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Melanoma: HELP
Articles by Mark C. Kelley
Based on 31 articles published since 2008
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Between 2008 and 2019, Mark Kelley wrote the following 31 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline Melanoma, version 4.2014. 2014

Coit, Daniel G / Thompson, John A / Andtbacka, Robert / Anker, Christopher J / Bichakjian, Christopher K / Carson, William E / Daniels, Gregory A / Daud, Adil / Dimaio, Dominick / Fleming, Martin D / Gonzalez, Rene / Guild, Valerie / Halpern, Allan C / Hodi, F Stephen / Kelley, Mark C / Khushalani, Nikhil I / Kudchadkar, Ragini R / Lange, Julie R / Martini, Mary C / Olszanski, Anthony J / Ross, Merrick I / Salama, April / Swetter, Susan M / Tanabe, Kenneth K / Trisal, Vijay / Urist, Marshall M / McMillian, Nicole R / Ho, Maria / Anonymous5170793. ·From 1Memorial Sloan-Kettering Cancer Center; 2Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance; 3Huntsman Cancer Institute at the University of Utah; 4University of Michigan Comprehensive Cancer Center; 5The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute; 6UC San Diego Moores Cancer Center; 7UCSF Helen Diller Family Comprehensive Cancer Center; 8Fred & Pamela Buffett Cancer Center at The Nebraska Medical Center; 9St. Jude Children's Research Hospital/The University of Tennessee Health Science Center; 10University of Colorado Cancer Center; 11Aim at Melanoma; 12Dana-Farber/Brigham and Women's Cancer Center; 13Vanderbilt-Ingram Cancer Center; 14Roswell Park Cancer Institute; 15Moffitt Cancer Center; 16The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; 17Robert H. Lurie Comprehensive Cancer Center of Northwestern University; 18Fox Chase Cancer Center; 19The University of Texas MD Anderson Cancer Center; 20Duke Cancer Institute; 21Stanford Cancer Institute; 22Massachusetts General Hospital Cancer Center; 23City of Hope Comprehensive Cancer Center; 24University of Alabama at Birmingham Comprehensive Cancer Center; and 25National Comprehensive Cancer Network. ·J Natl Compr Canc Netw · Pubmed #24812131.

ABSTRACT: The NCCN Guidelines for Melanoma provide multidisciplinary recommendations for the management of patients with melanoma. These NCCN Guidelines Insights highlight notable recent updates. Dabrafenib and trametinib, either as monotherapy (category 1) or combination therapy, have been added as systemic options for patients with unresectable metastatic melanoma harboring BRAF V600 mutations. Controversy continues regarding the value of adjuvant radiation for patients at high risk of nodal relapse. This is reflected in the category 2B designation to consider adjuvant radiation following lymphadenectomy for stage III melanoma with clinically positive nodes or recurrent disease.

2 Guideline Melanoma, version 2.2013: featured updates to the NCCN guidelines. 2013

Coit, Daniel G / Andtbacka, Robert / Anker, Christopher J / Bichakjian, Christopher K / Carson, William E / Daud, Adil / Dimaio, Dominick / Fleming, Martin D / Guild, Valerie / Halpern, Allan C / Hodi, F Stephen / Kelley, Mark C / Khushalani, Nikhil I / Kudchadkar, Ragini R / Lange, Julie R / Lind, Anne / Martini, Mary C / Olszanski, Anthony J / Pruitt, Scott K / Ross, Merrick I / Swetter, Susan M / Tanabe, Kenneth K / Thompson, John A / Trisal, Vijay / Urist, Marshall M / McMillian, Nicole / Ho, Maria / Anonymous4310755. ·Memorial Sloan-Kettering Cancer Center. ·J Natl Compr Canc Netw · Pubmed #23584343.

ABSTRACT: The NCCN Guidelines for Melanoma provide multidisciplinary recommendations on the clinical management of patients with melanoma. This NCCN Guidelines Insights report highlights notable recent updates. Foremost of these is the exciting addition of the novel agents ipilimumab and vemurafenib for treatment of advanced melanoma. The NCCN panel also included imatinib as a treatment for KIT-mutated tumors and pegylated interferon alfa-2b as an option for adjuvant therapy. Also important are revisions to the initial stratification of early-stage lesions based on the risk of sentinel lymph node metastases, and revised recommendations on the use of sentinel lymph node biopsy for low-risk groups. Finally, the NCCN panel reached clinical consensus on clarifying the role of imaging in the workup of patients with melanoma.

3 Guideline Melanoma. 2012

Coit, Daniel G / Andtbacka, Robert / Anker, Christopher J / Bichakjian, Christopher K / Carson, William E / Daud, Adil / Dilawari, Raza A / Dimaio, Dominick / Guild, Valerie / Halpern, Allan C / Hodi, F Stephen / Kelley, Mark C / Khushalani, Nikhil I / Kudchadkar, Ragini R / Lange, Julie R / Lind, Anne / Martini, Mary C / Olszanski, Anthony J / Pruitt, Scott K / Ross, Merrick I / Swetter, Susan M / Tanabe, Kenneth K / Thompson, John A / Trisal, Vijay / Urist, Marshall M / Anonymous590720. · ·J Natl Compr Canc Netw · Pubmed #22393197.

ABSTRACT: -- No abstract --

4 Review Immune Responses to BRAF-Targeted Therapy in Melanoma: Is Targeted Therapy Immunotherapy? 2016

Kelley, Mark C. ·Innov8 Cancer Care LLC, 8199 Poplar Creek Road, Nashville, TN 37221. ·Crit Rev Oncog · Pubmed #27481005.

ABSTRACT: Therapies targeting the mitogen-activated protein kinase signaling pathway can induce profound tumor regression in patients with advanced BRAF-mutated melanoma. Most patients develop resistance after several months of treatment, which is typically followed by rapid disease progression and death. BRAF- and mitogen-activated protein kinase kinase (MEK)-targeted therapies were initially thought to exert their therapeutic effects through direct inhibition of signaling within the tumor cell, resulting in cell death. Recent evidence suggests that BRAF-targeted therapy also augments the host immune response to melanoma. This is characterized by enhanced expression of melanoma differentiation antigens, reduced levels of immunosuppressive cytokines in the micro environment, and a CD8 T-cell response and T-cell-mediated cytotoxicity. These changes are noted within days of starting therapy, correlate with tumor response, reverse with resistance, and occur in metastatic and advanced, operable disease. Enhanced PDL-1 expression by melanoma cells and increased markers of immune exhaustion, including PD-1 and TIM-1, have been identified, suggesting that the immune response is down-modulated before resistance occurs. These findings indicate that BRAF- and MEK-targeted therapies have multiple, complex, and interrelated mechanisms of action and validate the investigation of combination treatment strategies with targeted therapy and immune checkpoint inhibitors, as well as other therapies that modulate the immune microenvironment. They also lend support for clinical trials investigating preoperative and adjuvant BRAF-targeted therapy for high-risk, BRAF-mutated melanoma. Together, these studies will enhance our understanding of the mechanism of action of BRAF-targeted therapies and may identify additional opportunities to improve the outcome of patients with advanced melanoma.

5 Review Talimogene laherparepvec (T-VEC) for the treatment of advanced melanoma. 2015

Johnson, Douglas B / Puzanov, Igor / Kelley, Mark C. ·Department of Medicine, Vanderbilt University Medical Center, 777 PRB, 2220 Pierce Ave, Nashville, TN 37232, USA. · Department of Surgery, Vanderbilt University Medical Center, TN, USA. ·Immunotherapy · Pubmed #26098919.

ABSTRACT: Melanoma often spreads to cutaneous or subcutaneous sites that are amenable to direct, intralesional injection. As such, developing effective injectable agents has been of considerable interest. Talimogene laherperepvec (T-VEC) is an injectable modified oncolytic herpes virus being developed for the treatment of advanced melanoma. Pre-clinical studies have shown that T-VEC preferentially infects melanoma cells and exerts antitumor activity through directly mediating cell death and by augmenting local and even distant immune responses. T-VEC has now been assessed in Phase II and III clinical trials and has demonstrated a tolerable side-effect profile and promising efficacy, showing an improved durable response rate and a trend toward superior overall survival compared to granulocyte-macrophage colony-stimulating factor. Despite these promising results, responses have been uncommon in patients with visceral metastases. T-VEC is currently being evaluated in combination with other immune therapies (ipilimumab and pembrolizumab) with early signs of activity. In this review, we discuss the preclinical rationale, the clinical experience, and future directions for T-VEC in advanced melanoma.

6 Clinical Trial Long-Term Survival after Complete Surgical Resection and Adjuvant Immunotherapy for Distant Melanoma Metastases. 2017

Faries, Mark B / Mozzillo, Nicola / Kashani-Sabet, Mohammed / Thompson, John F / Kelley, Mark C / DeConti, Ronald C / Lee, Jeffrey E / Huth, James F / Wagner, Jeffrey / Dalgleish, Angus / Pertschuk, Daniel / Nardo, Christopher / Stern, Stacey / Elashoff, Robert / Gammon, Guy / Morton, Donald L / Anonymous10680923. ·John Wayne Cancer Institute, Santa Monica, CA, USA. mfaries@theangelesclinic.org. · Istituto Nazionale dei Tumori de Napoli, Naples, Italy. · Mt. Zion Medical Center, University of California, San Francisco, San Francisco, CA, USA. · Royal Prince Alfred Hospital, Sydney, Australia. · Vanderbilt University, Nashville, TN, USA. · H. Lee Moffitt Cancer Center, Tampa, FL, USA. · MD Anderson Cancer Center, Houston, TX, USA. · Southwestern Medical Center at Dallas, University of Texas, Dallas, TX, USA. · Wagner & Associates, Indianapolis, IN, USA. · St. George's Hospital Medical School, London, Great Britain. · CancerVax Corp, Carlsbad, CA, USA. · John Wayne Cancer Institute, Santa Monica, CA, USA. · UCLA Life Sciences, Biomathematics, Los Angeles, CA, USA. ·Ann Surg Oncol · Pubmed #29019177.

ABSTRACT: BACKGROUND: This phase III study was undertaken to evaluate the efficacy of an allogeneic whole-cell vaccine (Canvaxin™) plus bacillus Calmette-Guerin (BCG) after complete resection of stage IV melanoma. METHODS: After complete resection of ≤5 distant metastases, patients were randomly assigned to BCG+Canvaxin (BCG/Cv) or BCG+placebo (BCG/Pl). The primary endpoint was overall survival (OS); secondary endpoints were disease-free survival (DFS), and immune response measured by skin test (ClinicalTrials.gov identifier: NCT00052156). RESULTS: Beginning in May 1998, 496 patients were randomized. In April 2005, the Data Safety Monitoring Board recommended stopping enrollment due to a low probability of efficacy. At that time, median OS and 5-year OS rate were 38.6 months and 44.9%, respectively, for BCG/Pl versus 31.4 months and 39.6% in the BCG/Cv group (hazard ratio (HR), 1.18; p = 0.250). Follow-up was extended at several trial sites through March 2010. Median OS and 5-year and 10-year survival was 39.1 months, 43.3 and 33.3%, respectively, for BCG/Pl versus 34.9 months, 42.5 and 36.4%, in the BCG/Cv group (HR 1.053; p = 0.696). Median DFS, 5- and 10-year DFS were 7.6 months, 23.8 and 21.7%, respectively, for BCG/Pl versus 8.5 months, 30.0%, and 30.0%, respectively, for the BCG/Cv group (HR 0.882; p = 0.260). Positive DTH skin testing correlated with increased survival. DISCUSSION: In this, the largest study of postsurgical adjuvant therapy for stage IV melanoma reported to date, BCG/Cv did not improve outcomes over BCG/placebo. Favorable long-term survival among study patients suggests that metastasectomy should be considered for selected patients with stage IV melanoma.

7 Clinical Trial Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma. 2017

Faries, Mark B / Thompson, John F / Cochran, Alistair J / Andtbacka, Robert H / Mozzillo, Nicola / Zager, Jonathan S / Jahkola, Tiina / Bowles, Tawnya L / Testori, Alessandro / Beitsch, Peter D / Hoekstra, Harald J / Moncrieff, Marc / Ingvar, Christian / Wouters, Michel W J M / Sabel, Michael S / Levine, Edward A / Agnese, Doreen / Henderson, Michael / Dummer, Reinhard / Rossi, Carlo R / Neves, Rogerio I / Trocha, Steven D / Wright, Frances / Byrd, David R / Matter, Maurice / Hsueh, Eddy / MacKenzie-Ross, Alastair / Johnson, Douglas B / Terheyden, Patrick / Berger, Adam C / Huston, Tara L / Wayne, Jeffrey D / Smithers, B Mark / Neuman, Heather B / Schneebaum, Schlomo / Gershenwald, Jeffrey E / Ariyan, Charlotte E / Desai, Darius C / Jacobs, Lisa / McMasters, Kelly M / Gesierich, Anja / Hersey, Peter / Bines, Steven D / Kane, John M / Barth, Richard J / McKinnon, Gregory / Farma, Jeffrey M / Schultz, Erwin / Vidal-Sicart, Sergi / Hoefer, Richard A / Lewis, James M / Scheri, Randall / Kelley, Mark C / Nieweg, Omgo E / Noyes, R Dirk / Hoon, Dave S B / Wang, He-Jing / Elashoff, David A / Elashoff, Robert M. ·From the John Wayne Cancer Institute at Saint John's Health Center, Santa Monica (M.B.F., D.S.B.H.), and the Departments of Pathology (A.J.C.), Biomathematics (H.-J.W., D.A.E., R.M.E.), and Medicine (D.A.E.), University of California, Los Angeles - both in California · Melanoma Institute Australia and the University of Sydney, Sydney (J.F.T., O.E.N.), Peter MacCallum Cancer Centre, Melbourne, VIC (M.H.), Princess Alexandra Hospital, Brisbane, QLD (B.M.S.), and Newcastle Melanoma Unit, Waratah, NSW (P.H.) - all in Australia · Huntsman Cancer Institute, Salt Lake City (R.H.A., R.D.N.), and Intermountain Healthcare Cancer Services-Intermountain Medical Center, Murray (T.L.B.) - both in Utah · Istituto Nazionale dei Tumori Napoli, Naples (N.M.), Istituto Europeo di Oncologia, Milan (A.T.), and Istituto Oncologico Veneto-University of Padua, Padua (C.R.R.) - all in Italy · H. Lee Moffitt Cancer Center, Tampa, FL (J.S.Z.) · Helsinki University Hospital, Helsinki (T.J.) · Dallas Surgical Group, Dallas (P.D.B.) · Universitair Medisch Centrum Groningen, Groningen (H.J.H.), and Netherlands Cancer Institute, Amsterdam (M.W.J.M.W.) - both in the Netherlands · Norfolk and Norwich University Hospital, Norwich (M. Moncrieff), and Guy's and St. Thomas' NHS Foundation Trust, London (A.M.-R.) - both in the United Kingdom · Swedish Melanoma Study Group-University Hospital Lund, Lund, Sweden (C.I.) · University of Michigan, Ann Arbor (M.S.S.) · Wake Forest University, Winston-Salem (E.A.L.), and Duke University, Durham (R.S.) - both in North Carolina · Ohio State University, Columbus (D.A.) · University of Zurich, Zurich (R.D.), and Centre Hospitalier Universitaire Vaudois, Lausanne (M. Matter) - both in Switzerland · Penn State Hershey Cancer Institute, Hershey (R.I.N.), Thomas Jefferson University (A.C.B.) and Fox Chase Cancer Center (J.M.F.), Philadelphia, and St. Luke's University Health Network, Bethlehem (D.C.D.) - all in Pennsylvania · Greenville Health System Cancer Center, Greenville, SC (S.D.T.) · Sunnybrook Research Institute, Toronto (F.W.), and Tom Baker Cancer Centre, Calgary, AB (G.M.) - both in Canada · University of Washington, Seattle (D.R.B.) · Saint Louis University, St. Louis (E.H.) · Vanderbilt University (D.B.J., M.C.K.), Nashville, and University of Tennessee, Knoxville (J.M.L.) - both in Tennessee · University Hospital Schleswig-Holstein-Campus Lübeck, Lübeck (P.T.), University Hospital of Würzburg, Würzburg (A.G.), and City Hospital of Nürnberg, Nuremberg (E.S.) - all in Germany · SUNY at Stony Brook Hospital Medical Center, Stony Brook (T.L.H.), Memorial Sloan Kettering Cancer Center, New York (C.E.A.), and Roswell Park Cancer Institute, Buffalo (J.M.K.) - all in New York · Northwestern University Feinberg School of Medicine (J.D.W.) and Rush University Medical Center (S.D.B.), Chicago · University of Wisconsin, Madison (H.B.N.) · Tel Aviv Sourasky Medical Center, Tel Aviv, Israel (S.S.) · M.D. Anderson Medical Center, Houston (J.E.G.) · Johns Hopkins University School of Medicine, Baltimore (L.J.) · University of Louisville, Louisville, KY (K.M.M.) · Dartmouth-Hitchcock Medical Center, Lebanon, NH (R.J.B.) · Hospital Clinic Barcelona, Barcelona (S.V.-S.) · and Sentara CarePlex Hospital, Hampton, VA (R.A.H.). ·N Engl J Med · Pubmed #28591523.

ABSTRACT: BACKGROUND: Sentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear. METHODS: In an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis. RESULTS: Immediate completion lymph-node dissection was not associated with increased melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis or among 1755 patients in the per-protocol analysis. In the per-protocol analysis, the mean (±SE) 3-year rate of melanoma-specific survival was similar in the dissection group and the observation group (86±1.3% and 86±1.2%, respectively; P=0.42 by the log-rank test) at a median follow-up of 43 months. The rate of disease-free survival was slightly higher in the dissection group than in the observation group (68±1.7% and 63±1.7%, respectively; P=0.05 by the log-rank test) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92±1.0% vs. 77±1.5%; P<0.001 by the log-rank test); these results must be interpreted with caution. Nonsentinel-node metastases, identified in 11.5% of the patients in the dissection group, were a strong, independent prognostic factor for recurrence (hazard ratio, 1.78; P=0.005). Lymphedema was observed in 24.1% of the patients in the dissection group and in 6.3% of those in the observation group. CONCLUSIONS: Immediate completion lymph-node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma-specific survival among patients with melanoma and sentinel-node metastases. (Funded by the National Cancer Institute and others; MSLT-II ClinicalTrials.gov number, NCT00297895 .).

8 Clinical Trial A phase II trial of erlotinib and bevacizumab for patients with metastatic melanoma. 2016

Mudigonda, Tejaswi V / Wyman, Kenneth / Spigel, David R / Dahlman, Kimberly B / Greco, F Anthony / Puzanov, Igor / Kelley, Mark C / Hainsworth, John D / Sosman, Jeffrey A / Johnson, Douglas B. ·Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. · Sarah Cannon Research Institute and Tennessee Oncology PLLC, Nashville, TN, USA. · Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA. · Division of Surgical Oncology, Vanderbilt University Medical Center, Nashville, TN, USA. ·Pigment Cell Melanoma Res · Pubmed #26176864.

ABSTRACT: -- No abstract --

9 Clinical Trial Preliminary results from a prospective trial of preoperative combined BRAF and MEK-targeted therapy in advanced BRAF mutation-positive melanoma. 2015

Johnson, Adam S / Crandall, Holly / Dahlman, Kimberly / Kelley, Mark C. ·Department of Pathology, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville, TN. · Department of Clinical Trials Shared Resource, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville, TN. · Department of Cancer Biology, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville, TN. · Department of Surgery, Division of Surgical Oncology and Endocrine Surgery, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville, TN. Electronic address: mark.kelley@vanderbilt.edu. ·J Am Coll Surg · Pubmed #25797743.

ABSTRACT: BACKGROUND: We conducted a prospective trial of BRAF and mitogen-activated protein kinase kinase (MEK) targeted therapy in advanced, operable BRAF mutation-positive melanoma to determine feasibility, tumor response rates, and biomarkers of response and resistance. STUDY DESIGN: Thirteen patients with locally or regionally advanced BRAF mutation-positive melanoma received dabrafenib 150 mg po bid for 14 days, followed by dabrafenib plus trametinib 2 mg po daily for 14 days before operation. Biopsies and tumor measurements were obtained at baseline and days 14 and 28. Formalin-fixed paraffin embedded specimens were analyzed with hematoxylin and eosin, Ki-67, cleaved caspase-3, CD8, phosphorylated extracellular signal-regulated kinase (ERK), and phosphorylated MEK immunostains. RESULTS: Therapy was tolerated well, with toxicity ≥ grade 3 in 2 of 13 (15%) patients. All 12 patients receiving >14 days of therapy had substantial reduction in tumor volume (65% at day 14 and 78% at day 28) and underwent resection. After 14 days of dabrafenib therapy, there was a marked reduction in viable melanoma cells and a CD8 T-cell--rich infiltrate. Proliferation of the residual melanoma cells was reduced and apoptosis was increased. The cells continued to express phosphorylated ERK and phosphorylated MEK consistent with incomplete mitogen-activated protein kinase pathway inhibition. CONCLUSIONS: Preoperative targeted therapy of advanced BRAF-mutant melanoma is feasible, well tolerated, induces brisk tumor responses, and facilitates correlative science. A CD8 T-cell-rich infiltrate indicates a potential immune-mediated mechanism of action. Both proliferation and apoptosis were inhibited, but the mitogen-activated protein kinase pathway remained activated, suggesting intrinsic resistance in a subset of tumor cells. Additional investigation of the anti-tumor immune response during targeted therapy and the mechanisms of intrinsic resistance can yield novel therapeutic strategies.

10 Clinical Trial Assessment of prognostic circulating tumor cells in a phase III trial of adjuvant immunotherapy after complete resection of stage IV melanoma. 2012

Hoshimoto, Sojun / Faries, Mark B / Morton, Donald L / Shingai, Tatsushi / Kuo, Christine / Wang, He-Jing / Elashoff, Robert / Mozzillo, Nicola / Kelley, Mark C / Thompson, John F / Lee, Jeffrey E / Hoon, Dave S B. ·Department of Molecular Oncology, John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA 90404, USA. ·Ann Surg · Pubmed #22202581.

ABSTRACT: OBJECTIVE: To verify circulating tumor cell (CTC) prognostic utility in stage IV resected melanoma patients in a prospective international phase III clinical trial. BACKGROUND: Our studies of melanoma patients in phase II clinical trials demonstrated prognostic significance for CTCs in patients with AJCC stage IV melanoma. CTCs were assessed to determine prognostic utility in follow-up of disease-free stage IV patients pre- and during treatment. METHODS: After complete metastasectomy, patients were prospectively enrolled in a randomized trial of adjuvant therapy with a whole-cell melanoma vaccine, Canvaxin, plus Bacille Calmette-Guerin (BCG) versus placebo plus BCG. Blood specimens obtained pretreatment (n = 244) and during treatment (n = 214) were evaluated by quantitative real-time reverse-transcriptase polymerase chain reaction (qPCR) for expression of MART-1, MAGE-A3, and PAX3 mRNA biomarkers. Univariate and multivariate Cox analyses examined CTC biomarker expression with respect to clinicopathological variables. RESULTS: CTC biomarker(s) (≥ 1) was detected in 54% of patients pretreatment and in 86% of patients over the first 3 months. With a median follow-up of 21.9 months, 71% of patients recurred and 48% expired. CTC levels were not associated with known prognostic factors or treatment arm. In multivariate analysis, pretreatment CTC (> 0 vs. 0 biomarker) status was significantly associated with disease-free survival (DFS; HR 1.64, P = 0.002) and overall survival (OS; HR 1.53, P = 0.028). Serial CTC (>0 vs. 0 biomarker) status was also significantly associated with DFS (HR 1.91, P = 0.02) and OS (HR 2.57, P = 0.012). CONCLUSION: CTC assessment can provide prognostic discrimination before and during adjuvant treatment for resected stage IV melanoma patients.

11 Clinical Trial A phase I trial of bortezomib with temozolomide in patients with advanced melanoma: toxicities, antitumor effects, and modulation of therapeutic targets. 2010

Su, Yingjun / Amiri, Katayoun I / Horton, Linda W / Yu, Yingchun / Ayers, Gregory D / Koehler, Elizabeth / Kelley, Mark C / Puzanov, Igor / Richmond, Ann / Sosman, Jeffrey A. ·Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37027, USA. ·Clin Cancer Res · Pubmed #20028756.

ABSTRACT: PURPOSE: Preclinical studies show that bortezomib, a proteasome inhibitor, blocks NF-kappaB activation and, combined with temozolomide, enhances activity against human melanoma xenografts and modulates other critical tumor targets. We initiated a phase I trial of temozolomide plus bortezomib in advanced melanoma. Objectives included defining a maximum tolerated dose for the combination, characterizing biomarker changes reflecting inhibition of both proteasome and NF-kappaB activity in blood (if possible tumor), and characterizing antitumor activity. EXPERIMENTAL DESIGN: Cohorts were enrolled onto escalating dose levels of temozolomide (50-75 mg/m(2)) daily, orally, for 6 of 9 weeks and bortezomib (0.75-1.5 mg/m(2)) by i.v. push on days 1, 4, 8, and 11 every 21 days. Peripheral blood mononuclear cells were assayed at specified time points for proteasome inhibition and NF-kappaB biomarker activity. RESULTS: Bortezomib (1.3 mg/m(2)) and temozolomide (75 mg/m(2)) proved to be the maximum tolerated dose. Dose-limiting toxicities included neurotoxicity, fatigue, diarrhea, and rash. Nineteen melanoma patients were enrolled onto four dose levels. This melanoma population (17 M1c, 10 elevated lactate dehydrogenase, 12 performance status 1-2) showed only one partial response (8 months) and three with stable disease >or=4 months. A significant reduction in proteasome-specific activity was observed 1 hour after infusion at all bortezomib doses. Changes in NF-kappaB electrophoretic mobility shift assay and circulating chemokines in blood failed to correlate with the schedule/dose of bortezomib, inhibition of proteasome activity, or clinical outcome. CONCLUSIONS: We have defined phase II doses for this schedule of temozolomide with bortezomib. Although proteasome activity was inhibited for a limited time in peripheral blood mononuclear cells, we were unable to show consistent effects on NF-kappaB activation.

12 Clinical Trial Verification of musculoskeletal FDG-PET-CT findings performed for melanoma staging. 2010

Mansour, Alfred A / Kelley, Mark C / Hatmaker, Allison R / Holt, Ginger E / Schwartz, Herbert S. ·Department of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA. alfred.mansour@vanderbilt.edu ·Ann Surg Oncol · Pubmed #19967460.

ABSTRACT: BACKGROUND: The purpose of this study is to establish the validity of F-18-deoxyglucose positron emission tomography-computed tomography (FDG-PET-CT) scan staging for cutaneous melanoma when a musculoskeletal image abnormality is detected. METHODS: An institutional review board (IRB)-approved prospective database was queried to identify 342 melanoma patients treated between 4/1999 and 12/2007. A total of 682 whole-body FDG-PET-CT scans performed for staging were retrospectively reviewed to identify FDG-avid lesions in the deep soft tissues/muscle, bone or joints (i.e., musculoskeletal sites). Images were correlated with follow-up patient records. RESULTS: There were 187 true-positive sites on 94 scans and 26 false-positive sites on 22 scans. The overall false-positive rate was 13.9% (26/187). The positive predictive value (PPV) of an isolated musculoskeletal FDG-avid site was 31%. The PPV was highest (100%) when findings were present in both the bone and deep soft tissues. The relative risk of an isolated FDG-avid site compared with multiple FDG-avid sites not being melanoma was 5.33 [95% confidence interval (CI) 2.85-9.94]. The relative risk of an FDG-avid site seen in the appendicular region not being melanoma was 1.78 (95% CI 0.87-3.64) that of a site seen in the axial region. CONCLUSIONS: FDG-PET-CT scanning for staging and surveillance in the extremities of patients with high-risk melanoma often creates confusing clinical scenarios. Our data suggest that a select subset of patients with isolated avid appendicular musculoskeletal scan may not have metastatic melanoma.

13 Article BRAF and MEK inhibitor therapy eliminates Nestin-expressing melanoma cells in human tumors. 2018

Doxie, Deon B / Greenplate, Allison R / Gandelman, Jocelyn S / Diggins, Kirsten E / Roe, Caroline E / Dahlman, Kimberly B / Sosman, Jeffrey A / Kelley, Mark C / Irish, Jonathan M. ·Department of Cell and Developmental Biology, School of Medicine, Vanderbilt University, Nashville, Tennessee. · Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee. · Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee. · Department of Medicine, Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, Tennessee. · Department of Medicine, Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Evanston, Illinois. · Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee. ·Pigment Cell Melanoma Res · Pubmed #29778085.

ABSTRACT: Little is known about the in vivo impacts of targeted therapy on melanoma cell abundance and protein expression. Here, 21 antibodies were added to an established melanoma mass cytometry panel to measure 32 cellular features, distinguish malignant cells, and characterize dabrafenib and trametinib responses in BRAF

14 Article MDM2 Antagonists Counteract Drug-Induced DNA Damage. 2017

Vilgelm, Anna E / Cobb, Priscilla / Malikayil, Kiran / Flaherty, David / Andrew Johnson, C / Raman, Dayanidhi / Saleh, Nabil / Higgins, Brian / Vara, Brandon A / Johnston, Jeffrey N / Johnson, Douglas B / Kelley, Mark C / Chen, Sheau-Chiann / Ayers, Gregory D / Richmond, Ann. ·Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN, United States; Vanderbilt University School of Medicine, Department of Cancer Biology, Nashville, TN, United States. Electronic address: anna.e.vilgelm@vanderbilt.edu. · Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN, United States; Vanderbilt University School of Medicine, Department of Cancer Biology, Nashville, TN, United States. · Meharry Medical College, Nashville, TN, United States. · Vanderbilt University Flow Cytometry Shared Resource, Nashville, TN, United States. · University of Toledo, Toledo, OH, United States. · Pharma Research and Early Development, Roche Innovation Center, New York, NY, United States. · Department of Chemistry, Vanderbilt Institute of Chemical Biology, Nashville, TN, United States. · Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States. · Division of Surgical Oncology, Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, United States. · Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, United States. ·EBioMedicine · Pubmed #29030058.

ABSTRACT: Antagonists of MDM2-p53 interaction are emerging anti-cancer drugs utilized in clinical trials for malignancies that rarely mutate p53, including melanoma. We discovered that MDM2-p53 antagonists protect DNA from drug-induced damage in melanoma cells and patient-derived xenografts. Among the tested DNA damaging drugs were various inhibitors of Aurora and Polo-like mitotic kinases, as well as traditional chemotherapy. Mitotic kinase inhibition causes mitotic slippage, DNA re-replication, and polyploidy. Here we show that re-replication of the polyploid genome generates replicative stress which leads to DNA damage. MDM2-p53 antagonists relieve replicative stress via the p53-dependent activation of p21 which inhibits DNA replication. Loss of p21 promoted drug-induced DNA damage in melanoma cells and enhanced anti-tumor activity of therapy combining MDM2 antagonist with mitotic kinase inhibitor in mice. In summary, MDM2 antagonists may reduce DNA damaging effects of anti-cancer drugs if they are administered together, while targeting p21 can improve the efficacy of such combinations.

15 Article Recurrent Tumor Cell-Intrinsic and -Extrinsic Alterations during MAPKi-Induced Melanoma Regression and Early Adaptation. 2017

Song, Chunying / Piva, Marco / Sun, Lu / Hong, Aayoung / Moriceau, Gatien / Kong, Xiangju / Zhang, Hong / Lomeli, Shirley / Qian, Jin / Yu, Clarissa C / Damoiseaux, Robert / Kelley, Mark C / Dahlman, Kimberley B / Scumpia, Philip O / Sosman, Jeffrey A / Johnson, Douglas B / Ribas, Antoni / Hugo, Willy / Lo, Roger S. ·Division of Dermatology, Department of Medicine, University of California, Los Angeles, California. · David Geffen School of Medicine, University of California, Los Angeles, California. · Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California. · Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California. · Department of Surgery, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee. · Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee. · Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee. · Division of Hematology and Oncology, Department of Medicine, University of California, Los Angeles, California. · Division of Surgical Oncology, Department of Surgery, University of California, Los Angeles, California. · Division of Dermatology, Department of Medicine, University of California, Los Angeles, California. rlo@mednet.ucla.edu. ·Cancer Discov · Pubmed #28864476.

ABSTRACT: Treatment of advanced

16 Article The Impact of Smoking on Sentinel Node Metastasis of Primary Cutaneous Melanoma. 2017

Jones, Maris S / Jones, Peter C / Stern, Stacey L / Elashoff, David / Hoon, Dave S B / Thompson, John / Mozzillo, Nicola / Nieweg, Omgo E / Noyes, Dirk / Hoekstra, Harald J / Zager, Jonathan S / Roses, Daniel F / Testori, Alessandro / Coventry, Brendon J / Smithers, Mark B / Andtbacka, Robert / Agnese, Doreen / Schultz, Erwin / Hsueh, Eddy C / Kelley, Mark / Schneebaum, Schlomo / Jacobs, Lisa / Bowles, Tawnya / Kashani-Sabet, Mohammed / Johnson, Douglas / Faries, Mark B. ·Division of Surgical Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA. · Department of Molecular Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA. · Department of Biostatistics, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA. · UCLA Department of Biostatistics, Los Angeles, CA, USA. · Melanoma Institute Australia, Sydney, NSW, Australia. · Istituto Nazionale dei Tumori Napoli, Napoli, Italy. · IHC Cancer Services, Intermountain Medical Center, Salt Lake City, UT, USA. · Universitair Medisch Centrum Groningen, Groningen, The Netherlands. · H. Lee Moffitt Cancer Center, Tampa, USA. · NYU Langone Medical Center, New York, USA. · Istituto Europeo di Oncologia, Milano, Italy. · Royal Adelaide Hospital Discipline of Surgery, Royal Adelaide HospitalUniversity of Adelaide, Adelaide, SA, Australia. · Princess Alexandra Hospital, Woolloongabba, Queensland, Australia. · Huntsman Cancer Institute, Salt Lake City, USA. · Ohio State University, Columbus, USA. · Nuremberg General Hospital - Paracelsus Medical University, Nuremberg, Germany. · Saint Louis University, St. Louis, USA. · Vanderbilt University, Nashville, USA. · Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel. · Johns Hopkins Medical Institute, Baltimore, USA. · California Pacific Medical Center, San Francisco, USA. · Department of Melanoma Research, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA. mark.faries@jwci.org. ·Ann Surg Oncol · Pubmed #28224364.

ABSTRACT: BACKGROUND: Although a well-established causative relationship exists between smoking and several epithelial cancers, the association of smoking with metastatic progression in melanoma is not well studied. We hypothesized that smokers would be at increased risk for melanoma metastasis as assessed by sentinel lymph node (SLN) biopsy. METHODS: Data from the first international Multicenter Selective Lymphadenectomy Trial (MSLT-I) and the screening-phase of the second trial (MSLT-II) were analyzed to determine the association of smoking with clinicopathologic variables and SLN metastasis. RESULTS: Current smoking was strongly associated with SLN metastasis (p = 0.004), even after adjusting for other predictors of metastasis. Among 4231 patients (1025 in MSLT-I and 3206 in MSLT-II), current or former smoking was also independently associated with ulceration (p < 0.001 and p < 0.001, respectively). Compared with current smoking, never smoking was independently associated with decreased Breslow thickness in multivariate analysis (p = 0.002) and with a 0.25 mm predicted decrease in thickness. CONCLUSION: The direct correlation between current smoking and SLN metastasis of primary cutaneous melanoma was independent of its correlation with tumor thickness and ulceration. Smoking cessation should be strongly encouraged among patients with or at risk for melanoma.

17 Article Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma. 2016

Hugo, Willy / Zaretsky, Jesse M / Sun, Lu / Song, Chunying / Moreno, Blanca Homet / Hu-Lieskovan, Siwen / Berent-Maoz, Beata / Pang, Jia / Chmielowski, Bartosz / Cherry, Grace / Seja, Elizabeth / Lomeli, Shirley / Kong, Xiangju / Kelley, Mark C / Sosman, Jeffrey A / Johnson, Douglas B / Ribas, Antoni / Lo, Roger S. ·Division of Dermatology, Department of Medicine, University of California, Los Angeles, CA 90095-1662, USA; David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1662, USA. · Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1662, USA; David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1662, USA. · Division of Hematology & Oncology, Department of Medicine, University of California, Los Angeles, CA 90095-1662, USA. · Department of Surgery, Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA. · Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA. · Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1662, USA; Division of Hematology & Oncology, Department of Medicine, University of California, Los Angeles, CA 90095-1662, USA; Division of Surgical Oncology, Department of Surgery, University of California, Los Angeles, CA 90095-1662, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095-1662, USA; David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1662, USA. · Division of Dermatology, Department of Medicine, University of California, Los Angeles, CA 90095-1662, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1662, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095-1662, USA; David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1662, USA. Electronic address: rlo@mednet.ucla.edu. ·Cell · Pubmed #26997480.

ABSTRACT: PD-1 immune checkpoint blockade provides significant clinical benefits for melanoma patients. We analyzed the somatic mutanomes and transcriptomes of pretreatment melanoma biopsies to identify factors that may influence innate sensitivity or resistance to anti-PD-1 therapy. We find that overall high mutational loads associate with improved survival, and tumors from responding patients are enriched for mutations in the DNA repair gene BRCA2. Innately resistant tumors display a transcriptional signature (referred to as the IPRES, or innate anti-PD-1 resistance), indicating concurrent up-expression of genes involved in the regulation of mesenchymal transition, cell adhesion, extracellular matrix remodeling, angiogenesis, and wound healing. Notably, mitogen-activated protein kinase (MAPK)-targeted therapy (MAPK inhibitor) induces similar signatures in melanoma, suggesting that a non-genomic form of MAPK inhibitor resistance mediates cross-resistance to anti-PD-1 therapy. Validation of the IPRES in other independent tumor cohorts defines a transcriptomic subset across distinct types of advanced cancer. These findings suggest that attenuating the biological processes that underlie IPRES may improve anti-PD-1 response in melanoma and other cancer types.

18 Article Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy. 2016

Johnson, Douglas B / Estrada, Monica V / Salgado, Roberto / Sanchez, Violeta / Doxie, Deon B / Opalenik, Susan R / Vilgelm, Anna E / Feld, Emily / Johnson, Adam S / Greenplate, Allison R / Sanders, Melinda E / Lovly, Christine M / Frederick, Dennie T / Kelley, Mark C / Richmond, Ann / Irish, Jonathan M / Shyr, Yu / Sullivan, Ryan J / Puzanov, Igor / Sosman, Jeffrey A / Balko, Justin M. ·Department of Medicine, Vanderbilt University, Nashville, 37232 Tennessee, USA. · Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, 37232 Tennessee, USA. · Department of Pathology, Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Boulevard de Waterloo 121, Brussels 1000, Belgium. · Department of Cancer Biology, Vanderbilt University, Nashville, 37232 Tennessee, USA. · Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, 37232 Tennessee, USA. · Department of Medicine, Massachusetts General Hospital, Boston, 02114 Massachusetts, USA. · Department of Surgical Oncology, Vanderbilt University, Nashville, 37232 Tennessee, USA. · Department of Biostatistics, Vanderbilt University, Nashville, 37232 Tennessee, USA. ·Nat Commun · Pubmed #26822383.

ABSTRACT: Anti-PD-1 therapy yields objective clinical responses in 30-40% of advanced melanoma patients. Since most patients do not respond, predictive biomarkers to guide treatment selection are needed. We hypothesize that MHC-I/II expression is required for tumour antigen presentation and may predict anti-PD-1 therapy response. In this study, across 60 melanoma cell lines, we find bimodal expression patterns of MHC-II, while MHC-I expression was ubiquitous. A unique subset of melanomas are capable of expressing MHC-II under basal or IFNγ-stimulated conditions. Using pathway analysis, we show that MHC-II(+) cell lines demonstrate signatures of 'PD-1 signalling', 'allograft rejection' and 'T-cell receptor signalling', among others. In two independent cohorts of anti-PD-1-treated melanoma patients, MHC-II positivity on tumour cells is associated with therapeutic response, progression-free and overall survival, as well as CD4(+) and CD8(+) tumour infiltrate. MHC-II(+) tumours can be identified by melanoma-specific immunohistochemistry using commercially available antibodies for HLA-DR to improve anti-PD-1 patient selection.

19 Article Connecting the Dots: Therapy-Induced Senescence and a Tumor-Suppressive Immune Microenvironment. 2016

Vilgelm, Anna E / Johnson, C Andrew / Prasad, Nripesh / Yang, Jinming / Chen, Sheau-Chiann / Ayers, Gregory D / Pawlikowski, Jeff S / Raman, Dayanidhi / Sosman, Jeffrey A / Kelley, Mark / Ecsedy, Jeffrey A / Shyr, Yu / Levy, Shawn E / Richmond, Ann. ·Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN (AEV, CAJ, JY, JSP, DR, AR) · Department of Cancer Biology (AEV, AJ, JY, SCC, JSP, DR, AR), Center for Quantitative Sciences (SCC), Division of Cancer Biostatistics, Department of Biostatistics (GDA, YS), Division of Hematology/Oncology, Department of Medicine (JAS), Vanderbilt University Medical Center, Nashville, TN · HudsonAlpha Institute for Biotechnology, Huntsville, Alabama (NP, SEL) · Division of Surgical Oncology, Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN (MK) · Translational Medicine, Takeda Pharmaceuticals International Co, Cambridge, MA (JAE). ·J Natl Cancer Inst · Pubmed #26719346.

ABSTRACT: BACKGROUND: Tumor cell senescence is a common outcome of anticancer therapy. Here we investigated how therapy-induced senescence (TIS) affects tumor-infiltrating leukocytes (TILs) and the efficacy of immunotherapy in melanoma. METHODS: Tumor senescence was induced by AURKA or CDK4/6 inhibitors (AURKAi, CDK4/6i). Transcriptomes of six mouse tumors with differential response to AURKAi were analyzed by RNA sequencing, and TILs were characterized by flow cytometry. Chemokine RNA and protein expression were determined by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Therapeutic response was queried in immunodeficient mice, in mice with CCL5-deficient tumors, and in mice cotreated with CD137 agonist to activate TILs. CCL5 expression in reference to TIS and markers of TILs was studied in human melanoma tumors using patient-derived xenografts (n = 3 patients, n = 3 mice each), in AURKAi clinical trial samples (n = 3 patients, before/after therapy), and in The Cancer Genome Atlas (n = 278). All statistical tests were two-sided. RESULTS: AURKAi response was associated with induction of the immune transcriptome (P = 3.5 x 10-29) while resistance inversely correlated with TIL numbers (Spearman r = -0.87, P < .001). AURKAi and CDK4/6i promoted the recruitment of TILs by inducing CCL5 secretion in melanoma cells (P ≤ .005) in an NF-κB-dependent manner. Therapeutic response to AURKAi was impaired in immunodeficient compared with immunocompetent mice (0% vs 67% tumors regressed, P = .01) and in mice bearing CCL5-deficient vs control tumors (P = .61 vs P = .02); however, AURKAi response was greatly enhanced in mice also receiving T-cell-activating immunotherapy (P < .001). In human tumors, CCL5 expression was also induced by AURKAi (P ≤ .02) and CDK4/6i (P = .01) and was associated with increased immune marker expression (P = 1.40 x 10-93). CONCLUSIONS: Senescent melanoma cells secret CCL5, which promotes recruitment of TILs. Combining TIS with immunotherapy that enhances tumor cell killing by TILs is a promising novel approach to improve melanoma outcomes.

20 Article Combining an Aurora Kinase Inhibitor and a Death Receptor Ligand/Agonist Antibody Triggers Apoptosis in Melanoma Cells and Prevents Tumor Growth in Preclinical Mouse Models. 2015

Liu, Yan / Hawkins, Oriana E / Vilgelm, Anna E / Pawlikowski, Jeffrey S / Ecsedy, Jeffrey A / Sosman, Jeffrey A / Kelley, Mark C / Richmond, Ann. ·Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee. Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. · Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee. · Translational Medicine, Takeda Pharmaceuticals International C, Cambridge, Massachusetts. · Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. · Division of Surgical Oncology, Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee. · Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee. ann.richmond@vanderbilt.edu. ·Clin Cancer Res · Pubmed #26152738.

ABSTRACT: PURPOSE: Preclinical studies show that inhibition of aurora kinases in melanoma tumors induces senescence and reduces tumor growth, but does not cause tumor regression. Additional preclinical models are needed to identify agents that will synergize with aurora kinase inhibitors to induce tumor regression. EXPERIMENTAL DESIGN: We combined treatment with an aurora kinase A inhibitor, MLN8237, with agents that activate death receptors (Apo2L/TRAIL or death receptor 5 agonists) and monitored the ability of this treatment to induce tumor apoptosis and melanoma tumor regression using human cell lines and patient-derived xenograft (PDX) mouse models. RESULTS: We found that this combined treatment led to apoptosis and markedly reduced cell viability. Mechanistic analysis showed that the induction of tumor cell senescence in response to the AURKA inhibitor resulted in a decreased display of Apo2L/TRAIL decoy receptors and increased display of one Apo2L/TRAIL receptor (death receptor 5), resulting in enhanced response to death receptor ligand/agonists. When death receptors were activated in senescent tumor cells, both intrinsic and extrinsic apoptotic pathways were induced independent of BRAF, NRAS, or p53 mutation status. Senescent tumor cells exhibited BID-mediated mitochondrial depolarization in response to Apo2L/TRAIL treatment. In addition, senescent tumor cells had a lower apoptotic threshold due to decreased XIAP and survivin expression. Melanoma tumor xenografts of one human cell line and one PDX displayed total blockage of tumor growth when treated with MLN8237 combined with DR5 agonist antibody. CONCLUSIONS: These findings provide a strong rationale for combining senescence-inducing therapeutics with death receptor agonists for improved cancer treatment.

21 Article ERBB activation modulates sensitivity to MEK1/2 inhibition in a subset of driver-negative melanoma. 2015

Hutchinson, Katherine E / Johnson, Douglas B / Johnson, Adam S / Sanchez, Violeta / Kuba, Maria / Lu, Pengcheng / Chen, Xi / Kelley, Mark C / Wang, Qingguo / Zhao, Zhongming / Kris, Mark / Berger, Michael F / Sosman, Jeffrey A / Pao, William. ·Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. · Department of Medicine/Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. · Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. · Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA. · Department of Surgery, Division of Surgical Oncology and Endocrine Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA. · Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA. · Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. · Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. · Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. · Currently an employee of Roche Pharma Research and Early Development, Basel, Switzerland. ·Oncotarget · Pubmed #26084293.

ABSTRACT: Melanomas are characterized by activating "driver" mutations in BRAF, NRAS, KIT, GNAQ, and GNA11. Resultant mitogen-activated protein kinase (MAPK) pathway signaling makes some melanomas susceptible to BRAF (BRAF V600 mutations), MEK1/2 (BRAF V600, L597, fusions; NRAS mutations), or other kinase inhibitors (KIT), respectively. Among driver-negative ("pan-negative") patients, an unexplained heterogeneity of response to MEK1/2 inhibitors has been observed. Analysis of 16 pan-negative melanoma cell lines revealed that 8 (50%; termed Class I) are sensitive to the MEK1/2 inhibitor, trametinib, similar to BRAF V600E melanomas. A second set (termed Class II) display reduced trametinib sensitivity, paradoxical activation of MEK1/2 and basal activation of ERBBs 1, 2, and 3 (4 lines, 25%). In 3 of these lines, PI3K/AKT and MAPK pathway signaling is abrogated using the ERBB inhibitor, afatinib, and proliferation is even further reduced upon the addition of trametinib. A potential mechanism of ERBB activation in Class II melanomas is minimal expression of the ERK1/2 phosphatase, DUSP4, as ectopic restoration of DUSP4 attenuated ERBB signaling through potential modulation of the ERBB ligand, amphiregulin (AREG). Consistent with these data, immunohistochemical analysis of patient melanomas revealed a trend towards lower overall DUSP4 expression in pan-negative versus BRAF- and NRAS-mutant tumors. This study is the first to demonstrate that differential ERBB activity in pan-negative melanoma may modulate sensitivity to clinically-available MEK1/2 inhibitors and provides rationale for the use of ERBB inhibitors, potentially in combination with MEK1/2 inhibitors, in subsets of this disease.

22 Article Mdm2 and aurora kinase a inhibitors synergize to block melanoma growth by driving apoptosis and immune clearance of tumor cells. 2015

Vilgelm, Anna E / Pawlikowski, Jeff S / Liu, Yan / Hawkins, Oriana E / Davis, Tyler A / Smith, Jessica / Weller, Kevin P / Horton, Linda W / McClain, Colt M / Ayers, Gregory D / Turner, David C / Essaka, David C / Stewart, Clinton F / Sosman, Jeffrey A / Kelley, Mark C / Ecsedy, Jeffrey A / Johnston, Jeffrey N / Richmond, Ann. ·Tennessee Valley Healthcare System, Department of Veterans Affairs, Vanderbilt University Medical Center, Nashville, Tennessee. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee. · Department of Chemistry and Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, Tennessee. · Meharry Medical College, Nashville, Tennessee. · Flow Cytometry Shared Resource, Vanderbilt University Medical Center, Nashville, Tennessee. · Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee. · Division of Cancer Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee. · Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee. · Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. · Division of Surgical Oncology, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee. · Takeda Pharmaceuticals International Co., Cambridge, Massachusetts. · Tennessee Valley Healthcare System, Department of Veterans Affairs, Vanderbilt University Medical Center, Nashville, Tennessee. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee. ann.richmond@vanderbilt.edu. ·Cancer Res · Pubmed #25398437.

ABSTRACT: Therapeutics that induce cancer cell senescence can block cell proliferation and promote immune rejection. However, the risk of tumor relapse due to senescence escape may remain high due to the long lifespan of senescent cells that are not cleared. Here, we show how combining a senescence-inducing inhibitor of the mitotic kinase Aurora A (AURKA) with an MDM2 antagonist activates p53 in senescent tumors harboring wild-type 53. In the model studied, this effect is accompanied by proliferation arrest, mitochondrial depolarization, apoptosis, and immune clearance of cancer cells by antitumor leukocytes in a manner reliant upon Ccl5, Ccl1, and Cxcl9. The AURKA/MDM2 combination therapy shows adequate bioavailability and low toxicity to the host. Moreover, the prominent response of patient-derived melanoma tumors to coadministered MDM2 and AURKA inhibitors offers a sound rationale for clinical evaluation. Taken together, our work provides a preclinical proof of concept for a combination treatment that leverages both senescence and immune surveillance to therapeutic ends.

23 Article Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. 2014

Shi, Hubing / Hugo, Willy / Kong, Xiangju / Hong, Aayoung / Koya, Richard C / Moriceau, Gatien / Chodon, Thinle / Guo, Rongqing / Johnson, Douglas B / Dahlman, Kimberly B / Kelley, Mark C / Kefford, Richard F / Chmielowski, Bartosz / Glaspy, John A / Sosman, Jeffrey A / van Baren, Nicolas / Long, Georgina V / Ribas, Antoni / Lo, Roger S. ·Division of Dermatology, Department of Medicine. · David Geffen School of Medicine, University of California, LA, California 90095-1662 USA. · Department of Molecular and Medical Pharmacology. · Division of Surgical Oncology, Department of Surgery. · Division of Hematology & Oncology, Department of Medicine. · Department of Medicine. · Vanderbilt-Ingram Cancer Center, Nashville, TN 37232. · Department of Cancer Biology. · Department of Surgery. · Melanoma Institute of Australia, Westmead Millenium Institute, Westmead Hospital, University of Sydney, New South Wales, Australia. · Jonsson Comprehensive Cancer Center. · Ludwig Institute for Cancer Research, Brussels Branch, Belgium. ·Cancer Discov · Pubmed #24265155.

ABSTRACT: BRAF inhibitors elicit rapid antitumor responses in the majority of patients with BRAF(V600)-mutant melanoma, but acquired drug resistance is almost universal. We sought to identify the core resistance pathways and the extent of tumor heterogeneity during disease progression. We show that mitogen-activated protein kinase reactivation mechanisms were detected among 70% of disease-progressive tissues, with RAS mutations, mutant BRAF amplification, and alternative splicing being most common. We also detected PI3K-PTEN-AKT-upregulating genetic alterations among 22% of progressive melanomas. Distinct molecular lesions in both core drug escape pathways were commonly detected concurrently in the same tumor or among multiple tumors from the same patient. Beyond harboring extensively heterogeneous resistance mechanisms, melanoma regrowth emerging from BRAF inhibitor selection displayed branched evolution marked by altered mutational spectra/signatures and increased fitness. Thus, melanoma genomic heterogeneity contributes significantly to BRAF inhibitor treatment failure, implying upfront, cotargeting of two core pathways as an essential strategy for durable responses.

24 Article Severe cutaneous and neurologic toxicity in melanoma patients during vemurafenib administration following anti-PD-1 therapy. 2013

Johnson, Douglas B / Wallender, Erika K / Cohen, Daniel N / Likhari, Sunaina S / Zwerner, Jeffrey P / Powers, Jennifer G / Shinn, Lisa / Kelley, Mark C / Joseph, Richard W / Sosman, Jeffrey A. ·Vanderbilt University Medical Center. · Mayo Clinic Jacksonville. ·Cancer Immunol Res · Pubmed #24490176.

ABSTRACT: Immune checkpoint inhibitors such as ipilimumab and targeted BRAF inhibitors have dramatically altered the landscape of melanoma therapeutics over the past few years. Agents targeting the programmed cell death-1/ligand (PD-1/PD-L1) axis are now being developed and appear to be highly active clinically with favorable toxicity profiles. We report two patients with BRAF V600E mutant melanoma who were treated with anti-PD-1 agents as first-line therapy without significant toxicity, followed by vemurafenib at disease progression. Both patients developed severe hypersensitivity drug eruptions with multi-organ injury early in their BRAF inhibitor treatment course. One patient subsequently developed acute inflammatory demyelinating polyneuropathy (AIDP) and the other developed anaphylaxis upon low-dose vemurafenib rechallenge. Further investigation of the immune response during combination or sequences of melanoma therapeutics is warranted. Furthermore, clinicians should maintain a high index of suspicion for these toxicities when vemurafenib is administered following an anti-PD-1 agent.

25 Article Targeting aurora kinases limits tumour growth through DNA damage-mediated senescence and blockade of NF-κB impairs this drug-induced senescence. 2013

Liu, Yan / Hawkins, Oriana E / Su, Yingjun / Vilgelm, Anna E / Sobolik, Tammy / Thu, Yee-Mon / Kantrow, Sara / Splittgerber, Ryan C / Short, Sarah / Amiri, Katayoun I / Ecsedy, Jeffery A / Sosman, Jeffery A / Kelley, Mark C / Richmond, Ann. ·Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA. ·EMBO Mol Med · Pubmed #23180582.

ABSTRACT: Oncogene-induced senescence can provide a protective mechanism against tumour progression. However, production of cytokines and growth factors by senescent cells may contribute to tumour development. Thus, it is unclear whether induction of senescence represents a viable therapeutic approach. Here, using a mouse model with orthotopic implantation of metastatic melanoma tumours taken from 19 patients, we observed that targeting aurora kinases with MLN8054/MLN8237 impaired mitosis, induced senescence and markedly blocked proliferation in patient tumour implants. Importantly, when a subset of tumour-bearing mice were monitored for tumour progression after pausing MLN8054 treatment, 50% of the tumours did not progress over a 12-month period. Mechanistic analyses revealed that inhibition of aurora kinases induced polyploidy and the ATM/Chk2 DNA damage response, which mediated senescence and a NF-κB-related, senescence-associated secretory phenotype (SASP). Blockade of IKKβ/NF-κB led to reversal of MLN8237-induced senescence and SASP. Results demonstrate that removal of senescent tumour cells by infiltrating myeloid cells is crucial for inhibition of tumour re-growth. Altogether, these data demonstrate that induction of senescence, coupled with immune surveillance, can limit melanoma growth.

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