeles, California, United States. · Systems Biology, UT MD Anderson Cancer Center, Houston, Texas, United States. ·Invest Ophthalmol Vis Sci · Pubmed #31596927.

ABSTRACT: Purpose: Metastatic uveal melanoma (UM) has a very poor prognosis and no effective therapy. Despite remarkable advances in treatment of cutaneous melanoma, UM remains recalcitrant to chemotherapy, small-molecule kinase inhibitors, and immune-based therapy. Methods: We assessed two sets of oxidative phosphorylation (OxPhos) genes within 9858 tumors across 31 cancer types. An OxPhos inhibitor was used to characterize differential metabolic programming of highly metastatic monosomy 3 (M3) UM. Seahorse analysis and global metabolomics profiling were done to identify metabolic vulnerabilities. Analyses of UM TCGA data set were performed to determine expressions of key OxPhos effectors in M3 and non-M3 UM. We used targeted knockdown of succinate dehydrogenase A (SDHA) to determine the role of SDHA in M3 UM in conferring resistance to OxPhos inhibition. Results: We identified UM to have among the highest median OxPhos levels and showed that M3 UM exhibits a distinct metabolic profile. M3 UM shows markedly low succinate levels and has highly increased levels of SDHA, the enzyme that couples the tricarboxylic acid cycle with OxPhos by oxidizing (lowering) succinate. We showed that SDHA-high M3 UM have elevated expression of key OxPhos molecules, exhibit abundant mitochondrial reserve respiratory capacity, and are resistant to OxPhos antagonism, which can be reversed by SDHA knockdown. Conclusions: Our study has identified a critical metabolic program within poor prognostic M3 UM. In addition to the heightened mitochondrial functional capacity due to elevated SDHA, M3 UM SDHA-high mediate resistance to therapy that is reversible with targeted treatment.

14 Article CD38-Mediated Immunosuppression as a Mechanism of Tumor Cell Escape from PD-1/PD-L1 Blockade. 2018

Chen, Limo / Diao, Lixia / Yang, Yongbin / Yi, Xiaohui / Rodriguez, B Leticia / Li, Yanli / Villalobos, Pamela A / Cascone, Tina / Liu, Xi / Tan, Lin / Lorenzi, Philip L / Huang, Anfei / Zhao, Qiang / Peng, Di / Fradette, Jared J / Peng, David H / Ungewiss, Christin / Roybal, Jonathon / Tong, Pan / Oba, Junna / Skoulidis, Ferdinandos / Peng, Weiyi / Carter, Brett W / Gay, Carl M / Fan, Youhong / Class, Caleb A / Zhu, Jingfen / Rodriguez-Canales, Jaime / Kawakami, Masanori / Byers, Lauren Averett / Woodman, Scott E / Papadimitrakopoulou, Vassiliki A / Dmitrovsky, Ethan / Wang, Jing / Ullrich, Stephen E / Wistuba, Ignacio I / Heymach, John V / Qin, F Xiao-Feng / Gibbons, Don L. ·Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Shanghai First People's Hospital, Shanghai, Shanghai, China. · Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, Shanghai, China. · Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · The Proteomics and Metabolomics Core Facility, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing; Suzhou Institute of Systems Medicine, Suzhou, China. · Sun Yat-sen University School of Life Sciences, Guangzhou, Guangdong, China. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Diagnostic Imaging, 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 Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · MedImmune, Gaithersburg, Maryland. · Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. dlgibbon@mdanderson.org. · Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. ·Cancer Discov · Pubmed #30012853.

ABSTRACT: Although treatment with immune checkpoint inhibitors provides promising benefit for patients with cancer, optimal use is encumbered by high resistance rates and requires a thorough understanding of resistance mechanisms. We observed that tumors treated with PD-1/PD-L1 blocking antibodies develop resistance through the upregulation of CD38, which is induced by all-trans retinoic acid and IFNβ in the tumor microenvironment.

15 Article Prospective Analysis of Adoptive TIL Therapy in Patients with Metastatic Melanoma: Response, Impact of Anti-CTLA4, and Biomarkers to Predict Clinical Outcome. 2018

Forget, Marie-Andrée / Haymaker, Cara / Hess, Kenneth R / Meng, Yuzhong Jeff / Creasy, Caitlin / Karpinets, Tatiana / Fulbright, Orenthial J / Roszik, Jason / Woodman, Scott E / Kim, Young Uk / Sakellariou-Thompson, Donastas / Bhatta, Ankit / Wahl, Arely / Flores, Esteban / Thorsen, Shawne T / Tavera, René J / Ramachandran, Renjith / Gonzalez, Audrey M / Toth, Christopher L / Wardell, Seth / Mansaray, Rahmatu / Patel, Vruti / Carpio, Destiny Joy / Vaughn, Carol / Farinas, Chantell M / Velasquez, Portia G / Hwu, Wen-Jen / Patel, Sapna P / Davies, Michael A / Diab, Adi / Glitza, Isabella C / Tawbi, Hussein / Wong, Michael K / Cain, Suzanne / Ross, Merrick I / Lee, Jeffrey E / Gershenwald, Jeffrey E / Lucci, Anthony / Royal, Richard / Cormier, Janice N / Wargo, Jennifer A / Radvanyi, Laszlo G / Torres-Cabala, Carlos A / Beroukhim, Rameen / Hwu, Patrick / Amaria, Rodabe N / Bernatchez, Chantale. ·Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas. · Department of Biostatistics, The University of Texas MDACC, Houston, Texas. · Broad Institute of Harvard and MIT, Cambridge, Massachusetts. · Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Genomic Medicine, The University of Texas MDACC, Houston, Texas. · Department of Surgical Oncology, The University of Texas MDACC, Houston, Texas. · Department of Pathology, The University of Texas MDACC, Houston, Texas. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas. cbernatchez@mdanderson.org rnamaria@mdanderson.org. ·Clin Cancer Res · Pubmed #29848573.

ABSTRACT:

16 Article Increased Tumor Glycolysis Characterizes Immune Resistance to Adoptive T Cell Therapy. 2018

Cascone, Tina / McKenzie, Jodi A / Mbofung, Rina M / Punt, Simone / Wang, Zhe / Xu, Chunyu / Williams, Leila J / Wang, Zhiqiang / Bristow, Christopher A / Carugo, Alessandro / Peoples, Michael D / Li, Lerong / Karpinets, Tatiana / Huang, Lu / Malu, Shruti / Creasy, Caitlin / Leahey, Sara E / Chen, Jiong / Chen, Yuan / Pelicano, Helen / Bernatchez, Chantale / Gopal, Y N Vashisht / Heffernan, Timothy P / Hu, Jianhua / Wang, Jing / Amaria, Rodabe N / Garraway, Levi A / Huang, Peng / Yang, Peiying / Wistuba, Ignacio I / Woodman, Scott E / Roszik, Jason / Davis, R Eric / Davies, Michael A / Heymach, John V / Hwu, Patrick / Peng, Weiyi. ·Department of Thoracic/Head & Neck 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, Houston, TX 77030, USA. · Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Institute for Applied Cancer Science, 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 Genomic Medicine, 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 Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. · Department of Palliative, Rehabilitation and Integrative Medicine, 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, Houston, TX 77030, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Lymphoma/Myeloma, 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 Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: phwu@mdanderson.org. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: wpeng@mdanderson.org. ·Cell Metab · Pubmed #29628419.

ABSTRACT: Adoptive T cell therapy (ACT) produces durable responses in some cancer patients; however, most tumors are refractory to ACT and the molecular mechanisms underlying resistance are unclear. Using two independent approaches, we identified tumor glycolysis as a pathway associated with immune resistance in melanoma. Glycolysis-related genes were upregulated in melanoma and lung cancer patient samples poorly infiltrated by T cells. Overexpression of glycolysis-related molecules impaired T cell killing of tumor cells, whereas inhibition of glycolysis enhanced T cell-mediated antitumor immunity in vitro and in vivo. Moreover, glycolysis-related gene expression was higher in melanoma tissues from ACT-refractory patients, and tumor cells derived from these patients exhibited higher glycolytic activity. We identified reduced levels of IRF1 and CXCL10 immunostimulatory molecules in highly glycolytic melanoma cells. Our findings demonstrate that tumor glycolysis is associated with the efficacy of ACT and identify the glycolysis pathway as a candidate target for combinatorial therapeutic intervention.

17 Article The RNA-binding Protein MEX3B Mediates Resistance to Cancer Immunotherapy by Downregulating HLA-A Expression. 2018

Huang, Lu / Malu, Shruti / McKenzie, Jodi A / Andrews, Miles C / Talukder, Amjad H / Tieu, Trang / Karpinets, Tatiana / Haymaker, Cara / Forget, Marie-Andrée / Williams, Leila J / Wang, Zhe / Mbofung, Rina M / Wang, Zhi-Qiang / Davis, Richard Eric / Lo, Roger S / Wargo, Jennifer A / Davies, Michael A / Bernatchez, Chantale / Heffernan, Timothy / Amaria, Rodabe N / Korkut, Anil / Peng, Weiyi / Roszik, Jason / Lizée, Gregory / Woodman, Scott E / Hwu, Patrick. ·Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Surgical Oncology, 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 Genomic Medicine, 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 Medicine, The University of California, Los Angeles, Los Angeles, California. · Department of Bioinformatics and Computational 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. phwu@mdanderson.org. ·Clin Cancer Res · Pubmed #29496759.

ABSTRACT:

18 Article Retrospective review of metastatic melanoma patients with leptomeningeal disease treated with intrathecal interleukin-2. 2018

Glitza, Isabella C / Rohlfs, Michelle / Guha-Thakurta, Nandita / Bassett, Roland L / Bernatchez, Chantale / Diab, Adi / Woodman, Scott E / Yee, Cassian / Amaria, Rodabe N / Patel, Sapna P / Tawbi, Hussein / Wong, Michael / Hwu, Wen-Jen / Hwu, Patrick / Heimberger, Amy / McCutcheon, Ian E / Papadopoulos, Nicholas / Davies, Michael A. ·Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. · Department of Diagnostic Radiology/ Neuro Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. · Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. · Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. ·ESMO Open · Pubmed #29387478.

ABSTRACT: Objectives: Metastatic melanoma patients with leptomeningeal disease (LMD) have an extremely poor prognosis, with a median survival measured in weeks, and few treatment options. Outcomes of a retrospective cohort of patients with LMD that were treated with intrathecal interleukin-2 (IT IL-2) were reviewed to assess the long-term efficacy of this therapy. Methods: The records of metastatic melanoma patients with LMD who were treated with IT IL-2 from 2006 to 2014 in a Compassionate Investigational New Drug study were reviewed. IL-2 (1.2 mIU) was administered intrathecally via Ommaya reservoir up to five times per week in the inpatient setting for 4 weeks; patients with good tolerance and clinical benefit received maintenance IT IL-2 every 1-3 months thereafter. Results: The cohort included 43 patients. The median age of the patients was 47 years (range 18-71), and 32 (74%) were male. 23 patients (53%) had positive cerebrospinal fluid (CSF) cytology and radiographic evidence of LMD, 8 (19%) had positive CSF cytology only, 9 (21%) had radiographic evidence only and 3 (7%) were diagnosed based on pathology review after craniotomy. The median overall survival (OS) from initiation of IT IL-2 was 7.8 months (range, 0.4-90.8 months), with 1-year, 2-year and 5-year OS rates of 36%, 26% and 13%. The presence of neurological symptoms (HR 2.1, P=0.03), positive baseline CSF cytology (HR 4.1, P=0.001) and concomitant use of targeted therapy (HR 3.0, P=0.02) was associated with shorter OS on univariate analysis. All patients developed symptoms due to increased intracranial pressure which was managed with supportive medications and/or CSF removal, and there were no treatment-related deaths. Conclusion: These results demonstrate that despite their historically dismal prognosis a subset of metastatic melanoma patients with LMD treated with IT IL-2 can achieve long-term survival, but these data need to be verified in a prospective trial setting.

19 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 (

20 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 / Anonymous1140916 / 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.

21 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.

22 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.

23 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

24 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.

25 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.

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