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Melanoma: HELP
Articles by Jennifer A. Wargo
Based on 85 articles published since 2009
(Why 85 articles?)
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Between 2009 and 2019, J. Wargo wrote the following 85 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Editorial Immunotherapy resistance: the answers lie ahead - not in front - of us. 2017

Andrews, Miles C / Wargo, Jennifer A. ·Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Unit Number 1484, Houston, TX 77030 USA. · Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Unit Number 1484, Houston, TX 77030 USA. ·J Immunother Cancer · Pubmed #28239464.

ABSTRACT: Mechanisms of innate and adaptive resistance to checkpoint blockade immunotherapy are under intense investigation with a view to broadening the therapeutic potential of this form of treatment. In a recent manuscript by Zaretsky and colleagues, mutational events were identified that effectively crippled ongoing immunotherapy responses in patients treated with anti-PD-1 therapy. These results are discussed in the light of other recent and ongoing research efforts exploring both mutational and non-mutational resistance mechanisms, highlighting the critical translational importance of longitudinal tumor sampling.

2 Review Combination Immunotherapy Development in Melanoma. 2018

Eggermont, Alexander M M / Crittenden, Marka / Wargo, Jennifer. ·From the Gustave Roussy Cancer Institute and University Paris-Saclay, Villejuif, France; Earle A. Chiles Research Institute, Portland, OR; The University of Texas MD Anderson Cancer Center, Houston, TX. ·Am Soc Clin Oncol Educ Book · Pubmed #30231333.

ABSTRACT: Melanoma has been the most important cancer to drive immunotherapy development of solid tumors. Since 2010, immunotherapy has been revolutionized by the concept of breaking tolerance. It represents a major paradigm shift and marks the beginning of a new era. The impact of the first immune checkpoint inhibitors, anti-CTLA-4 and anti-PD-1/anti-PD-L1, is unprecedented. In 7 years, it transformed advanced-stage melanoma into a curable disease in over 50% of patients. Another major step has been the development of the combination of BRAF inhibitors plus MEK inhibitors in the treatment of BRAF-mutant melanomas. For the treatment of advanced disease, approvals were obtained for the immune checkpoint inhibitors ipilimumab (2011), nivolumab (2014), pembrolizumab (2014), the combination ipilimumab plus nivolumab (2015), and the oncolytic virus vaccine laherparepvec (2015). The combination dabrafenib plus trametinib for BRAF-mutant melanoma was approved in 2014, with similar success for other BRAF plus MEK inhibitor combinations. Because of its unique therapeutic index (high efficacy and low toxicity) anti-PD-1 agents (nivolumab and pembrolizumab) have now been placed at the center of practically all combination therapy development strategies in melanoma. Anti-PD-1 agents are the central molecule for combinations with a great variety of other immunotherapeutics such as immune checkpoint inhibitors, agonists, IDO inhibitors, macrophage polarizing agents, monoclonal antibodies, vaccines, targeted agents, chemotherapeutics, radiation therapy, and even microbiome modulators.

3 Review Interaction of molecular alterations with immune response in melanoma. 2017

Szczepaniak Sloane, Robert A / Gopalakrishnan, Vancheswaran / Reddy, Sangeetha M / Zhang, Xue / Reuben, Alexandre / Wargo, Jennifer A. ·Department of Surgical Oncology, 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 Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. ·Cancer · Pubmed #28543700.

ABSTRACT: Major advances have been made in melanoma treatment with the use of molecularly targeted therapies and immunotherapies, and numerous regimens are now approved by the US Food and Drug Administration for patients with stage IV disease. However, therapeutic resistance remains an issue to both classes of agents, and reliable biomarkers of therapeutic response and resistance are lacking. Mechanistic insights are being gained through preclinical studies and translational research, offering potential strategies to enhance responses and survival in treated patients. A comprehensive understanding of the immune effects of common mutations at play in melanoma is critical, as is an appreciation of the molecular mechanisms contributing to therapeutic resistance to immunotherapy. These mechanisms and the interplay between them are discussed herein. Cancer 2017;123:2130-42. © 2017 American Cancer Society.

4 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.

5 Review Novel Treatments in Development for Melanoma. 2016

Bernatchez, Chantale / Cooper, Zachary A / Wargo, Jennifer A / Hwu, Patrick / Lizée, Gregory. ·University of Texas MD Anderson Cancer Center, Houston, TX, USA. · University of Texas MD Anderson Cancer Center, Houston, TX, USA. phwu@mdanderson.org. ·Cancer Treat Res · Pubmed #26601872.

ABSTRACT: The past several years can be considered a renaissance era in the treatment of metastatic melanoma. Following a 30-year stretch in which oncologists barely put a dent in a very grim overall survival (OS) rate for these patients, things have rapidly changed course with the recent approval of three new melanoma drugs by the FDA. Both oncogene-targeted therapy and immune checkpoint blockade approaches have shown remarkable efficacy in a subset of melanoma patients and have clearly been game-changers in terms of clinical impact. However, most patients still succumb to their disease, and thus, there remains an urgent need to improve upon current therapies. Fortunately, innovations in molecular medicine have led to many silent gains that have greatly increased our understanding of the nature of cancer biology as well as the complex interactions between tumors and the immune system. They have also allowed for the first time a detailed understanding of an individual patient's cancer at the genomic and proteomic level. This information is now starting to be employed at all stages of cancer treatment, including diagnosis, choice of drug therapy, treatment monitoring, and analysis of resistance mechanisms upon recurrence. This new era of personalized medicine will foreseeably lead to paradigm shifts in immunotherapeutic treatment approaches such as individualized cancer vaccines and adoptive transfer of genetically modified T cells. Advances in xenograft technology will also allow for the testing of drug combinations using in vivo models, a truly necessary development as the number of new drugs needing to be tested is predicted to skyrocket in the coming years. This chapter will provide an overview of recent technological developments in cancer research, and how they are expected to impact future diagnosis, monitoring, and development of novel treatments for metastatic melanoma.

6 Review Surgical management of melanoma. 2009

Wargo, Jennifer A / Tanabe, Kenneth. ·Department of Surgery, Harvard Medical School, Boston, MA, USA. ajwargo@partners.org ·Hematol Oncol Clin North Am · Pubmed #19464603.

ABSTRACT: Melanoma is an increasing health care problem worldwide. Up to 80,000 cases of melanoma are diagnosed per year and it is the sixth leading cause of cancer death in the United States. The lifetime risk is estimated to be 1 in 75 individuals for the development of melanoma. Surgery remains the mainstay of treatment of melanoma, and in most cases it is curative. Several important surgical issues are discussed in this review, including the extent of surgical margins, Mohs micrographic surgery for melanoma in situ, the use of sentinel lymph node biopsy, the usefulness of lymphadenectomy, isolated limb perfusion, and the role of metastasectomy.

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 Tumor-associated B-cells induce tumor heterogeneity and therapy resistance. 2017

Somasundaram, Rajasekharan / Zhang, Gao / Fukunaga-Kalabis, Mizuho / Perego, Michela / Krepler, Clemens / Xu, Xiaowei / Wagner, Christine / Hristova, Denitsa / Zhang, Jie / Tian, Tian / Wei, Zhi / Liu, Qin / Garg, Kanika / Griss, Johannes / Hards, Rufus / Maurer, Margarita / Hafner, Christine / Mayerhöfer, Marius / Karanikas, Georgios / Jalili, Ahmad / Bauer-Pohl, Verena / Weihsengruber, Felix / Rappersberger, Klemens / Koller, Josef / Lang, Roland / Hudgens, Courtney / Chen, Guo / Tetzlaff, Michael / Wu, Lawrence / Frederick, Dennie Tompers / Scolyer, Richard A / Long, Georgina V / Damle, Manashree / Ellingsworth, Courtney / Grinman, Leon / Choi, Harry / Gavin, Brian J / Dunagin, Margaret / Raj, Arjun / Scholler, Nathalie / Gross, Laura / Beqiri, Marilda / Bennett, Keiryn / Watson, Ian / Schaider, Helmut / Davies, Michael A / Wargo, Jennifer / Czerniecki, Brian J / Schuchter, Lynn / Herlyn, Dorothee / Flaherty, Keith / Herlyn, Meenhard / Wagner, Stephan N. ·The Wistar Institute, Philadelphia, PA, 19104, USA. Shyam@wistar.org. · The Wistar Institute, Philadelphia, PA, 19104, USA. · Department of Pathology and Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. · Division of Immunology, Allergy and Infectious Diseases (DIAID), Department of Dermatology, Medical University of Vienna, Vienna, A-1090, Austria. · New Jersey Institute of Technology, Newark, NJ, 07102, USA. · Department of Dermatology and Venereology, Karl Landsteiner University of Health Sciences, St. Pölten, A-3100, Austria. · Department of Radiology, Division of Nuclear Medicine, Medical University of Vienna, Vienna, A-1090, Austria. · Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, A-1090, Austria. · Department of Dermatology and Venereology, The Rudolfstiftung Hospital, Teaching Hospital of the Medical University Vienna, Vienna, A-1030, Austria. · Department of Dermatology, Paracelsus Medical University Salzburg, Salzburg, A-5020, Austria. · Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77040, USA. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77040, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, 02115, USA. · Melanoma Institute of Australia, and The University of Sydney, Sydney, 2065, Australia. · Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA. · Abramson Cancer Center, Hospital of University of Pennsylvania, Philadelphia, PA, 19104, USA. · SRI International, Menlo Park, CA, 94025, USA. · CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, A-1090, Austria. · Department of Biochemistry, McGill University, Montreal, QC, Canada, H3A0G4. · Dermatology Research Center, University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, 4102, Australia. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer, Center, Houston, TX, 77040, USA. · Moffitt Cancer Center, Tampa, FL, 33612, USA. · The Wistar Institute, Philadelphia, PA, 19104, USA. Herlynm@wistar.org. · Division of Immunology, Allergy and Infectious Diseases (DIAID), Department of Dermatology, Medical University of Vienna, Vienna, A-1090, Austria. stephan.wagner@meduniwien.ac.at. ·Nat Commun · Pubmed #28928360.

ABSTRACT: In melanoma, therapies with inhibitors to oncogenic BRAF

10 Clinical Trial Clinical, Molecular, and Immune Analysis of Dabrafenib-Trametinib Combination Treatment for BRAF Inhibitor-Refractory Metastatic Melanoma: A Phase 2 Clinical Trial. 2016

Chen, Guo / McQuade, Jennifer L / Panka, David J / Hudgens, Courtney W / Amin-Mansour, Ali / Mu, Xinmeng Jasmine / Bahl, Samira / Jané-Valbuena, Judit / Wani, Khalida M / Reuben, Alexandre / Creasy, Caitlyn A / Jiang, Hong / Cooper, Zachary A / Roszik, Jason / Bassett, Roland L / Joon, Aron Y / Simpson, Lauren M / Mouton, Rosalind D / Glitza, Isabella C / Patel, Sapna P / Hwu, Wen-Jen / Amaria, Rodabe N / Diab, Adi / Hwu, Patrick / Lazar, Alexander J / Wargo, Jennifer A / Garraway, Levi A / Tetzlaff, Michael T / Sullivan, Ryan J / Kim, Kevin B / Davies, Michael A. ·Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston. · Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston. · Beth Israel Deaconess Medical Center, Boston, Massachusetts. · Departments of Pathology and Translational and Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston. · Broad Institute, Cambridge, Massachusetts. · Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston7Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston. · Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston. · Massachusetts General Hospital, Boston. · California Pacific Medical Center Research Institute, San Francisco. · Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston11Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston. ·JAMA Oncol · Pubmed #27124486.

ABSTRACT: IMPORTANCE: Combined treatment with dabrafenib and trametinib (CombiDT) achieves clinical responses in only about 15% of patients with BRAF inhibitor (BRAFi)-refractory metastatic melanoma in contrast to the higher response rate observed in BRAFi-naïve patients. Identifying correlates of response and mechanisms of resistance in this population will facilitate clinical management and rational therapeutic development. OBJECTIVE: To determine correlates of benefit from CombiDT therapy in patients with BRAFi-refractory metastatic melanoma. DESIGN, SETTING, AND PARTICIPANTS: Single-center, single-arm, open-label phase 2 trial of CombiDT treatment in patients with BRAF V600 metastatic melanoma resistant to BRAFi monotherapy conducted between September 2012 and October 2014 at the University of Texas MD Anderson Cancer Center. Key eligibility criteria for participants included BRAF V600 metastatic melanoma, prior BRAFi monotherapy, measurable disease (RECIST 1.1), and tumor accessible for biopsy. INTERVENTIONS: Patients were treated with dabrafenib (150 mg, twice daily) and trametinib (2 mg/d) continuously until disease progression or intolerance. All participants underwent a mandatory baseline biopsy, and optional biopsy specimens were obtained on treatment and at disease progression. Whole-exome sequencing, reverse transcription polymerase chain reaction analysis for BRAF splicing, RNA sequencing, and immunohistochemical analysis were performed on tumor samples, and blood was analyzed for levels of circulating BRAF V600. MAIN OUTCOMES AND MEASURES: The primary end point was overall response rate (ORR). Progression-free survival (PFS) and overall survival (OS) were secondary clinical end points. RESULTS: A total of 28 patients were screened, and 23 enrolled. Among evaluable patients, the confirmed ORR was 10%; disease control rate (DCR) was 45%, and median PFS was 13 weeks. Clinical benefit was associated with duration of prior BRAFi therapy greater than 6 months (DCR, 73% vs 11% for ≤6 months; P = .02) and decrease in circulating BRAF V600 at day 8 of cycle 1 (DCR, 75% vs 18% for no decrease; P = .02) but not with pretreatment mitogen-activated protein kinase (MAPK) pathway mutations or activation. Biopsy specimens obtained during treatment demonstrated that CombiDT therapy failed to achieve significant MAPK pathway inhibition or immune infiltration in most patients. CONCLUSIONS AND RELEVANCE: The baseline presence of MAPK pathway alterations was not associated with benefit from CombiDT in patients with BRAFi-refractory metastatic melanoma. Failure to inhibit the MAPK pathway provides a likely explanation for the limited clinical benefit of CombiDT in this setting. Circulating BRAF V600 is a promising early biomarker of clinical response. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01619774.

11 Clinical Trial Clinical profiling of BCL-2 family members in the setting of BRAF inhibition offers a rationale for targeting de novo resistance using BH3 mimetics. 2014

Frederick, Dennie T / Salas Fragomeni, Roberto A / Schalck, Aislyn / Ferreiro-Neira, Isabel / Hoff, Taylor / Cooper, Zachary A / Haq, Rizwan / Panka, David J / Kwong, Lawrence N / Davies, Michael A / Cusack, James C / Flaherty, Keith T / Fisher, David E / Mier, James W / Wargo, Jennifer A / Sullivan, Ryan J. ·Division of Surgical Oncology, Massachusetts General Hospital, Boston, Massachusetts, United States of America. · Division of Surgical Oncology, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Harvard Medical School, Boston, Massachusetts, United States of America. · Division of Medical Oncology, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, United States of America. · Department of Surgical Oncology and Genomic Medicine, University of Texas, M.D.Anderson Cancer Center, Houston, Texas, United States of America. · Harvard Medical School, Boston, Massachusetts, United States of America; Division of Medical Oncology, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, United States of America. · Harvard Medical School, Boston, Massachusetts, United States of America; Division of Hematology Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America. · Harvard Medical School, Boston, Massachusetts, United States of America; Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts, United States of America. ·PLoS One · Pubmed #24983357.

ABSTRACT: While response rates to BRAF inhibitiors (BRAFi) are high, disease progression emerges quickly. One strategy to delay the onset of resistance is to target anti-apoptotic proteins such as BCL-2, known to be associated with a poor prognosis. We analyzed BCL-2 family member expression levels of 34 samples from 17 patients collected before and 10 to 14 days after treatment initiation with either vemurafenib or dabrafenib/trametinib combination. The observed changes in mRNA and protein levels with BRAFi treatment led us to hypothesize that combining BRAFi with a BCL-2 inhibitor (the BH3-mimetic navitoclax) would improve outcome. We tested this hypothesis in cell lines and in mice. Pretreatment mRNA levels of BCL-2 negatively correlated with maximal tumor regression. Early increases in mRNA levels were seen in BIM, BCL-XL, BID and BCL2-W, as were decreases in MCL-1 and BCL2A. No significant changes were observed with BCL-2. Using reverse phase protein array (RPPA), significant increases in protein levels were found in BIM and BID. No changes in mRNA or protein correlated with response. Concurrent BRAF (PLX4720) and BCL2 (navitoclax) inhibition synergistically reduced viability in BRAF mutant cell lines and correlated with down-modulation of MCL-1 and BIM induction after PLX4720 treatment. In xenograft models, navitoclax enhanced the efficacy of PLX4720. The combination of a selective BRAF inhibitor with a BH3-mimetic promises to be an important therapeutic strategy capable of enhancing the clinical efficacy of BRAF inhibition in many patients that might otherwise succumb quickly to de novo resistance. Trial registrations: ClinicalTrials.gov NCT01006980; ClinicalTrials.gov NCT01107418; ClinicalTrials.gov NCT01264380; ClinicalTrials.gov NCT01248936; ClinicalTrials.gov NCT00949702; ClinicalTrials.gov NCT01072175.

12 Clinical Trial MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition. 2014

Wagle, Nikhil / Van Allen, Eliezer M / Treacy, Daniel J / Frederick, Dennie T / Cooper, Zachary A / Taylor-Weiner, Amaro / Rosenberg, Mara / Goetz, Eva M / Sullivan, Ryan J / Farlow, Deborah N / Friedrich, Dennis C / Anderka, Kristin / Perrin, Danielle / Johannessen, Cory M / McKenna, Aaron / Cibulskis, Kristian / Kryukov, Gregory / Hodis, Eran / Lawrence, Donald P / Fisher, Sheila / Getz, Gad / Gabriel, Stacey B / Carter, Scott L / Flaherty, Keith T / Wargo, Jennifer A / Garraway, Levi A. ·1Department of Medical Oncology, Dana-Farber Cancer Institute; 2Department of Medicine, Brigham and Women's Hospital; 3Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston; 4Broad Institute of Harvard and MIT; and 5Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts. ·Cancer Discov · Pubmed #24265154.

ABSTRACT: Treatment of BRAF-mutant melanoma with combined dabrafenib and trametinib, which target RAF and the downstream MAP-ERK kinase (MEK)1 and MEK2 kinases, respectively, improves progression-free survival and response rates compared with dabrafenib monotherapy. Mechanisms of clinical resistance to combined RAF/MEK inhibition are unknown. We performed whole-exome sequencing (WES) and whole-transcriptome sequencing (RNA-seq) on pretreatment and drug-resistant tumors from five patients with acquired resistance to dabrafenib/trametinib. In three of these patients, we identified additional mitogen-activated protein kinase (MAPK) pathway alterations in the resistant tumor that were not detected in the pretreatment tumor, including a novel activating mutation in MEK2 (MEK2(Q60P)). MEK2(Q60P) conferred resistance to combined RAF/MEK inhibition in vitro, but remained sensitive to inhibition of the downstream kinase extracellular signal-regulated kinase (ERK). The continued MAPK signaling-based resistance identified in these patients suggests that alternative dosing of current agents, more potent RAF/MEK inhibitors, and/or inhibition of the downstream kinase ERK may be needed for durable control of BRAF-mutant melanoma.

13 Clinical Conference Case records of the Massachusetts General Hospital. Case 21-2013. A 68-year-old man with metastatic melanoma. 2013

Sullivan, Ryan J / Lawrence, Donald P / Wargo, Jennifer A / Oh, Kevin S / Gonzalez, R Gilberto / Piris, Adriano. ·Department of Medicine, Massachusetts General Hospital, Boston, USA. ·N Engl J Med · Pubmed #23841733.

ABSTRACT: -- No abstract --

14 Article Comparison of immune infiltrates in melanoma and pancreatic cancer highlights VISTA as a potential target in pancreatic cancer. 2019

Blando, Jorge / Sharma, Anu / Higa, Maria Gisela / Zhao, Hao / Vence, Luis / Yadav, Shalini S / Kim, Jiseong / Sepulveda, Alejandro M / Sharp, Michael / Maitra, Anirban / Wargo, Jennifer / Tetzlaff, Michael / Broaddus, Russell / Katz, Matthew H G / Varadhachary, Gauri R / Overman, Michael / Wang, Huamin / Yee, Cassian / Bernatchez, Chantale / Iacobuzio-Donahue, Christine / Basu, Sreyashi / Allison, James P / Sharma, Padmanee. ·The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX 77054. · Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. · Janssen Oncology Therapeutic Area, Janssen Research and Development, LLC, Pharmaceutical Companies of Johnson & Johnson, Spring House, PA 19477. · Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. · Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. · Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. · David Rubenstein Pancreatic Cancer Research Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065. · The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX 77054; jallison@mdanderson.org padsharma@mdanderson.org. · Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. ·Proc Natl Acad Sci U S A · Pubmed #30635425.

ABSTRACT: Immune checkpoint therapy (ICT) has transformed cancer treatment in recent years; however, treatment response is not uniform across tumor types. The tumor immune microenvironment plays a critical role in determining response to ICT; therefore, understanding the differential immune infiltration between ICT-sensitive and ICT-resistant tumor types will help to develop effective treatment strategies. We performed a comprehensive analysis of the immune tumor microenvironment of an ICT-sensitive tumor (melanoma,

15 Article A PAX3/BRN2 rheostat controls the dynamics of BRAF mediated MITF regulation in MITF 2019

Smith, Michael P / Rana, Sareena / Ferguson, Jennifer / Rowling, Emily J / Flaherty, Keith T / Wargo, Jennifer A / Marais, Richard / Wellbrock, Claudia. ·Manchester Cancer Research Centre, Faculty of Biology, Medicine & Health, Division of Cancer Sciences, The University of Manchester, Manchester, UK. · Division of Molecular Pathology, The Institute of Cancer Research, London, UK. · Massachusetts General Hospital Cancer Center, Boston, Massachusetts. · Divison of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas. · Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Astra Zeneca Logistics Centre, Macclesfield, UK. ·Pigment Cell Melanoma Res · Pubmed #30277012.

ABSTRACT: The BRAF kinase and the MAPK pathway are targets of current melanoma therapies. However, MAPK pathway inhibition results in dynamic changes of downstream targets that can counteract inhibitor-action not only in during treatment, but also in acquired resistant tumours. One such dynamic change involves the expression of the transcription factor MITF, a crucial regulator of cell survival and proliferation in untreated as well as drug-addicted acquired resistant melanoma. Tight control over MITF expression levels is required for optimal melanoma growth, and while it is well established that the MAPK pathway regulates MITF expression, the actual mechanism is insufficiently understood. We reveal here, how BRAF through action on the transcription factors BRN2 and PAX3 executes control over the regulation of MITF expression in a manner that allows for considerable plasticity. This plasticity provides robustness to the BRAF mediated MITF regulation and explains the dynamics in MITF expression that are observed in patients in response to MAPK inhibitor therapy.

16 Article Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma. 2018

Sade-Feldman, Moshe / Yizhak, Keren / Bjorgaard, Stacey L / Ray, John P / de Boer, Carl G / Jenkins, Russell W / Lieb, David J / Chen, Jonathan H / Frederick, Dennie T / Barzily-Rokni, Michal / Freeman, Samuel S / Reuben, Alexandre / Hoover, Paul J / Villani, Alexandra-Chloé / Ivanova, Elena / Portell, Andrew / Lizotte, Patrick H / Aref, Amir R / Eliane, Jean-Pierre / Hammond, Marc R / Vitzthum, Hans / Blackmon, Shauna M / Li, Bo / Gopalakrishnan, Vancheswaran / Reddy, Sangeetha M / Cooper, Zachary A / Paweletz, Cloud P / Barbie, David A / Stemmer-Rachamimov, Anat / Flaherty, Keith T / Wargo, Jennifer A / Boland, Genevieve M / Sullivan, Ryan J / Getz, Gad / Hacohen, Nir. ·Massachusetts General Hospital Cancer Center, Harvard Medical School (HMS), Boston, MA, USA; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA; Department of Medicine, Massachusetts General Hospital, HMS, Boston, MA, USA. · Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School (HMS), Boston, MA, USA; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School (HMS), Boston, MA, USA; Department of Medicine, Massachusetts General Hospital, HMS, Boston, MA, USA; Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA. · Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA; Department of Pathology, Massachusetts General Hospital, HMS, Boston, MA, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School (HMS), Boston, MA, USA. · Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA; Department of Biomedical Informatics, HMS, Boston, MA, USA. · Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA; Brigham & Women's Hospital, Division of Rheumatology, Immunology and Allergy, Boston, MA, USA. · Department of Medicine, Massachusetts General Hospital, HMS, Boston, MA, USA; Belfer Center for Applied Cancer Science, Dana Farber Cancer Institute, Boston, MA, USA. · Department of Pathology, Massachusetts General Hospital, HMS, Boston, MA, USA. · Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA; Department of Virology, Harvard Medical School, Boston, MA, USA. · Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Medicine, Massachusetts General Hospital, HMS, Boston, MA, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School (HMS), Boston, MA, USA; Department of Medicine, Massachusetts General Hospital, HMS, Boston, MA, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School (HMS), Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, HMS, Boston, MA, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School (HMS), Boston, MA, USA; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA; Department of Pathology, Massachusetts General Hospital, HMS, Boston, MA, USA; Department of Pathology, Harvard Medical School, Boston, MA, USA. Electronic address: gadgetz@broadinstitute.org. · Massachusetts General Hospital Cancer Center, Harvard Medical School (HMS), Boston, MA, USA; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA; Department of Medicine, Massachusetts General Hospital, HMS, Boston, MA, USA. Electronic address: nhacohen@mgh.harvard.edu. ·Cell · Pubmed #30388456.

ABSTRACT: Treatment of cancer has been revolutionized by immune checkpoint blockade therapies. Despite the high rate of response in advanced melanoma, the majority of patients succumb to disease. To identify factors associated with success or failure of checkpoint therapy, we profiled transcriptomes of 16,291 individual immune cells from 48 tumor samples of melanoma patients treated with checkpoint inhibitors. Two distinct states of CD8

17 Article Immune Checkpoint Blockade across the Cancer Care Continuum. 2018

Helmink, Beth A / Gaudreau, Pierre-Olivier / Wargo, Jennifer A. ·Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. · Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. Electronic address: jwargo@mdanderson.org. ·Immunity · Pubmed #29924973.

ABSTRACT: Four studies recently reported in the New England Journal of Medicine highlight advances in treatment with immune checkpoint blockade across the cancer care continuum. These findings demonstrate efficacy of these agents in the treatment of early and late-stage disease, as monotherapy or in combination, and in addition to-or in place of-standard front-line therapy.

18 Article Metastatic melanoma with balloon/histiocytoid cytomorphology after treatment with immunotherapy: A histologic mimic and diagnostic pitfall. 2018

Farah, Maya / Nagarajan, Priyadharsini / Torres-Cabala, Carlos A / Curry, Jonathan L / Amaria, Rodabe N / Wargo, Jennifer / Tawbi, Hussein / Ivan, Doina / Prieto, Victor G / Tetzlaff, Michael T / Aung, Phyu P. ·Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas. · Department of Dermatology, University of Texas M.D. Anderson Cancer Center, Houston, Texas. · Department of Melanoma Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas. · Department of Melanoma surgical oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas. ·J Cutan Pathol · Pubmed #29672900.

ABSTRACT: Epithelioid cells with foamy cytoplasm (histiocytoid features) are typical histopathologic findings among benign and malignant histiocytic neoplasms such as xanthoma and atypical fibroxanthoma. However, these changes are unusual in melanoma, which is typically composed of nested and variably pigmented atypical epithelioid cells. Here, we report a patient with metastatic melanoma in lymph nodes presenting with prominent balloon cell/histiocytoid features expressing melanocytic markers, after treatment with nivolumab. This report suggests that the spectrum of neoplasms with histiocytoid features should be expanded to include melanoma, a pattern that, to the best of our knowledge, is uncommon, especially in the setting of post-neoadjuvant therapy.

19 Article Association of body-mass index and outcomes in patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective, multicohort analysis. 2018

McQuade, Jennifer L / Daniel, Carrie R / Hess, Kenneth R / Mak, Carmen / Wang, Daniel Y / Rai, Rajat R / Park, John J / Haydu, Lauren E / Spencer, Christine / Wongchenko, Matthew / Lane, Stephen / Lee, Dung-Yang / Kaper, Mathilde / McKean, Meredith / Beckermann, Kathryn E / Rubinstein, Samuel M / Rooney, Isabelle / Musib, Luna / Budha, Nageshwar / Hsu, Jessie / Nowicki, Theodore S / Avila, Alexandre / Haas, Tomas / Puligandla, Maneka / Lee, Sandra / Fang, Shenying / Wargo, Jennifer A / Gershenwald, Jeffrey E / Lee, Jeffrey E / Hwu, Patrick / Chapman, Paul B / Sosman, Jeffrey A / Schadendorf, Dirk / Grob, Jean-Jacques / Flaherty, Keith T / Walker, Dana / Yan, Yibing / McKenna, Edward / Legos, Jeffrey J / Carlino, Matteo S / Ribas, Antoni / Kirkwood, John M / Long, Georgina V / Johnson, Douglas B / Menzies, Alexander M / Davies, Michael A. ·University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: jmcquade@mdanderson.org. · University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Novartis Pharmaceuticals, East Hanover, NJ, USA. · Vanderbilt University Medical Center, Nashville, TN, USA. · Melanoma Institute Australia and University of Sydney, North Sydney, NSW, Australia. · Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead NSW, Australia. · Genentech, San Francisco, CA, USA. · University of California Los Angeles Medical Center, Los Angeles, CA, USA. · Bristol-Myers Squibb, New York, NY, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. · Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Northwestern University, Chicago, IL, USA. · University Hospital Essen and German Cancer Consortium, Essen, Germany. · Centre Hospitalo-Universitaire Timone, Aix Marseille University, Marseille, France. · Massachusetts General Hospital Cancer Center, Boston, MA, USA. · Melanoma Institute Australia and University of Sydney, North Sydney, NSW, Australia; Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead NSW, Australia. · Hillman University of Pittsburgh Medical Center Cancer Center, Pittsburgh, PA, USA. · Melanoma Institute Australia and University of Sydney, North Sydney, NSW, Australia; Royal North Shore and Mater Hospitals, St Leonards, NSW, Australia. ·Lancet Oncol · Pubmed #29449192.

ABSTRACT: BACKGROUND: Obesity has been linked to increased mortality in several cancer types; however, the relation between obesity and survival outcomes in metastatic melanoma is unknown. The aim of this study was to examine the association between body-mass index (BMI) and progression-free survival or overall survival in patients with metastatic melanoma who received targeted therapy, immunotherapy, or chemotherapy. METHODS: This retrospective study analysed independent cohorts of patients with metastatic melanoma assigned to treatment with targeted therapy, immunotherapy, or chemotherapy in randomised clinical trials and one retrospective study of patients treated with immunotherapy. Patients were classified according to BMI, following the WHO definitions, as underweight, normal, overweight, or obese. Patients without BMI and underweight patients were excluded. The primary outcomes were the associations between BMI and progression-free survival or overall survival, stratified by treatment type and sex. We did multivariable analyses in the independent cohorts, and combined adjusted hazard ratios in a mixed-effects meta-analysis to provide a precise estimate of the association between BMI and survival outcomes; heterogeneity was assessed with meta-regression analyses. Analyses were done on the predefined intention-to-treat population in the randomised controlled trials and on all patients included in the retrospective study. FINDINGS: The six cohorts consisted of a total of 2046 patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy between Aug 8, 2006, and Jan 15, 2016. 1918 patients were included in the analysis. Two cohorts containing patients from randomised controlled trials treated with targeted therapy (dabrafenib plus trametinib [n=599] and vemurafenib plus cobimetinib [n=240]), two cohorts containing patients treated with immunotherapy (one randomised controlled trial of ipilimumab plus dacarbazine [n=207] and a retrospective cohort treated with pembrolizumab, nivolumab, or atezolizumab [n=331]), and two cohorts containing patients treated with chemotherapy (two randomised controlled trials of dacarbazine [n=320 and n=221]) were classified according to BMI as normal (694 [36%] patients), overweight (711 [37%]), or obese (513 [27%]). In the pooled analysis, obesity, compared with normal BMI, was associated with improved survival in patients with metastatic melanoma (average adjusted hazard ratio [HR] 0·77 [95% CI 0·66-0·90] for progression-free survival and 0·74 [0·58-0·95] for overall survival). The survival benefit associated with obesity was restricted to patients treated with targeted therapy (HR 0·72 [0·57-0·91] for progression-free survival and 0·60 [0·45-0·79] for overall survival) and immunotherapy (HR 0·75 [0·56-1·00] and 0·64 [0·47-0·86]). No associations were observed with chemotherapy (HR 0·87 [0·65-1·17, p INTERPRETATION: Our results suggest that in patients with metastatic melanoma, obesity is associated with improved progression-free survival and overall survival compared with those outcomes in patients with normal BMI, and that this association is mainly seen in male patients treated with targeted or immune therapy. These results have implications for the design of future clinical trials for patients with metastatic melanoma and the magnitude of the benefit found supports further investigation of the underlying mechanism of these associations. FUNDING: ASCO/CCF Young Investigator Award, ASCO/CCF Career Development Award, MD Anderson Cancer Center (MDACC) Melanoma Moonshot Program, MDACC Melanoma SPORE, and the Dr Miriam and Sheldon G Adelson Medical Research Foundation.

20 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 (

21 Article A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma. 2017

Krepler, Clemens / Sproesser, Katrin / Brafford, Patricia / Beqiri, Marilda / Garman, Bradley / Xiao, Min / Shannan, Batool / Watters, Andrea / Perego, Michela / Zhang, Gao / Vultur, Adina / Yin, Xiangfan / Liu, Qin / Anastopoulos, Ioannis N / Wubbenhorst, Bradley / Wilson, Melissa A / Xu, Wei / Karakousis, Giorgos / Feldman, Michael / Xu, Xiaowei / Amaravadi, Ravi / Gangadhar, Tara C / Elder, David E / Haydu, Lauren E / Wargo, Jennifer A / Davies, Michael A / Lu, Yiling / Mills, Gordon B / Frederick, Dennie T / Barzily-Rokni, Michal / Flaherty, Keith T / Hoon, Dave S / Guarino, Michael / Bennett, Joseph J / Ryan, Randall W / Petrelli, Nicholas J / Shields, Carol L / Terai, Mizue / Sato, Takami / Aplin, Andrew E / Roesch, Alexander / Darr, David / Angus, Steve / Kumar, Rakesh / Halilovic, Ensar / Caponigro, Giordano / Jeay, Sebastien / Wuerthner, Jens / Walter, Annette / Ocker, Matthias / Boxer, Matthew B / Schuchter, Lynn / Nathanson, Katherine L / Herlyn, Meenhard. ·Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, PA 19104, USA. · Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. · Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. · MD Anderson Cancer Center, University of Texas, Houston, TX 77030, USA. · Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA. · Translational Molecular Medicine, John Wayne Cancer Institute, Santa Monica, CA 90404, USA. · Helen F. Graham Cancer Center at Christiana Care, Newark, DE 19713, USA. · Ocular Oncology Service, Wills Eye Hospital, Philadelphia, PA 19107, USA. · Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107. · Department of Dermatology, University Duisburg-Essen, University Hospital Essen, 45147 Essen, Germany; German Consortium of Translational Cancer Research, Heidelberg, Germany. · Lineberger Cancer Center, University of North Carolina Chapel Hill, NC 27514, USA. · Glaxosmithkline, Collegeville, PA 19426, USA. · Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA. · Bayer Pharma AG, Berlin 13353, Germany. · National Center for Advancing Translational Sciences, NIH, Rockville, MD 20850, USA. · Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, PA 19104, USA. Electronic address: herlynm@wistar.org. ·Cell Rep · Pubmed #29141225.

ABSTRACT: Therapy of advanced melanoma is changing dramatically. Following mutational and biological subclassification of this heterogeneous cancer, several targeted and immune therapies were approved and increased survival significantly. To facilitate further advancements through pre-clinical in vivo modeling, we have established 459 patient-derived xenografts (PDX) and live tissue samples from 384 patients representing the full spectrum of clinical, therapeutic, mutational, and biological heterogeneity of melanoma. PDX have been characterized using targeted sequencing and protein arrays and are clinically annotated. This exhaustive live tissue resource includes PDX from 57 samples resistant to targeted therapy, 61 samples from responders and non-responders to immune checkpoint blockade, and 31 samples from brain metastasis. Uveal, mucosal, and acral subtypes are represented as well. We show examples of pre-clinical trials that highlight how the PDX collection can be used to develop and optimize precision therapies, biomarkers of response, and the targeting of rare genetic subgroups.

22 Article Genetic and Genomic Characterization of 462 Melanoma Patient-Derived Xenografts, Tumor Biopsies, and Cell Lines. 2017

Garman, Bradley / Anastopoulos, Ioannis N / Krepler, Clemens / Brafford, Patricia / Sproesser, Katrin / Jiang, Yuchao / Wubbenhorst, Bradley / Amaravadi, Ravi / Bennett, Joseph / Beqiri, Marilda / Elder, David / Flaherty, Keith T / Frederick, Dennie T / Gangadhar, Tara C / Guarino, Michael / Hoon, David / Karakousis, Giorgos / Liu, Qin / Mitra, Nandita / Petrelli, Nicholas J / Schuchter, Lynn / Shannan, Batool / Shields, Carol L / Wargo, Jennifer / Wenz, Brandon / Wilson, Melissa A / Xiao, Min / Xu, Wei / Xu, Xaiowei / Yin, Xiangfan / Zhang, Nancy R / Davies, Michael A / Herlyn, Meenhard / Nathanson, Katherine L. ·Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. · The Wistar Institute, Molecular and Cellular Oncogenesis Program, Tumor Microenvironment and Metastasis Program, and Melanoma Research Center, Philadelphia, PA, USA. · Department of Statistics, The Wharton School, University of Pennsylvania, Philadelphia, PA, USA. · Department of Medicine, Division of Hematology/Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. · Helen F. Graham Cancer Center at Christiana Care Health System, Newark, DE, USA. · Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. · Department of Medicine, Division of Hematology & Oncology, Massachusetts General Hospital, Boston, MA, USA. · Department of Translational Molecular Medicine, John Wayne Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA, USA. · Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. · Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. · Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA, USA. · Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Perlmutter Cancer Center, NYU School of Medicine, NYU Langone Medical Center, New York, NY, USA. · Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. · Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address: knathans@upenn.edu. ·Cell Rep · Pubmed #29141224.

ABSTRACT: Tumor-sequencing studies have revealed the widespread genetic diversity of melanoma. Sequencing of 108 genes previously implicated in melanomagenesis was performed on 462 patient-derived xenografts (PDXs), cell lines, and tumors to identify mutational and copy number aberrations. Samples came from 371 unique individuals: 263 were naive to treatment, and 108 were previously treated with targeted therapy (34), immunotherapy (54), or both (20). Models of all previously reported major melanoma subtypes (BRAF, NRAS, NF1, KIT, and WT/WT/WT) were identified. Multiple minor melanoma subtypes were also recapitulated, including melanomas with multiple activating mutations in the MAPK-signaling pathway and chromatin-remodeling gene mutations. These well-characterized melanoma PDXs and cell lines can be used not only as reagents for a large array of biological studies but also as pre-clinical models to facilitate drug development.

23 Article Cancer Evolution during Immunotherapy. 2017

Andrews, M C / Wargo, J A. ·Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA. Electronic address: jwargo@mdanderson.org. ·Cell · Pubmed #29100071.

ABSTRACT: Immune checkpoint blockade has revolutionized cancer treatment. In this issue of Cell, insights from a longitudinal multi-omics analysis of the largest yet-reported cohort of melanoma patients reveal how tumor and immunity co-evolve during anti-PD-1 therapy.

24 Article Distinct Cellular Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 Checkpoint Blockade. 2017

Wei, Spencer C / Levine, Jacob H / Cogdill, Alexandria P / Zhao, Yang / Anang, Nana-Ama A S / Andrews, Miles C / Sharma, Padmanee / Wang, Jing / Wargo, Jennifer A / Pe'er, Dana / Allison, James P. ·Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: scwei@mdanderson.org. · Computational and Systems Biology Program, Sloan Kettering Institute, New York, NY 10065, USA. · Department of Immunology, 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 Bioinformatics and Computational Biology, 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 Surgical Oncology, 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; Parker Institute for Cancer Immunotherapy, 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; Parker Institute for Cancer Immunotherapy, 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 Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Parker Institute for Cancer Immunotherapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: jallison@mdanderson.org. ·Cell · Pubmed #28803728.

ABSTRACT: Immune-checkpoint blockade is able to achieve durable responses in a subset of patients; however, we lack a satisfying comprehension of the underlying mechanisms of anti-CTLA-4- and anti-PD-1-induced tumor rejection. To address these issues, we utilized mass cytometry to comprehensively profile the effects of checkpoint blockade on tumor immune infiltrates in human melanoma and murine tumor models. These analyses reveal a spectrum of tumor-infiltrating T cell populations that are highly similar between tumor models and indicate that checkpoint blockade targets only specific subsets of tumor-infiltrating T cell populations. Anti-PD-1 predominantly induces the expansion of specific tumor-infiltrating exhausted-like CD8 T cell subsets. In contrast, anti-CTLA-4 induces the expansion of an ICOS

25 Article Targeting endothelin receptor signalling overcomes heterogeneity driven therapy failure. 2017

Smith, Michael P / Rowling, Emily J / Miskolczi, Zsofia / Ferguson, Jennifer / Spoerri, Loredana / Haass, Nikolas K / Sloss, Olivia / McEntegart, Sophie / Arozarena, Imanol / von Kriegsheim, Alex / Rodriguez, Javier / Brunton, Holly / Kmarashev, Jivko / Levesque, Mitchell P / Dummer, Reinhard / Frederick, Dennie T / Andrews, Miles C / Cooper, Zachary A / Flaherty, Keith T / Wargo, Jennifer A / Wellbrock, Claudia. ·Manchester Cancer Research Centre, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK. · Translational Research Institute, The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Qld, Australia. · Discipline of Dermatology, University of Sydney, Sydney, NSW, Australia. · Navarrabiomed-Fundación Miguel Servet-Idisna, Pamplona, Spain. · Systems Biology Ireland, School of Medicine, UCD, Dublin 4, Ireland. · Department of Dermatology, Universitätsspital Zürich, University of Zurich, Zurich, Switzerland. · Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA, USA. · Division of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Manchester Cancer Research Centre, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK claudia.wellbrock@manchester.ac.uk. ·EMBO Mol Med · Pubmed #28606996.

ABSTRACT: Approaches to prolong responses to BRAF targeting drugs in melanoma patients are challenged by phenotype heterogeneity. Melanomas of a "MITF-high" phenotype usually respond well to BRAF inhibitor therapy, but these melanomas also contain subpopulations of the

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