bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A09: ErbB3/ErbB2 complexes as a therapeutic target in a subset of wild-type BRAF/NRAS cutaneous melanomas
Authors: Capparelli Claudia , Rosenbaum Sheera , Berman-Booty Lisa D. , Gaborit Nadège , Zhan Tingting , Davies Michael A. , Setiady Yulius Y. , Yarden Yosef , Aplin Andrew E. 
Published: July 2015

Abstract
The treatment options remain poor for melanoma patients who are wild-type for both BRAF and NRAS (WT/WT). ErbB3 regulates melanocyte homeostasis and elevated ErbB3 expression in malignant melanomas correlates with reduced patient survival; however, the effect of selectively targeting ErbB3 in melanoma remains poorly characterized. We demonstrate that a subgroup of WT/WT melanomas display high basal phosphorylation of ErbB3 that is associated with autocrine production of the ErbB3 ligand, neuregulin-1 (NRG1). In phospho-ErbB3-high WT/WT cell lines, knockdown of NRG1 reduced cell viability that was associated with decreased phosphorylation of ErbB3, its co-receptor ErbB2 and its downstream target, AKT. Analogous effects were obtained targeting ErbB3 with either small interfering RNAs or the neutralizing ErbB3 monoclonal antibodies, huHER3-8 and NG33. Additionally, pertuzumab-mediated inhibition of ErbB2 heterodimerization decreased AKT phosphorylation, cell growth in vitro and xenograft growth in vivo. Our study demonstrates that targeting ErbB3-ErbB2 signaling in a cohort WT/WT melanomas leads to tumor growth reduction. These findings are supportive of targeting the NRG1-ErbB3-ErbB2 axis as a novel treatment strategy in a subset of malignant cutaneous melanoma.
Citation Format: Claudia Capparelli, Sheera Rosenbaum, Lisa D. Berman-Booty, Nadège Gaborit, Tingting Zhan, Michael A. Davies, Yulius Y. Setiady, Yosef Yarden, Andrew E. Aplin. ErbB3/ErbB2 complexes as a therapeutic target in a subset of wild-type BRAF/NRAS cutaneous melanomas. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr A09.
Abstract A13: MSX1-induced neural crest-like reprograming promotes melanoma progression
Authors: Heppt Markus V. , Joshua Wang X. , Hristova Denitsa M. , Wei Zhi , Irmler Martin , Berking Carola , Besch Robert , Beckers Johannes , Rauscher Frank J. , Fisher David E. , Herlyn Meenhard , Fukunaga-Kalabis Mizuho 
Published: July 2015

Abstract
Melanoma cells share many biological properties with neural crest cells. Here, we show that the homeodomain transcription factor Msh homeobox 1 (MSX1), which is essential for neural crest specification, reprograms melanocytes towards a neural crest precursor-like state. MSX1-reprogrammed melanocytes express the neural crest marker p75 and are able to differentiate into neuronal and mesenchymal lineages. Mechanistically, MSX1 suppresses the proximal promoter of microphthalmia-associated transcription factor (MITF), the master transcriptional regulator of melanogenesis. MSX1 expression is also significantly correlated with melanoma progression. MSX1 prompts melanoma cell motility and depletion of MSX1 significantly inhibits melanoma metastasis. These results demonstrate that not only can neural crest-like reprogramming in melanocytes be achieved by a single factor, but also that similar dedifferentiation is a critical process for melanoma progression.
Citation Format: Markus V. Heppt, Wang X. Joshua, Denitsa M. Hristova, Zhi Wei, Martin Irmler, Carola Berking, Robert Besch, Johannes Beckers, Frank J. Rauscher, III, David E. Fisher, Meenhard Herlyn, Mizuho Fukunaga-Kalabis. MSX1-induced neural crest-like reprograming promotes melanoma progression. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr A13.
Abstract A14: Hyperactivation of RSK1 is a hallmark of metastatic nodular melanoma
Authors: Salhi Amel , Farhadian Joshua A. , Giles Keith M. , Miera Eleazar C. Vega-Saenz de , Silva Ines Pires Da , Bourque Caitlin , Yeh Karen , Chhangawala Sagar , Wang Jinhua , Ye Fei , Zhang David Y. , Hernando-Monge Eva , Houvras Yariv , Osman Iman 
Published: July 2015

Abstract
It is generally accepted that superficial spreading (SSM) and nodular melanoma (NM), the most common melanoma histologic subtypes, are biologically indistinct once they invade and metastasize. Consequently, targeted therapy is dictated by the mutational profile of metastatic disease, regardless of the histologic subtype of the primary melanoma. Here, we show that p90 ribosomal S6 kinase (RSK1) is constitutively phosphorylated in human melanoma cell lines derived from NM but not SSM. Significantly, metastases from primary NM patients showed p-RSK1 overexpression and a distinct metalloproteinase profile compared with metastases from primary SSM patients. Interestingly, p-RSK1 hyper-activation could not be solely explained by MAPK activation due to BRAF mutations. We show that NM-derived cell lines were more sensitive to genetic and pharmacological RSK1 inhibition than SSM-derived cell lines. Using a zebrafish model, we demonstrate that activated RSK1 significantly accelerates melanoma progression. In addition, RNAseq revealed up-regulation of extracellular matrix degradation, cell migration, and cell proliferation genes in the RSK1 mutant-expressing tumors. Together, our data demonstrate that metastatic melanoma originating from different histologic subtypes might depend on distinct oncogenic pathways. Data also support constitutive RSK1 activation as a driver of nodular metastatic melanoma, a finding that supports the concept of subtype-specific melanoma therapy.
Citation Format: Amel Salhi, Joshua A. Farhadian, Keith M. Giles, Eleazar C. Vega-Saenz de Miera, Ines Pires Da Silva, Caitlin Bourque, Karen Yeh, Sagar Chhangawala, Jinhua Wang, Fei Ye, David Y. Zhang, Eva Hernando-Monge, Yariv Houvras, Iman Osman. Hyperactivation of RSK1 is a hallmark of metastatic nodular melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr A14.
Abstract A19: Expression of BRAFV600E in melanocytes induces Schwannian differentiation in vivo
Authors: Pietruska Jodie R. , Luo Chi , Hinds Philip W. 
Published: July 2015

Abstract
Transgenic mice expressing BRAFV600E targeted to melanocytes via the tyrosinase promoter display hyperpigmentation of the skin, ears, tail, and paws, as well as profound graying of the hair, benign melanocytic hyperplasias and a low frequency of spontaneous melanomas on a mixed genetic background. In order to investigate the underlying mechanism of BRAFV600E-induced alterations in skin and hair, mice were backcrossed extensively onto a C57BL/6 background. Backcrossed BRAFV600E mice retained the phenotype of mixed background transgenic animals with respect to skin hyperpigmentation as well as premature hair graying. Analysis of skin samples from mice of different ages revealed an accumulation and mislocalization of hyperproliferative melanocytes, suggesting a developmental defect in melanocyte homing to hair follicles in response to activated BRAF. Moreover, melanocytic lesions in the skin developed into benign tumors resembling nerve sheath tumors of Schwannian origin, presumably due to the phenotypic switching of melanocytes into Schwann cells in response to chronic BRAFV600E stimulation. These benign tumors seldom progressed to melanoma in the absence of Akt pathway activation. A role for Akt activation in repressing the Schwannian differentiation program is suggested, as treatment of melanoma-derived cell lines with the Akt inhibitor MK-2206 results in elevated expression of Schwannian lineage markers at the transcript level. Therefore, in addition to induction of oncogene-induced senescence, eliciting lineage-switching from melanocytes into Schwann cells in response to oncogenic BRAF represents a potential tumor suppression mechanism to protect melanocytes from transformation, and repression of this phenotypic switch via activation of the Akt pathway may facilitate the ability of BRAFV600E to drive melanomagenesis.
Citation Format: Jodie R. Pietruska, Chi Luo, Philip W. Hinds. Expression of BRAFV600E in melanocytes induces Schwannian differentiation in vivo. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr A19.
Abstract A20: Deregulation of cell cycle and apoptotic mechanisms in UVB-irradiated p16-mutant inducible melanoma cell lines
Authors: Ouhtit Allal , Gupta Ishita , Elmageed Zakariya Y. Abd , Becker Therese M. 
Published: July 2015

Abstract
Melanoma is the deadliest skin cancer as it progresses to a highly aggressive and metastatic tumor during melanomagenesis. However, its underlying mechanisms regulating melanoma-genesis remain nascent. Our previous studies have demonstrated that the p53 and p16INK4a sub-pathways components of the Rb-signaling pathway, plays a critical role in UVB-induced skin cancer. The aim of this study was to study the molecular changes in the expression/function of the different components of the Rb signaling pathway associated with UVB-induced cell cycle and apoptotic programs. Pursuant to this goal, normal melanocytes, and a panel of p16-induced cell lines (wild-type p16INK4a-inducible clone p16wt-A4, and the N-terminal 8 amino-acid duplication p16INK4a-inducible clone p16Dp1 (+24 base pairs) were used to elucidate the early molecular events especially associated with the p16INK4a/Rb-signaling pathway regulating cell-cycle and apoptotic responses. Our results showed that: 1) in the menlanocytes high UVB dose induced p16 but not p53, and the Bax/Bcl2 ratio was also increased, suggesting that the cells had selected to undergo apoptosis in a p53-independent manner; 2) In the wt-p16 melanoma cells however, while low UVB irradiation upregulated p16, high dose reduced p16 expression and abrogated Cdk6 but not Cdk4; 3) Interestingly, mutant-p16 melanoma cells over-expressed cell cycle proteins Cdk4/6 and pRb proteins upon p16 induction, however, UVB exposure did not affect this increase; and 4) The anti-apoptotic properties of mutant cells were predominant at high dose of exposure associated with a decrease in Bax and an increase in Bcl2 expression. These data put together, suggest that the mutant p16 dictate cell cycle deregulation and causes resistance of melanoma cells to apoptosis. In conclusion, our study shows that UVB radiation-induced deregulation of p16INK4a/Cdk4 sub-pathway is a critical early event in melanomagenesis.
Citation Format: Allal Ouhtit, Ishita Gupta, Zakariya Y. Abd Elmageed, Therese M. Becker. Deregulation of cell cycle and apoptotic mechanisms in UVB-irradiated p16-mutant inducible melanoma cell lines. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr A20.
Abstract A26: Protein phosphatase 4 (PP4) as a potential therapeutic target gene for BRAF wild type melanoma
Authors: Essner Richard , Gong Ke Wei , Kaufman David , Chen Hsiaowang , Ginther Charles , Dering Judy , Euw Erika von , Chmielowski Bartosz , Finn Richard , Slamon Dennis 
Published: July 2015

Abstract
Protein phosphatase 4 (PP4) participates in cell cycle progression and regulation of centrosome maturation. Gene expression of PP4 is elevated in cancerous tissues of various origins and its overexpression in pancreatic cancer is of prognostic importance. Microarray analysis from primary and metastatic melanoma tissues (N=89) showed that PP4 mRNA expression was up-regulated in metastatic melanoma as compared to primary melanoma of any thickness (relative expression: 1.12 ±0.14, p&lt;0.01). Expression levels from thin (&lt;2 mm) were less than thicker primary melanoma (&gt;2 mm), and varied for the site of metastases from lung&gt; intestine&gt; skin and subcutaneous tissue. Human melanoma cell lines also demonstrate PP4 gene expression with variable levels. We hypothesized that PP4 may be a novel target for treatment of metastatic melanoma through a BRAF and MEK independent pathway.
We performed western blot analysis of human melanoma cell lines: M275 (BRAF wild-type) that had a high level of PP4 gene expression and demonstrated its resistant to BRAF inhibitor (PLX4032) and MEK inhibitor (MEK162) treatment. M275 were chosen for PP4 siRNA gene silencing because of its high level of PP4 protein expression. PP4 protein level was reduced by 20% and 60%, respectively in this cell line at day 4 and 6, respectively; and PP4 siRNA gene silencing reduced cell proliferation by 19.9% and 63.6%. Flow cytometry demonstrated there was higher percentage of apoptotic cells after PP4 siRNA gene silencing as compared to controls (54.4% vs. 15.5%, p, 0.05). PP4 is overexpressed in melanoma as it advances from the skin primary to metastases, and varies to the site of the metastases. We demonstrated that PP4 gene silencing leads to cell cycle arrest and apoptosis. PP4 may be a novel target for BRAF wild type melanoma.
Note: This abstract was not presented at the conference.
Citation Format: Richard Essner, Ke Wei Gong, David Kaufman, Hsiaowang Chen, Charles Ginther, Judy Dering, Erika von Euw, Bartosz Chmielowski, Richard Finn, Dennis Slamon. Protein phosphatase 4 (PP4) as a potential therapeutic target gene for BRAF wild type melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr A26.
Abstract A30: Small molecule kinase inhibitor mediated modulation of immunotherapy in melanoma
Authors: Suriano Robert , Tuli Neha , Geliebter Jan , Tiwari Raj K. , Wallack Marc 
Published: July 2015

Abstract
As the BRAFV600E mutation is observed in over 60% of melanomas, the development of the small inhibitor, PLX4032, which specifically targets mutated BRAF, represents a novel therapeutic approach. This targeted inhibition of BRAF effectively blocks activation of key signaling molecules of the mitogen activated protein kinase (MAPK) pathway, such as Mek and Erk, thus halting cell proliferation. In addition, since MAPK signaling targets the micropthalmia transcription factor (MITF), which is linked to the expression of various melanoma associated antigens (MAAs), we hypothesize that the inhibition of BRAFV600E can modulate the expression of MAAs thus serving as a viable target for immunotherapy of melanoma. Our lab has developed a vaccinia virus based immunotherapeutic vaccine using patient derived melanoma cell lines which express various MAAs. The melanoma cell lines have been characterized as far as the status of the BRAFV600E mutation and were found to be either homozygous or heterozygous for the mutation and are responsive to PLX4032, as evidenced by inhibition of two key MAPK pathway molecules, namely Mek and Erk. Phenotypically, the cells invasive and migratory properties were also modulated upon treatment with PLX4032. Interestingly was the observation that upon treatment with PLX4032, the expression of various MAAs was enhanced. Expression of gp100, MART-1, and tyrosinase increased both on the RNA level as well as on the protein level. The expression of MMAs were well maintained in vivo following the analysis of melanoma cell xenografts in BALB/c nude mice. We conclude that an effective multivalent immunotherapeutic vaccine requires the use of various MAAs and since PLX4032 upregulates expression of MAAs, further studies are warranted to determine the clinical effectiveness of combining BRAFV600E inhibitors with our melanoma cell line derived preparation.
Citation Format: Robert Suriano, Neha Tuli, Jan Geliebter, Raj K. Tiwari, Marc Wallack. Small molecule kinase inhibitor mediated modulation of immunotherapy in melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr A30.
Abstract A35: Integration of melanoma genotyping in clinical care
Authors: Salhi Amel , Silva Ines Pires Da , Lui Kevin P. , Ismaili Naima , Wu Chaowei , Miera Eleazar C. Vega-Saenz de , Shapiro Richard L. , Berman Russell S. , Pavlick Anna C. , Zhong Judy , Heguy Adriana , Osman Iman 
Published: July 2015

Abstract
Background: Molecularly targeted therapy is improving response rates and overall survival in subsets of melanoma patients. However, targeted therapy for triple negative patients (BRAF, NRAS and c-KIT wild type) is not yet defined. In addition, new evidence suggests that germline variants may have an impact in melanoma progression and response to therapy. In this study, we attempt to define the utility of a recently developed clinical assay that encompasses targeted sequencing of 50 genes with known impact on cancer progression.
Methods: We used the AmpliSeq Cancer Panel HotSpot.V2 from Ion Torrent. The panel targets sequencing of Hotspot regions including 2,800 COSMIC mutations within 50 oncogenes and tumor suppressor genes. Tumor and blood germline DNAs were studied. All identified mutations were independently validated by Sanger sequencing. We then linked the molecular profile to extensive clinicopathological information including treatment and prospective clinical follow-up.
Results: We examined 35 tumor samples from 35 melanoma patients (2 patients had 2 specimens). 14/35 (40%) had BRAF mutations, 15/35 (34%) had NRAS, KRAS or HRAS mutations and 1 had c-KIT mutant tumor. Eight patients were triple negative and presented with mutations in TP53, ERBB4, PIK3CA, NOTCH, EZH2 and VHL. We detected germline variants in TP53 (49%), KDR (VEGFR2 - 34%), APC (31%), KIT (23%) and PIK3CA (14%) genes. Notably, KDR Q472H has been shown to affect VEGFR2 function. Patients with KDR Q742H had higher microvessels density and higher VEGF production. In addition, melanoma cell lines with KDR Q472H variant proliferate and invade more when compared with WT cell lines. More important, only cell lines with that variant respond to anti-VEGFR2 treatment. Finally, the presence of the KDR Q472H variant is associated with a higher prevalence of brain metastases and with a shorter survival (15.1 months compared to 54.6 months).
Conclusions: Sequencing using a validated clinical assay was informative of several targetable mutations in triple negative melanoma. Inhibitors targeting some of these mutations are already FDA approved for non-melanoma and others are currently tested in clinical trials. Our data also revealed a role of germline variant KDR Q472H in melanoma progression, that was not reported before, suggesting that further functional studies are warranted.
Citation Format: Amel Salhi, Ines Pires Da Silva, Kevin P. Lui, Naima Ismaili, Chaowei Wu, Eleazar C. Vega-Saenz de Miera, Richard L. Shapiro, Russell S. Berman, Anna C. Pavlick, Judy Zhong, Adriana Heguy, Iman Osman. Integration of melanoma genotyping in clinical care. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr A35.
Abstract A37: The signet ring cell melanoma - rare morphological variant of melanoma: Case report
Authors: Maksimovic Sinisa 
Published: July 2015

Abstract
Introduction: Melanoma is a malignant tumor of melanocytes of skin. The histopathological variants of malignant melanoma include the common type (lentigo maligna (5%), superficial spreading melanoma (65%), nodular melanoma (15%), acrolentiginous melanoma (5%). The signet ring cell melanoma is a rare form melanoma, being seen in some 0.5% of melanomas.
Aim of work: That showed young women with signet ring cell melanoma is a rare form melanoma.
Material and methods: We describe a 39-year-old patient with a primary signet-ring cell melanoma of the skin located on the left upper quadrant of abdominal wall.
Results: Diagnosis the tumour of skin was in department of surgery and histhopatology in General hospital in Bijeljini in December of the 2007. We performed clinical and histhopatologic examination. Physical examination revealed a well circumscribed and firm mass measuring 150x 100x 80 mm of the skin located on the upper quadrant of abdominal wall and solid mass in pelvis. Because of high suspect melanoma in patient performed surgical excision of skin tumor. Pathohysthology diagnosis was: Melanoma nodularis achromaticum. Immunohistochemistry showed positive reaction of the tumor cells for S-100, HMB-45 protein and vimentin, confirming their melanocytic differentiation. Tumor cells were negative for cytokeratins, epithelial membrane antigen (EMA), and carcinoembryonic antigen (CEA). After immunohistochemistry analysis definitive pathohystology was: Signet ring cell melanoma. The signet-ring cell melanoma disclosed an invasion to Clark Level V and tumor thickness Breslow level III.
Tumor from pelvis was appertain uterus and histopathologic diagnosis is a leomyoma.
Conclusion: Signet-ring cell melanoma is a rare morphologic variant of melanoma. Its recognition is important for differentiation from other tumors featuring signet ring cells.
Note: This abstract was not presented at the conference.
Citation Format: Sinisa Maksimovic. The signet ring cell melanoma - rare morphological variant of melanoma: Case report. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr A37.
Abstract B09: Phosphorylation of BRAF by AMPK impairs BRAF-KSR1 association and cell proliferation
Authors: Shen Che-Hung , Yuan Ping , Perez-Lorenzo Rolando , Zhang Yaqing , Lee Sze Xian , Ou Yang , Cai Li , Asara John M. , Cantley Lewis C. , Zheng Bin 
Published: July 2015

Abstract
BRAF is an oncogenic protein kinase that drives cell growth and proliferation through the MEK-ERK signaling pathway. BRAF inhibitors have demonstrated antitumor efficacy in melanoma therapy but have also been found to be associated with the development of cutaneous squamous cell carcinomas (cSCCs) in certain patients. Here, we report that BRAF is phosphorylated at Ser729 by AMP-activated protein kinase (AMPK), a critical energy sensor. This phosphorylation promotes the association of BRAF with 14-3-3 proteins and disrupts its interaction with the KSR1 scaffolding protein, leading to attenuation of the MEK-ERK signaling. We also show that phosphorylation of BRAF by AMPK impairs keratinocyte cell proliferation and cell-cycle progression. Furthermore, AMPK activation attenuates BRAF inhibitor-induced ERK hyperactivation in keratinocytes and epidermal hyperplasia in mouse skin. Our findings reveal a mechanism for regulating BRAF signaling in response to energy stress and suggest a strategy for preventing the development of cSCCs associated with BRAF-targeted therapy.
Citation Format: Che-Hung Shen, Ping Yuan, Rolando Perez-Lorenzo, Yaqing Zhang, Sze Xian Lee, Yang Ou, Li Cai, John M. Asara, Lewis C. Cantley, Bin Zheng. Phosphorylation of BRAF by AMPK impairs BRAF-KSR1 association and cell proliferation. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr B09.