Publications by authors named "James S Goydos"

59 Publications

Randomized controlled trial of the mySmartSkin web-based intervention to promote skin self-examination and sun protection behaviors among individuals diagnosed with melanoma: study design and baseline characteristics.

Contemp Clin Trials 2019 08 27;83:117-127. Epub 2019 Jun 27.

Center for Behavioral Health and Technology, Department of Psychiatry and Neurobehavioral Sciences, University of Virginia School of Medicine, Charlottesville, VA, United States.

>1.2 million people in the United States have a personal history of melanoma skin cancer and are at increased risk for disease recurrence and second primary melanomas. Many of these individuals do not follow recommendations to conduct regular, thorough skin self-examinations that facilitate early disease detection and do not sufficiently engage in sun protection behaviors. In this project, we are conducting a randomized controlled trial of an innovative, tailored, theory-driven Internet intervention-called mySmartSkin-to promote these behaviors among melanoma patients. This paper outlines the study design and characteristics of the study sample. A total of 441 patients were recruited (40.9% response rate) and randomized to the mySmartSkin or a Usual Care condition. Participants complete surveys at baseline and 8 weeks, 24 weeks, and 48 weeks later. The primary aim of the project is to examine the impact of mySmartSkin versus Usual Care on skin self-examination and sun protection behaviors. The secondary aim focuses on identifying mediators of the intervention's effects. In an exploratory aim, we will examine potential moderators of the impact of the intervention. At baseline, the recruited participants had a mean age of 61 years, 49% were female, 7.5% met criteria for having conducted a recent, thorough skin self-examination, and the mean score on the index of sun protection behaviors was 3.3 (on a scale from 1 to 5). The results of the project will determine whether the mySmartSkin intervention is efficacious in promoting skin self-examination and sun protection behaviors among individuals diagnosed with melanoma. Trial registration: ClinicalTrials.govNCT03028948.
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http://dx.doi.org/10.1016/j.cct.2019.06.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690854PMC
August 2019

Participation of xCT in melanoma cell proliferation in vitro and tumorigenesis in vivo.

Oncogenesis 2018 Nov 14;7(11):86. Epub 2018 Nov 14.

Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08901, USA.

Our research group demonstrated that riluzole, an inhibitor of glutamatergic signaling reduced melanoma cell proliferation in vitro and tumor progression in vivo. The underlying mechanisms of riluzole are largely unknown. Microarray analyses on two human melanoma cell lines revealed that riluzole stimulates expression of the cystine-glutamate amino acid antiporter, xCT (SLC7A11). Western immunoblot analysis from cultured human melanoma or normal melanocytic cells showed that xCT was significantly overexpressed in most melanomas, but not normal cells. Studies using human tumor biopsy samples demonstrated that overexpression of xCT was correlated with cancer stage and progression. To further investigate if xCT is involved in melanoma cell growth, we derived several stable clones through transfection of exogenous xCT to melanoma cells that originally showed very low expression of xCT. The elevated xCT expression promoted cell proliferation in vitro and inversely, these melanoma clones showed a dose-dependent decrease in cell proliferation in response to riluzole treatment. Xenograft studies showed that these clones formed very aggressive tumors at a higher rate compared to vector controls. Conversely, treatment of xenograft-bearing animals with riluzole down-regulated xCT expression suggesting that xCT is a molecular target of riluzole. Furthermore, protein lysates from tumor biopsies of patients that participated in a riluzole monotherapy phase II clinical trial showed a reduction in xCT levels in post-treatment specimens from patients with stable disease. Taken together, our results show that xCT may be utilized as a marker to monitor patients undergoing riluzole-based chemotherapies.
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http://dx.doi.org/10.1038/s41389-018-0098-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234219PMC
November 2018

A phase II trial of riluzole, an antagonist of metabotropic glutamate receptor 1 (GRM1) signaling, in patients with advanced melanoma.

Pigment Cell Melanoma Res 2018 07 10;31(4):534-540. Epub 2018 Apr 10.

Rutgers Cancer Institute of New Jersey/Robert Wood Johnson Medical School, New Brunswick, NJ, USA.

Studies demonstrate that GRM, expressed by >60% of human melanomas, may be a therapeutic target. We performed a phase II trial of 100 mg PO bid of riluzole, an inhibitor of GRM1 signaling, in patients with advanced melanoma with the primary endpoint of response rate. Thirteen patients with GRM1-positive tumors were enrolled. No objective responses were observed, and accrual was stopped. Stable disease was noted in six (46%) patients, with one patient on study for 42 weeks. Riluzole was well tolerated, with fatigue (62%) as the most common adverse event. Downregulation of MAPK and PI3K/AKT was noted in 33% of paired tumor biopsies. Hypothesis-generating correlative studies suggested that downregulation of angiogenic markers and increased leukocytes at the active edge of tumor correlate with clinical benefit. Pharmacokinetic analysis showed interpatient variability consistent with prior riluzole studies. Future investigations should interrogate mechanisms of biologic activity and advance the development of agents with improved bioavailability.
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http://dx.doi.org/10.1111/pcmr.12694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013351PMC
July 2018

Exosomes released by metabotropic glutamate receptor 1 (GRM1) expressing melanoma cells increase cell migration and invasiveness.

Oncotarget 2018 Jan 19;9(1):1187-1199. Epub 2017 Dec 19.

Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The State University, Piscataway, NJ 08854, USA.

Exosomes are naturally occurring membrane-bound nanovesicles generated constitutively and released by various cell types, and often in higher quantities by tumor cells. Exosomes may facilitate communication between the primary tumor and its local microenvironment, supporting cell invasion and other early events in metastasis. A neuronal receptor, metabotropic glutamate receptor 1 (GRM1), when ectopically expressed in melanocytes, induces melanocytic transformation and spontaneous malignant melanoma development in a transgenic mouse model. Our earlier studies showed that genetic modulation in GRM1 expression by siRNA or disruption of GRM1-mediated glutamate signaling interfere with downstream effectors resulting in a decrease in both cell proliferation and tumor progression . In this study, we sought to determine whether exosome formation might play a role in GRM1 mediated melanoma development and progression. To test this, we utilized cultured cells in which GRM1 expression and function could be modulated by pharmacological and genetic means and determined effects on exosome production. We also tested the effects of exosomes from GRM1 expressing melanoma cells on growth, migration and invasion of GRM1 negative cells. Our results show that although GRM1 expression has no influence on exosome quantity, exosomes produced by GRM1-positive cells modulate the ability of the recipient cell to migrate, invade and exhibit anchorage-independent cell growth.
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http://dx.doi.org/10.18632/oncotarget.23455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787429PMC
January 2018

Parent and Child Characteristics Associated with Child Sunburn and Sun Protection Among U.S. Hispanics.

Pediatr Dermatol 2017 May;34(3):315-321

Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, New Jersey.

Background/objectives: Skin cancer incidence has been increasing in U.S. Hispanics over several decades and the postdiagnosis outcomes are worse for Hispanics than for non-Hispanic whites. Parents are influential in children's health preventive behaviors, but little is known about parental factors associated with children's skin cancer-related behaviors in the U.S. Hispanic population. The present study examined parental and child correlates of skin cancer-related behaviors (sunburns, sunbathing, sun-protective clothing use, and sunscreen use) of children of Hispanic parents.

Methods: This survey study included a population-based sample of 360 U.S. Hispanic parents (44.8% male) who had a child 14 years of age or younger. Measures included parental reports of parent and child demographic characteristics, parent skin cancer knowledge and linguistic acculturation, and parent and child skin cancer-related behaviors.

Results: Approximately 28% of children and 31.9% of parents experienced at least one sunburn in the past year and approximately 29% of children and 36.7% of parents were reported to sunbathe. Moderate use of sun-protective clothing and sunscreen was reported for parents and their children. Child sun-protective clothing use and sunscreen use, sunburns, and sunbathing were associated with the corresponding behaviors of their parents.

Conclusions: Future research should consider the role of acculturation and perceived risk in the sun protection behaviors of U.S. Hispanic children, particularly in those who report a fair skin type. Hispanic parents should be included in interventions targeting their children's skin cancer-related behaviors, and it is suggested that such interventions could also encourage parents to improve their own behaviors.
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http://dx.doi.org/10.1111/pde.13136DOI Listing
May 2017

The transcription factor RUNX2 regulates receptor tyrosine kinase expression in melanoma.

Oncotarget 2016 May;7(20):29689-707

Division of Surgical Oncology, Department of Surgery, Robert Wood Johnson Medical School, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA.

Receptor tyrosine kinases-based autocrine loops largely contribute to activate the MAPK and PI3K/AKT pathways in melanoma. However, the molecular mechanisms involved in generating these autocrine loops are still largely unknown. In the present study, we examine the role of the transcription factor RUNX2 in the regulation of receptor tyrosine kinase (RTK) expression in melanoma. We have demonstrated that RUNX2-deficient melanoma cells display a significant decrease in three receptor tyrosine kinases, EGFR, IGF-1R and PDGFRβ. In addition, we found co-expression of RUNX2 and another RTK, AXL, in both melanoma cells and melanoma patient samples. We observed a decrease in phosphoAKT2 (S474) and phosphoAKT (T308) levels when RUNX2 knock down resulted in significant RTK down regulation. Finally, we showed a dramatic up regulation of RUNX2 expression with concomitant up-regulation of EGFR, IGF-1R and AXL in melanoma cells resistant to the BRAF V600E inhibitor PLX4720. Taken together, our results strongly suggest that RUNX2 might be a key player in RTK-based autocrine loops and a mediator of resistance to BRAF V600E inhibitors involving RTK up regulation in melanoma.
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http://dx.doi.org/10.18632/oncotarget.8822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045426PMC
May 2016

Final Results of the Sunbelt Melanoma Trial: A Multi-Institutional Prospective Randomized Phase III Study Evaluating the Role of Adjuvant High-Dose Interferon Alfa-2b and Completion Lymph Node Dissection for Patients Staged by Sentinel Lymph Node Biopsy.

J Clin Oncol 2016 Apr 8;34(10):1079-86. Epub 2016 Feb 8.

Kelly M. McMasters, Michael E. Egger, Robert C.G. Martin II, and Charles R. Scoggins, University of Louisville, James Graham Brown Cancer Center; Arnold J. Stromberg, University of Kentucky; and Lee J. Hagendoorn, Advertek Louisville, KY; Michael J. Edwards and Jeffrey J. Sussman, University of Cincinnati, Cincinnati, OH; Merrick I. Ross and Jeffrey E. Gershenwald, University of Texas MD Anderson Cancer Center, Houston; Peter D. Beitsch, Dallas Surgical Group, Dallas, TX; Douglas S. Reintgen, University of South Florida School of Medicine, Tampa, FL; R. Dirk Noyes, LDS Hospital, Salt Lake City, UT; James S. Goydos, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ; Marshall M. Urist, University of Alabama School of Medicine, Birmingham, AL; Stephan Ariyan, Yale University School of Medicine, New Haven, CT; and B. Scott Davidson, Northside Hospital Cancer Institute, Melanoma and Sarcoma Specialists of Georgia, Atlanta, GA.

Purpose: The Sunbelt Melanoma Trial is a prospective randomized trial evaluating the role of high-dose interferon alfa-2b therapy (HDI) or completion lymph node dissection (CLND) for patients with melanoma staged by sentinel lymph node (SLN) biopsy.

Patients And Methods: Patients were eligible if they were age 18 to 70 years with primary cutaneous melanoma ≥ 1.0 mm Breslow thickness and underwent SLN biopsy. In Protocol A, patients with a single tumor-positive lymph node after SLN biopsy underwent CLND and were randomly assigned to observation versus HDI. In Protocol B, patients with tumor-negative SLN by standard histopathology and immunohistochemistry underwent molecular staging by reverse transcriptase polymerase chain reaction (RT-PCR). Patients positive by RT-PCR were randomly assigned to observation versus CLND versus CLND+HDI. Primary end points were disease-free survival (DFS) and overall survival (OS).

Results: In the Protocol A intention-to-treat analysis, there were no significant differences in DFS (hazard ratio, 0.82; P = .45) or OS (hazard ratio, 1.10; P = .68) for patients randomly assigned to HDI versus observation. In the Protocol B intention-to-treat analysis, there were no significant differences in overall DFS (P = .069) or OS (P = .77) across the three randomized treatment arms. Similarly, efficacy analysis (excluding patients who did not receive the assigned treatment) did not demonstrate significant differences in DFS or OS in Protocol A or Protocol B. Median follow-up time was 71 months.

Conclusion: No survival benefit for adjuvant HDI in patients with a single positive SLN was found. Among patients with tumor-negative SLN by conventional pathology but with melanoma detected in the SLN by RT-PCR, there was no OS benefit for CLND or CLND+HDI.
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http://dx.doi.org/10.1200/JCO.2015.63.3776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321066PMC
April 2016

Acral Lentiginous Melanoma.

Cancer Treat Res 2016 ;167:321-9

Plastic and Reconstructive Surgery, Robert Wood Johnson University Hospital, New Jersey, USA.

Acral lentiginous melanoma (ALM) is a rare subtype of melanoma mainly arising on the palms, soles, and nail beds. ALM is the most common subtype of melanoma found in patients of Asian or African descent and tends to more advanced at presentation due to delays in diagnosis. Surgical treatment is difficult owing to the complexity and functional importance of the hands and feet and reconstruction after resection is usually needed. The prognosis for patients with ALM depends on stage of disease and tends to be worse than with other subtypes of melanoma. Newer treatment modalities such as immunotherapies and targeted agents are being tested in patients with advanced ALM with some promising preliminary results.
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http://dx.doi.org/10.1007/978-3-319-22539-5_14DOI Listing
January 2016

Occupational sunscreen use among US Hispanic outdoor workers.

BMC Res Notes 2015 Oct 17;8:578. Epub 2015 Oct 17.

Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ, 08901, USA.

Background: Occupational ultraviolet radiation (UVR) exposure is a risk factor for skin cancer, and Hispanic individuals are over-represented in a number of outdoor occupations (e.g., farming, landscaping). This study examined predictors of occupational sunscreen use in a group of US Hispanic adults who work outdoors.

Results: A population-based sample of outdoor workers (n = 149, 85 % male) completed survey measures regarding their demographics, melanoma risk, perceived skin cancer risk, skin cancer knowledge, and their occupational sunscreen use. Sixty-nine percent of the sample reported never or rarely wearing sunscreen while working outdoors. Being female (p = .02), having a higher level of education (p = .03), and residing at a higher latitude (p = .04) were associated with more frequent sunscreen use.

Conclusions: This study highlights the importance of interventions to promote sun protection behaviors among US Hispanic outdoor workers, and identifies potential intervention targets.
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http://dx.doi.org/10.1186/s13104-015-1558-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4609133PMC
October 2015

Receptivity to Internet-Delivered Interventions to Promote Skin Self-examination and Sun Protection Behaviors in Patients With Melanoma.

JAMA Dermatol 2016 Feb;152(2):213-5

Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick.

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http://dx.doi.org/10.1001/jamadermatol.2015.2978DOI Listing
February 2016

Skin self-examination behaviors among individuals diagnosed with melanoma.

Melanoma Res 2016 Feb;26(1):71-6

aRutgers Cancer Institute of New Jersey bDepartment of Medicine cDepartment of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick dDepartment of Health Education and Behavioral Science, Rutgers School of Public Health, Rutgers, The State University of New Jersey, Piscataway, New Jersey, USA.

Many melanoma patients do not regularly perform thorough skin self-examinations. We examined the extent to which melanoma patients conduct thorough skin self-examination, how they perform skin self-examination, and their related knowledge and self-efficacy. A sample of 176 individuals (61.5% response rate) diagnosed with primary pathologic stage 0-III cutaneous malignant melanoma at a single cancer center completed a written or telephone survey regarding their skin self-examination behaviors and associated factors. Almost all participants (98.9%) reported their race as white. Almost three-quarters (71.6%) of participants reported doing an examination in the past 2 months. However, only 14.2% had examined all areas of the body in the past 2 months. Few participants reported always using a full-length mirror (13.4%), hand-held mirror (11.3%), or having someone help (9.2%) when doing an examination. Having a higher level of education, greater knowledge of the ABCDE rule for detecting potential melanoma, higher skin self-examination self-efficacy, being shown how to do skin self-examination, and being shown what a suspicious mole would look like were all significantly associated with conducting more thorough skin self-examination. Most melanoma patients do not engage in regular, thorough skin self-examination, and when they do examine their skin they typically do not sufficiently utilize tools and techniques to facilitate a thorough examination and tracking of potentially suspicious moles. Efforts to promote skin self-examination among melanoma patients should focus on increasing knowledge and self-efficacy and providing education about the why, when, and how of conducting self-examination and mole tracking.
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http://dx.doi.org/10.1097/CMR.0000000000000204DOI Listing
February 2016

Targeting Glutamatergic Signaling and the PI3 Kinase Pathway to Halt Melanoma Progression.

Transl Oncol 2015 Feb;8(1):1-9

Department of Surgery, Division of Surgical Oncology, Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA. Electronic address:

Our group has previously reported that the majority of human melanomas (>60%) express the metabotropic glutamate receptor 1 (GRM1) and that the glutamate release inhibitor riluzole, a drug currently used to treat amyotrophic lateral sclerosis, can induce apoptosis in GRM1-expressing melanoma cells. Our group previously reported that in vitro riluzole treatment reduces cell growth in three-dimensional (3D) soft agar colony assays by 80% in cells with wildtype phosphoinositide 3-kinase (PI3K) pathway activation. However, melanoma cell lines harboring constitutive activating mutations of the PI3K pathway (PTEN and NRAS mutations) showed only a 35% to 40% decrease in colony formation in soft agar in the presence of riluzole. In this study, we have continued our preclinical studies of riluzole and its effect on melanoma cells alone and in combination with inhibitors of the PI3 kinase pathway: the AKT inhibitor, API-2, and the mammalian target of rapamycin (mTOR) inhibitor, rapamycin. We modeled these combinatorial therapies on various melanoma cell lines in 3D and 2D systems and in vivo. Riluzole combined with mTOR inhibition is more effective at halting melanoma anchorage-independent growth and xenograft tumor progression than either agent alone. PI3K signaling changes associated with this combinatorial treatment shows that 3D (nanoculture) modeling of cell signaling more closely resembles in vivo signaling than monolayer models. Riluzole combined with mTOR inhibition is effective at halting tumor cell progression independent of BRAF mutational status. This makes this combinatorial therapy a potentially viable alternative for metastatic melanoma patients who are BRAF WT and are therefore ineligible for vemurafenib therapy.
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http://dx.doi.org/10.1016/j.tranon.2014.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4350641PMC
February 2015

Interdigitating dendritic cell sarcoma presenting in the skin: diagnosis and the role of surgical resection, chemotherapy and radiotherapy in management.

Rare Tumors 2014 Oct 11;6(4):5573. Epub 2014 Dec 11.

Department of Surgical Oncology, Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School , New Brunswick, NJ, USA.

We report the case of an interdigitating dendritic cell sarcoma (IDCS) presenting in the skin. A 41-year old woman had a slowly enlarging mass on her right scapula that was excised multiple times under a presumptive diagnosis of a recurrent sebaceous cyst. However, the lesion was refractory to standard therapies. History and physical exam was unrevealing for any systemic signs or symptoms of disease. The patient's metastatic work-up was negative. The lesion was resected with wide margins and was found to be consistent with IDCS. Patients that present with IDCS on the skin may present concurrently with metastatic disease and may have increased risk of secondary malignancies. The use of adjuvant chemoradiation after primary resection is controversial. However, the use of chemoradiation likely has benefit for local regional control for primary tumors that are unamendable to complete primary resection.
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http://dx.doi.org/10.4081/rt.2014.5573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4274444PMC
October 2014

Riluzole is a radio-sensitizing agent in an in vivo model of brain metastasis derived from GRM1 expressing human melanoma cells.

Pigment Cell Melanoma Res 2015 Jan 28;28(1):105-9. Epub 2014 Nov 28.

Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The State University, Piscataway, NJ, USA; Joint Graduate Program of Toxicology and Pharmacology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.

Approximately 50% of patients having metastatic melanoma develop brain metastases during the course of their illness. Evidence exists that melanoma cells have increased aptitude for the repair of sublethal DNA damage caused by ionizing radiation therapy. To address the radio-resistance of melanoma, many groups adopted radiotherapy schedules that deliver larger daily fractions of radiation, but due to the risk of neurotoxicity, these large fractions cannot be delivered to the whole brain for patients with brain metastases. Here, we used orthotopic implanted GRM1 expressing human melanoma cell xenografts in mice, to demonstrate that animals receiving concurrent glutamate signaling blockade (riluzole) and radiation led to a decrease in intracranial tumor growth compared to either modality alone. These preclinical results suggest riluzole may cause radio-sensitization that offers enhanced efficacy for a subset of human melanoma patients undergoing radiotherapy for brain metastasis.
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http://dx.doi.org/10.1111/pcmr.12327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5661976PMC
January 2015

Epac1 increases migration of endothelial cells and melanoma cells via FGF2-mediated paracrine signaling.

Pigment Cell Melanoma Res 2014 Jul 9;27(4):611-20. Epub 2014 May 9.

Department of Cell Biology and Molecular Medicine, New Jersey Medical School-Rutgers, The State University of New Jersey, Newark, NJ, USA.

Fibroblast growth factor (FGF2) regulates endothelial and melanoma cell migration. The binding of FGF2 to its receptor requires N-sulfated heparan sulfate (HS) glycosamine. We have previously reported that Epac1, an exchange protein activated by cAMP, increases N-sulfation of HS in melanoma. Therefore, we examined whether Epac1 regulates FGF2-mediated cell-cell communication. Conditioned medium (CM) of melanoma cells with abundant expression of Epac1 increased migration of human umbilical endothelial cells (HUVEC) and melanoma cells with poor expression of Epac1. CM-induced increase in migration was inhibited by antagonizing FGF2, by the removal of HS and by the knockdown of Epac1. In addition, knockdown of Epac1 suppressed the binding of FGF2 to FGF receptor in HUVEC, and in vivo angiogenesis in melanoma. Furthermore, knockdown of Epac1 reduced N-sulfation of HS chains attached to perlecan, a major secreted type of HS proteoglycan that mediates the binding of FGF2 to FGF receptor. These data suggested that Epac1 in melanoma cells regulates melanoma progression via the HS-FGF2-mediated cell-cell communication.
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http://dx.doi.org/10.1111/pcmr.12250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4283731PMC
July 2014

RUNX2 is overexpressed in melanoma cells and mediates their migration and invasion.

Cancer Lett 2014 Jun 18;348(1-2):61-70. Epub 2014 Mar 18.

Rutgers Cancer Institute of New Jersey, Department of Medicine, Division of Medical Oncology - Rutgers, The State University of New Jersey, Robert Wood Johnson Medical School, 195 Little Albany Street, New Brunswick, NJ 08903, USA. Electronic address:

In the present study, we investigated the role of the transcription factor RUNX2 in melanomagenesis. We demonstrated that the expression of transcriptionally active RUNX2 was increased in melanoma cell lines as compared with human melanocytes. Using a melanoma tissue microarray, we showed that RUNX2 levels were higher in melanoma cells as compared with nevic melanocytes. RUNX2 knockdown in melanoma cell lines significantly decreased Focal Adhesion Kinase expression, and inhibited their cell growth, migration and invasion ability. Finally, the pro-hormone cholecalciferol reduced RUNX2 transcriptional activity and decreased migration of melanoma cells, further suggesting a role of RUNX2 in melanoma cell migration.
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http://dx.doi.org/10.1016/j.canlet.2014.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4041161PMC
June 2014

Store-operated Ca2+ entry (SOCE) regulates melanoma proliferation and cell migration.

PLoS One 2014 21;9(2):e89292. Epub 2014 Feb 21.

Cardiovascular Research Institute, Yokohama City University School of Medicine, Yokohama, Japan ; Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, United States of America.

Store-operated Ca(2+) entry (SOCE) is a major mechanism of Ca(2) (+) import from extracellular to intracellular space, involving detection of Ca(2+) store depletion in endoplasmic reticulum (ER) by stromal interaction molecule (STIM) proteins, which then translocate to plasma membrane and activate Orai Ca(2+) channels there. We found that STIM1 and Orai1 isoforms were abundantly expressed in human melanoma tissues and multiple melanoma/melanocyte cell lines. We confirmed that these cell lines exhibited SOCE, which was inhibited by knockdown of STIM1 or Orai1, or by a pharmacological SOCE inhibitor. Inhibition of SOCE suppressed melanoma cell proliferation and migration/metastasis. Induction of SOCE was associated with activation of extracellular-signal-regulated kinase (ERK), and was inhibited by inhibitors of calmodulin kinase II (CaMKII) or Raf-1, suggesting that SOCE-mediated cellular functions are controlled via the CaMKII/Raf-1/ERK signaling pathway. Our findings indicate that SOCE contributes to melanoma progression, and therefore may be a new potential target for treatment of melanoma, irrespective of whether or not Braf mutation is present.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0089292PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931742PMC
January 2015

Psychosocial correlates of sun protection behaviors among U.S. Hispanic adults.

J Behav Med 2014 Dec 15;37(6):1082-90. Epub 2014 Feb 15.

Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ, 08903, USA,

The incidence of skin cancer among U.S. Hispanics increased 1.3% annually from 1992 to 2008. However, little research has focused on skin cancer prevention among the rapidly growing Hispanic population. In this study, we examined theory-driven, psychosocial correlates of sun protection behaviors in a population-based sample of 787 Hispanic adults (49.6% female, mean age = 41.0 years) residing in five southern or western U.S. states. Participants completed an English- or Spanish-language online survey in September 2011. The outcomes of focus were sunscreen use, shade seeking, and use of sun protective clothing. The correlates included suntan benefits, sun protection benefits and barriers, skin color preference, perceived natural skin protection, photo-aging concerns, perceived skin cancer risk, skin cancer worry, skin cancer fatalism, and sun protection descriptive norms. Results of multiple linear regression analyses revealed the following: sun protection barriers were negatively associated with each outcome; descriptive norms were positively associated with each outcome; perceived natural skin protection was inversely associated with sunscreen use; skin cancer worry was positively associated with shade seeking and use of sun protective clothing; skin cancer fatalism was negatively associated with shade seeking; and skin color preference was negatively associated with use of sun protective clothing. A number of additional statistically significant associations were identified in bivariate correlation analyses. This study informs the potential content of interventions to promote engagement in sun protection behaviors among U.S. Hispanics.
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http://dx.doi.org/10.1007/s10865-014-9558-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134426PMC
December 2014

Activation of the glutamate receptor GRM1 enhances angiogenic signaling to drive melanoma progression.

Cancer Res 2014 May 3;74(9):2499-509. Epub 2014 Feb 3.

Authors' Affiliations: Division of Surgical Oncology, Department of Surgery; Division of Medical Oncology, Department of Medicine, Rutgers Robert Wood Johnson Medical School; Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway; and Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.

Glutamate-triggered signal transduction is thought to contribute widely to cancer pathogenesis. In melanoma, overexpression of the metabotropic glutamate receptor (GRM)-1 occurs frequently and its ectopic expression in melanocytes is sufficient for neoplastic transformation. Clinical evaluation of the GRM1 signaling inhibitor riluzole in patients with advanced melanoma has demonstrated tumor regressions that are associated with a suppression of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathways. Together, these results prompted us to investigate the downstream consequences of GRM1 signaling and its disruption in more detail. We found that melanoma cells with enhanced GRM1 expression generated larger tumors in vivo marked by more abundant blood vessels. Media conditioned by these cells in vitro contained relatively higher concentrations of interleukin-8 and VEGF due to GRM1-mediated activation of the AKT-mTOR-HIF1 pathway. In clinical specimens from patients receiving riluzole, we confirmed an inhibition of MAPK and PI3K/AKT activation in posttreatment as compared with pretreatment tumor specimens, which exhibited a decreased density of blood vessels. Together, our results demonstrate that GRM1 activation triggers proangiogenic signaling in melanoma, offering a mechanistic rationale to design treatment strategies for the most suitable combinatorial use of GRM1 inhibitors in patients.
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http://dx.doi.org/10.1158/0008-5472.CAN-13-1531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4008638PMC
May 2014

Metabotropic glutamate receptor-1 contributes to progression in triple negative breast cancer.

PLoS One 2014 3;9(1):e81126. Epub 2014 Jan 3.

Department of Surgery, Wayne State University School of Medicine, Detroit, Michigan, United States of America ; Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, United States of America ; Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan, United States of America.

TNBC is an aggressive breast cancer subtype that does not express hormone receptors (estrogen and progesterone receptors, ER and PR) or amplified human epidermal growth factor receptor type 2 (HER2), and there currently exist no targeted therapies effective against it. Consequently, finding new molecular targets in triple negative breast cancer (TNBC) is critical to improving patient outcomes. Previously, we have detected the expression of metabotropic glutamate receptor-1 (gene: GRM1; protein: mGluR1) in TNBC and observed that targeting glutamatergic signaling inhibits TNBC growth both in vitro and in vivo. In this study, we explored how mGluR1 contributes to TNBC progression, using the isogenic MCF10 progression series, which models breast carcinogenesis from nontransformed epithelium to malignant basal-like breast cancer. We observed that mGluR1 is expressed in human breast cancer and that in MCF10A cells, which model nontransformed mammary epithelium, but not in MCF10AT1 cells, which model atypical ductal hyperplasia, mGluR1 overexpression results in increased proliferation, anchorage-independent growth, and invasiveness. In contrast, mGluR1 knockdown results in a decrease in these activities in malignant MCF10CA1d cells. Similarly, pharmacologic inhibition of glutamatergic signaling in MCF10CA1d cells results in a decrease in proliferation and anchorage-independent growth. Finally, transduction of MCF10AT1 cells, which express c-Ha-ras, using a lentiviral construct expressing GRM1 results in transformation to carcinoma in 90% of resultant xenografts. We conclude that mGluR1 cooperates with other factors in hyperplastic mammary epithelium to contribute to TNBC progression and therefore propose that glutamatergic signaling represents a promising new molecular target for TNBC therapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0081126PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3880256PMC
September 2014

Disruption of GRM1-mediated signalling using riluzole results in DNA damage in melanoma cells.

Pigment Cell Melanoma Res 2014 Mar 22;27(2):263-74. Epub 2014 Jan 22.

Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA; Joint Graduate Program of Toxicology, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA.

Gain of function of the neuronal receptor, metabotropic glutamate receptor 1 (Grm1), was sufficient to induce melanocytic transformation in vitro and spontaneous melanoma development in vivo when ectopically expressed in melanocytes. The human form of this receptor, GRM1, has been shown to be ectopically expressed in a subset of human melanomas but not benign nevi or normal melanocytes, suggesting that misregulation of GRM1 is involved in the pathogenesis of certain human melanomas. Sustained stimulation of Grm1 by the ligand, glutamate, is required for the maintenance of transformed phenotypes in vitro and tumorigenicity in vivo. In this study, we investigate the mechanism of an inhibitor of glutamate release, riluzole, on human melanoma cells that express metabotropic glutamate receptor 1 (GRM1). Various in vitro assays conducted show that inhibition of glutamate release in several human melanoma cell lines resulted in an increase of oxidative stress and DNA damage response markers.
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http://dx.doi.org/10.1111/pcmr.12207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3947419PMC
March 2014

Who should be offered a sentinel node biopsy for melanoma less than 1 mm in thickness?

Authors:
James S Goydos

J Clin Oncol 2013 Dec 4;31(35):4385-6. Epub 2013 Nov 4.

Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway; Cancer Institute of New Jersey, New Brunswick, NJ.

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http://dx.doi.org/10.1200/JCO.2013.51.8423DOI Listing
December 2013

Linguistic acculturation and skin cancer-related behaviors among Hispanics in the southern and western United States.

JAMA Dermatol 2013 Jun;149(6):679-86

The Cancer Institute of New Jersey, 195 Little Albany St, Room 5567, New Brunswick, NJ 08901, USA.

Objective: To examine the association between linguistic acculturation (assessed using the Language Use and Linguistic Preference subscales from the Bidimensional Acculturation Scale for Hispanics) and skin cancer-related behaviors among US Hispanic adults to determine whether, compared with Hispanics denoted as Spanish-acculturated, English-acculturated Hispanics would report less frequent shade seeking and use of sun protective clothing and higher rates of sunscreen use, sunbathing, and indoor tanning.

Design: Online survey study conducted in September 2011.

Setting: Five southern and western US states.

Participants: A population-based sample of 788 Hispanic adults drawn from a nationally representative web panel.

Main Outcome Measures: Self-reported sunscreen use, shade seeking, use of sun protective clothing, sunbathing, and indoor tanning.

Results: Multivariate regression analyses were conducted to examine predictors of the skin cancer-related behaviors. As hypothesized, English-acculturated Hispanics had lower rates of shade seeking and use of sun protective clothing and reported higher rates of sunbathing and indoor tanning than Spanish-acculturated Hispanics. English-acculturated Hispanics and bicultural Hispanics (ie, those with high Spanish and high English acculturation) reported comparably high rates of sunbathing and indoor tanning. Results suggested that bicultural Hispanics seek shade and wear sun protective clothing less often than Spanish-acculturated Hispanics but more often than English-acculturated Hispanics. Acculturation was not associated with sunscreen use.

Conclusions: Hispanic adults do not routinely engage in behaviors that reduce their risk of skin cancer. Bicultural and English-acculturated Hispanics are particularly in need of skin cancer prevention interventions.
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http://dx.doi.org/10.1001/jamadermatol.2013.745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689859PMC
June 2013

Skin cancer surveillance behaviors among US Hispanic adults.

J Am Acad Dermatol 2013 Apr 19;68(4):576-584. Epub 2012 Nov 19.

The Cancer Institute of New Jersey, New Brunswick, New Jersey; Department of Surgery, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey.

Background: Little skin cancer prevention research has focused on the US Hispanic population.

Objective: This study examined the prevalence and correlates of skin cancer surveillance behaviors among Hispanic adults.

Methods: A population-based sample of 788 Hispanic adults residing in 5 southern and western states completed an online survey in English or Spanish in September 2011. The outcomes were ever having conducted a skin self-examination (SSE) and having received a total cutaneous examination (TCE) from a health professional. The correlates included sociodemographic, skin cancer-related, and psychosocial factors.

Results: The rates of ever conducting a SSE or having a TCE were 17.6% and 9.2%, respectively. Based on the results of multivariable logistic regressions, factors associated with ever conducting a SSE included older age, English linguistic acculturation, a greater number of melanoma risk factors, more frequent sunscreen use, sunbathing, job-related sun exposure, higher perceived skin cancer risk, physician recommendation, more SSE benefits, and fewer SSE barriers. Factors associated with ever having a TCE were older age, English linguistic acculturation, a greater number of melanoma risk factors, ever having tanned indoors, greater skin cancer knowledge, higher perceived skin cancer severity, lower skin cancer worry, physician recommendation, more TCE benefits, and fewer SSE barriers.

Limitations: The cross-sectional design limits conclusions regarding the causal nature of observed associations.

Conclusions: Few Hispanic adults engage in skin cancer surveillance behaviors. The study highlights Hispanic subpopulations that are least likely to engage in skin cancer surveillance behaviors and informs the development of culturally appropriate interventions to promote these behaviors.
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http://dx.doi.org/10.1016/j.jaad.2012.09.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3608735PMC
April 2013

Sun protection and exposure behaviors among Hispanic adults in the United States: differences according to acculturation and among Hispanic subgroups.

BMC Public Health 2012 Nov 15;12:985. Epub 2012 Nov 15.

The Cancer Institute of New Jersey, New Brunswick, 08901, USA.

Background: Skin cancer prevention interventions that target the growing number of U.S. Hispanics are lacking. The current study examined the prevalence and correlates of sun protection and exposure behaviors (i.e., sunscreen use, shade seeking, use of sun protective clothing, and sunburns) among U.S. Hispanics with sun sensitive skin, with a focus on potential differences according to acculturation and Hispanic origin.

Methods: The sample consisted of 1676 Hispanic adults who reported having sun sensitive skin (i.e., they would experience a sunburn if they went out in the sun for one hour without protection after several months of not being in the sun). Participants completed survey questions as part of the nationally representative 2010 National Health Interview Survey. Analyses were conducted in August 2012.

Results: Greater acculturation was linked with both risky (i.e., not wearing sun protective clothing) and protective (i.e., using sunscreen) sun-related practices and with an increased risk of sunburns. Sun protection and exposure behaviors also varied according to individuals' Hispanic origin, with for example individuals of Mexican heritage having a higher rate of using sun protective clothing and experiencing sunburns than several other subgroups.

Conclusions: Several Hispanic subpopulations (e.g., those who are more acculturated or from certain origins) represent important groups to target in skin cancer prevention interventions. Future research is needed to test culturally relevant, tailored interventions to promote sun protection behaviors among U.S. Hispanics. Such initiatives should focus on public health education and increasing healthcare provider awareness of the importance of skin cancer prevention among Hispanics.
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http://dx.doi.org/10.1186/1471-2458-12-985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3533808PMC
November 2012

Non-canonical Smads phosphorylation induced by the glutamate release inhibitor, riluzole, through GSK3 activation in melanoma.

PLoS One 2012 12;7(10):e47312. Epub 2012 Oct 12.

Division of Medical Oncology, Department of Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, The Cancer Institute of New Jersey, New Brunswick, New Jersey, United States of America.

Riluzole, an inhibitor of glutamate release, has shown the ability to inhibit melanoma cell xenograft growth. A phase 0 clinical trial of riluzole as a single agent in patients with melanoma resulted in involution of tumors associated with inhibition of both the mitogen-activated protein kinase (MAPK) and phophoinositide-3-kinase/AKT (PI3K/AKT) pathways in 34% of patients. In the present study, we demonstrate that riluzole inhibits AKT-mediated glycogen synthase kinase 3 (GSK3) phosphorylation in melanoma cell lines. Because we have demonstrated that GSK3 is involved in the phosphorylation of two downstream effectors of transforming growth factor beta (TGFβ), Smad2 and Smad3, at their linker domain, our aim was to determine whether riluzole could induce GSK3β-mediated linker phosphorylation of Smad2 and Smad3. We present evidence that riluzole increases Smad2 and Smad3 linker phosphorylation at the cluster of serines 245/250/255 and serine 204 respectively. Using GSK3 inhibitors and siRNA knock-down, we demonstrate that the mechanism of riluzole-induced Smad phosphorylation involved GSK3β. In addition, GSK3β could phosphorylate the same linker sites in vitro. The riluzole-induced Smad linker phosphorylation is mechanistically different from the Smad linker phosphorylation induced by TGFβ. We also demonstrate that riluzole-induced Smad linker phosphorylation is independent of the expression of the metabotropic glutamate receptor 1 (GRM1), which is one of the glutamate receptors whose involvement in human melanoma has been documented. We further show that riluzole upregulates the expression of INHBB and PLAU, two genes associated with the TGFβ signaling pathway. The non-canonical increase in Smad linker phosphorylation induced by riluzole could contribute to the modulation of the pro-oncogenic functions of Smads in late stage melanomas.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0047312PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3470581PMC
July 2013

Plant lectin can target receptors containing sialic acid, exemplified by podoplanin, to inhibit transformed cell growth and migration.

PLoS One 2012 23;7(7):e41845. Epub 2012 Jul 23.

Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey, Stratford, New Jersey, United States of America.

Cancer is a leading cause of death of men and women worldwide. Tumor cell motility contributes to metastatic invasion that causes the vast majority of cancer deaths. Extracellular receptors modified by α2,3-sialic acids that promote this motility can serve as ideal chemotherapeutic targets. For example, the extracellular domain of the mucin receptor podoplanin (PDPN) is highly O-glycosylated with α2,3-sialic acid linked to galactose. PDPN is activated by endogenous ligands to induce tumor cell motility and metastasis. Dietary lectins that target proteins containing α2,3-sialic acid inhibit tumor cell growth. However, anti-cancer lectins that have been examined thus far target receptors that have not been identified. We report here that a lectin from the seeds of Maackia amurensis (MASL) with affinity for O-linked carbohydrate chains containing sialic acid targets PDPN to inhibit transformed cell growth and motility at nanomolar concentrations. Interestingly, the biological activity of this lectin survives gastrointestinal proteolysis and enters the cardiovascular system to inhibit melanoma cell growth, migration, and tumorigenesis. These studies demonstrate how lectins may be used to help develop dietary agents that target specific receptors to combat malignant cell growth.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0041845PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3402461PMC
November 2012

Functional effects of GRM1 suppression in human melanoma cells.

Mol Cancer Res 2012 Nov 13;10(11):1440-50. Epub 2012 Jul 13.

Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, USA

Ectopic expression of a neuronal receptor, metabotropic glutamate receptor 1 (Grm1), in melanocytes has been implicated in melanoma development in mouse models. The human relevance of this receptor's involvement in melanoma pathogenesis was shown by detecting GRM1 expression in subsets of human melanomas, an observation lacking in benign nevi or normal melanocytes. Grm1-transformed mouse melanocytes and a conditional Grm1 transgenic mouse model confirmed a requirement for sustained expression of Grm1 for the maintenance of transformed phenotypes in vitro and tumorigenicity in vivo. Here, we investigate if continued GRM1 expression is also required in human melanoma cell lines by using two inducible, silencing RNA systems: the ecdysone/Ponasterone A and tetracycline on/off approaches to regulate GRM1 expression in the presence of each inducer. Various in vitro assays were conducted to assess the consequences of a reduction in GRM1 expression on cell proliferation, apoptosis, downstream targeted signaling pathways, and in vivo tumorigenesis. We showed that suppression of GRM1 expression in several human melanoma cell lines resulted in a reduction in the number of viable cells and a decrease in stimulated mitogen-activated protein kinase (MAPK) and PI3K/AKT and suppressed tumor progression in vivo. These results reinforce earlier observations where a reduction in cell growth in vitro and tumorigenesis in vivo were correlated with decreased GRM1 activities by pharmacologic inhibitors of the receptor, supporting the notion that GRM1 plays a role in the maintenance of transformed phenotypes in human melanoma cells in vitro and in vivo and could be a potential therapeutic target for the treatment of melanoma.
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http://dx.doi.org/10.1158/1541-7786.MCR-12-0158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501593PMC
November 2012

Glutamatergic pathway targeting in melanoma: single-agent and combinatorial therapies.

Clin Cancer Res 2011 Nov 15;17(22):7080-92. Epub 2011 Aug 15.

Department of Biological Science, Sookmyung Women's University, Seoul, South Korea.

Purpose: Melanoma is a heterogeneous disease where monotherapies are likely to fail due to variations in genomic signatures. B-RAF inhibitors have been clinically inadequate but response might be augmented with combination therapies targeting multiple signaling pathways. We investigate the preclinical efficacy of combining the multikinase inhibitor sorafenib or the mutated B-RAF inhibitor PLX4720 with riluzole, an inhibitor of glutamate release that antagonizes metabotropic glutamate receptor 1 (GRM1) signaling in melanoma cells.

Experimental Design: Melanoma cell lines that express GRM1 and either wild-type B-RAF or mutated B-RAF were treated with riluzole, sorafenib, PLX4720, or the combination of riluzole either with sorafenib or with PLX4720. Extracellular glutamate levels were determined by glutamate release assays. MTT assays and cell-cycle analysis show effects of the compounds on proliferation, viability, and cell-cycle profiles. Western immunoblotting and immunohistochemical staining showed apoptotic markers. Consequences on mitogen-activated protein kinase pathway were assessed by Western immunoblotting. Xenograft tumor models were used to determine the efficacy of the compounds in vivo.

Results: The combination of riluzole with sorafenib exhibited enhanced antitumor activities in GRM1-expressing melanoma cells harboring either wild-type or mutated B-RAF. The combination of riluzole with PLX4720 showed lessened efficacy compared with the combination of riluzole and sorafenib in suppressing the growth of GRM1-expressing cells harboring the B-RAF(V600E) mutation.

Conclusions: The combination of riluzole with sorafenib seems potent in suppressing tumor proliferation in vitro and in vivo in GRM1-expressing melanoma cells regardless of B-RAF genotype and may be a viable therapeutic clinical combination.
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http://dx.doi.org/10.1158/1078-0432.CCR-11-0098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3218300PMC
November 2011
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