bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A31: A novel melanoma-derived cyclic decapeptide dimer mediates restoration of contact inhibition of growth and reversal of the malignant phenotype
Authors: Rosenberg Martin , Bethard Jennifer R. , Aronoff Linda , Lipkin George 
Published: June 2022

Abstract
Knowledge of the molecular basis for contact inhibition of growth, an in vitro property differentiating benign from malignant cells and correlated with in vivo growth control, could provide new targets for reestablishing control of malignant cell proliferation. We previously reported a soluble Contact Inhibitory Factor (CIF) in culture medium from a revertant contact inhibited melanoma cell line that restored contact-, serum-, and anchorage-dependent growth control to melanoma cells, closely linked to reversal of multiple malignant properties and whose contact inhibitory effects extended to a wide spectrum of other cancers. We now report identification, purification, and synthesis of the molecule, CIF, responsible for restoring contact inhibition: a structurally novel cyclic decapeptide dimer. Its discovery has both clinical and theoretical implications. Availability of CIF should not only facilitate evaluation of its therapeutic potential but also may provide the key to its target and the sequence of molecular events linking contact inhibition to broad phenotypic reversal. CIF may be the ligand for a widely distributed contact inhibitory checkpoint, one that is defective in cancer cells but pharmacologically correctible by CIF, and controlling replication at a single locus, potentially simplifying treatment. CIF is the first cell-derived peptide that restores contact inhibition of growth to melanoma and a wide spectrum of other cancers, with an obligatory link in melanoma to reversal of multiple aspects of the malignant phenotype. It suggests the possibility of an alternative approach to treatment of intractable melanoma and other cancers: broad-spectrum, endogenous peptide-based control of malignancy through phenotypic reversal that tilts the biologic balance to favor host recapture of control over tumor.
Citation Format: Martin Rosenberg, Jennifer R. Bethard, Linda Aronoff, George Lipkin. A novel melanoma-derived cyclic decapeptide dimer mediates restoration of contact inhibition of growth and reversal of the malignant phenotype [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr A31.
Abstract B01: Genome-scale shRNA screen provides insight into the role of CUL3 in adaptive mechanisms of resistance to mutant BRAF inhibition
Authors: Vanneste Marion , Zhu Eliot , Feddersen Charlotte , Varzavand Afshin , Foley Tyler , Zhao Lei , Piper Rob , Stipp Christopher , Dupuy Adam , Henry Michael 
Published: June 2022

Abstract
MAPK inhibition with targeted BRAF inhibitors has revolutionized the treatment of BRAF-mutant melanoma. However, in most cases, the effects of mutant BRAF inhibition are transient, owing to the acquisition of drug resistance. To resolve mechanisms that drive resistance to mutant BRAF inhibition, we performed a genome-scale shRNA screen capable of revealing genes whose loss of function confers resistance to vemurafenib (VEM). We validated ten of our top candidates with independent lentiviral shRNA constructs. We found that knockdown of NF1 and CUL3 confers resistance to VEM. This result is consistent with previous genome-scale loss-of-function screens that have also identified NF1 and CUL3 as drivers of resistance to mutant BRAF inhibition. NF1 encodes a protein that hydrolyzes Ras-GTP. Not surprisingly, it has been shown that loss of NF1 results in increased Ras-GTP levels that lead to reactivation of MAPK in the presence of VEM. However, little is known about the mechanistic changes that underlie CUL3-mediated resistance. Here, we show that unlike the classical reactivation of MAPK that is seen with the loss of NF1, loss of CUL3 results in increased signaling through a Rac1-dependent focal-adhesion-like process that is accompanied by sustained MAPK activity in the presence of VEM. Furthermore, we show that this mechanism of resistance can be abrogated by inhibiting the Src kinase family, a nine-member protein family that critically mediates integrin signaling. In relation to other known drivers of resistance to mutant BRAF inhibition, loss of NF1 reactivates MAPK in a manner much like RAS mutations or BRAF alterations/amplification. By contrast, loss of CUL3 leads to resistance reminiscent of a reversible therapy-resistant state that lacks the key genomic alterations in MAPK signaling proteins.
Citation Format: Marion Vanneste, Eliot Zhu, Charlotte Feddersen, Afshin Varzavand, Tyler Foley, Lei Zhao, Rob Piper, Christopher Stipp, Adam Dupuy, Michael Henry. Genome-scale shRNA screen provides insight into the role of CUL3 in adaptive mechanisms of resistance to mutant BRAF inhibition [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr B01.
Abstract B07: Rho-mediated gene transcription promotes BRAFi resistance in de-differentiated melanoma cells
Authors: Misek Sean A. , Appleton Kate M. , Dexheimer Tom S. , Lisabeth Erika M. , Lo Roger S. , Larsen Scott D. , Gallo Kathleen A. , Neubig Richard R. 
Published: June 2022

Abstract
The goal of this study is to identify pharmacologically tractable resistance mechanisms, and ultimately to prevent or reverse drug resistance in melanoma. We demonstrate that a subset of BRAFi-resistant melanoma cell lines showed diminished expression of melanocyte differentiation markers (e.g., Sox10). The transcriptional signature of 15% of treatment-naïve TCGA SKCM (skin cutaneous melanoma) tumors is similar to that of de-differentiated BRAFi-resistant cell lines. This transcriptional signature in BRAFi-resistant melanoma cells and human tumors is associated with increased Rho activation and increased expression of a RhoA/C gene signature. Using a machine learning approach, we predict that these tumors have decreased sensitivity to multiple BRAF/MEK inhibitors, consistent with our observations in multiple cell line models. De-differentiated tumors are predicted to have increased sensitivity to multiple ROCK inhibitors, and this prediction was validated in multiple BRAFi-resistant cell line models. Since ROCK is one of the canonical Rho effector proteins, these data suggest that melanoma cells and tumors with low differentiation characteristics activate the Rho pathway and are sensitive to Rho pathway inhibition. As a consequence of the effect of Rho on the actin cytoskeleton, Rho regulates gene transcription through modulating transcriptional co-activators such as MRTFA and YAP1. Both MRTFA and YAP1 are activated in de-differentiated BRAFi-resistant cells and are predicted to be activated in human tumors with a similar transcriptomic profile. Consistent with our predictions, melanoma cells with MRTFA activation are sensitive to an MRTFA pathway inhibitor and those with high YAP1 activity are sensitive to indirect blockade of YAP1 activation. In total, these results demonstrate that over the course of drug resistance a subset of cells and tumors lose melanocyte lineage characteristics and gain Rho activation. In summary, our work has used bioinformatics/ML approaches to identify Rho-mediated gene transcription as an important, targetable mechanism of BRAFi resistance in de-differentiated melanomas. We experimentally demonstrate the efficacy of this approach in multiple BRAFi-resistant models, highlighting the potential of targeting Rho-mediated transcription for treating drug-resistant melanomas.
Citation Format: Sean A. Misek, Kate M. Appleton, Tom S. Dexheimer, Erika M. Lisabeth, Roger S. Lo, Scott D. Larsen, Kathleen A. Gallo, Richard R. Neubig. Rho-mediated gene transcription promotes BRAFi resistance in de-differentiated melanoma cells [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr B07.
Abstract B21: Arylsulfatase B (ARSB) is reduced in melanoma metastases and decline in ARSB increases programmed death-ligand (PDL) 1
Authors: Tobacman Joanne K. , Bhattacharyya Sumit , Feferman Leo 
Published: June 2022

Abstract
Arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) is the enzyme that removes 4-sulfate groups from chondroitin 4-sulfate (C4S) and dermatan sulfate. In previous work, we have shown decline in ARSB with increasing aggressiveness of melanoma cell lines. C4S increased as ARSB declined in the cultured melanoma cell lines. Decline in ARSB was associated with increased expression of chondroitin sulfate proteoglycan (CSPG) 4 and matrix metalloproteinase (MMP) 2. The increase in CSPG4 was attributed to reduced binding of galectin-3 with C4S, and the increase of MMP2 was attributed to inhibition of SHP2, the tyrosine-protein phosphatase nonreceptor type 11 (PTPN11), due to increased binding with C4S. The invasiveness of the cultured melanoma cells increased when ARSB was silenced by siRNA. To further address the role of ARSB in melanoma progression, metastatic melanoma tissue was obtained from the biorepository of the University of Illinois at Chicago. ARSB activity and expression were reduced in the metastatic tissues and ARSB promoter methylation was increased. ARSB promoter methylation was also increased in cultured metastatic melanoma cells compared to normal melanocytes and to radial growth phase melanoma cells. In the metastatic tissues from skin and liver, SHP2 activity declined, and mRNA expression of MMP2 and CSPG4 increased. When ARSB was silenced by siRNA in the cultured normal melanocytes, Programmed Death-Ligand (PD-L) 1 increased from 78 ± 7 pg/mg protein to 128 ± 11 pg/mg protein by ELISA (p&lt;0.001). In a metastatic melanoma cell line, PD-L1 increased from baseline value of 407 ± 34 pg/mg to 462 ± 26 pg/mg when ARSB was silenced. These findings indicate that decline in ARSB contributes to the progression of metastatic melanoma and to the immune checkpoint responsiveness of the melanoma cells. Further studies are required to determine how ARSB leads to increased PD-L1 expression and how treatment with recombinant ARSB can retard the progression of melanoma.
Citation Format: Joanne K. Tobacman, Sumit Bhattacharyya, Leo Feferman. Arylsulfatase B (ARSB) is reduced in melanoma metastases and decline in ARSB increases programmed death-ligand (PDL) 1 [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr B21.
Abstract B27: MT1-MMP targeting in melanoma brain metastasis
Authors: Escandon Julia , Thakur Varsha , Bedogni Barbara 
Published: June 2022

Abstract
Background: Melanoma brain metastases contribute to morbidity and mortality of melanoma, and the treatment is limited due to its accessibility for drugs and also for surgical approaches. Radiotherapy is a widely used approach for disseminated metastatic foci in the brain. However, there is a gap in therapeutics since there are few to no alternatives to melanoma brain metastasis after the radiotherapy dose has been maximized. MT1-MMP is a metalloproteinase that has shown a direct correlation with metastasis and whose inhibition slows down the occurrence of metastasis and tumor growth. By microarray analysis, it has been found that inhibition of MT1-MMP downregulates the expression of DNA-damage response genes.
Objective/Hypothesis: We hypothesize that the inhibition of MT1-MMP in combination with radiotherapy will enhance the tumor cell killing efficacy by means of preventing cells from responding to the DNA damage that is caused by radiation. Further, we hypothesize that the Integrin beta 1 pathway downstream of MT1-MMP is the mediator in the downregulation of DNA-damage response genes.
Methods: We utilized melanoma cell lines, A375, WM-266-4-Luciferase, and K457, in which we introduced shMT1-MMP lentivirus with control shGFP. Cell culture assays compared the response of shMT1-MMP cells and shGFP cells in the presence of radiotherapy and the assays included comet assay, foci of gammaH2AX staining, clonogenic assay, and evaluation of radiotherapy response by Western blot. Furthermore, a nude mouse model was utilized in which WM-266-4-luciferase shMT1-MMP and control shGFP cells were inoculated by stereotactic injection. In vivo imaging system (IVIS) was utilized to follow up the tumors.
Results: Ongoing experiments aim to look at the response of shMT1-MMP cells to radiotherapy compared to shGFP cells by DNA damage evaluation assays (Comet assay, gammaH2AX foci, DNA-damage response proteins by Western blot), downstream signaling of Integrin beta 1 pathway, and the survival of nude mice in shMT1-MMP inoculated tumors and their response to radiotherapy.
Impact: This project has the potential to advance the current treatment of melanoma brain metastasis and also has the potential of advancing the understanding of the DNA-damage response in melanoma.
Citation Format: Julia Escandon, Varsha Thakur, Barbara Bedogni. MT1-MMP targeting in melanoma brain metastasis [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr B27.
Abstract B30: The histone demethylase PHF8 epigenetically regulates the TGFbeta pathway to promote melanoma metastasis
Authors: Moubarak Rana , De Pablos-Aragoneses Ana , Ortiz-Barahona Vanessa , Von Itter Richard , Gong Yixiao , Gowen Michael , Stefan Sebastian , Argibay Diana , De Miera-Vega Eleazar , Dolgalev Igor , Sokolova Elena , Darvishian Farbod , Tsirigos Aristotelis , Osman Iman , Hernando Eva 
Published: June 2022

Abstract
The specific contribution of epigenetic dysregulation to the metastatic process remains understudied. Through a meta-analysis of gene expression datasets followed by a functional mini-screen, we identified PHF8, a histone demethylase of the Jumonji C proteins family, as a novel prometastatic factor in melanoma. Loss- and gain-of-function approaches demonstrate that PHF8 promotes cell invasion without affecting proliferation in vitro, and increases dissemination but not tumor growth in vivo, thus strengthening its specific contribution to the acquisition of metastatic potential. PHF8 demethylase activity is required for its proinvasive role. Transcriptomic and epigenomic analyses revealed that PHF8 orchestrates molecular changes that directly control the TGFβ signaling pathway and, as a direct consequence, melanoma invasion.
Citation Format: Rana Moubarak, Ana De Pablos-Aragoneses, Vanessa Ortiz-Barahona, Richard Von Itter, Yixiao Gong, Michael Gowen, Sebastian Stefan, Diana Argibay, Eleazar De Miera-Vega, Igor Dolgalev, Elena Sokolova, Farbod Darvishian, Aristotelis Tsirigos, Iman Osman, Eva Hernando. The histone demethylase PHF8 epigenetically regulates the TGFbeta pathway to promote melanoma metastasis [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr B30.
Abstract IA02: Next targets for immune checkpoint blockade in melanoma
Authors: Chauvin Joe-Marc , Ka Mignane , Pagliano Ornella , Foucade Julien , Menna Carmine , Davar Diwakar , Kirkwood John , Kuchroo Vijay , Anderson Ana , Korman Alan , Zarour Hassane 
Published: June 2022

Abstract
Multiple mechanisms of melanoma-induced immune escape contribute to the failure of T-cell responses to control tumor growth in humans. Many inhibitory pathways play a critical role in impeding T-cell responses to tumor antigens (TAs), including PD-1, the T-cell immunoglobulin and mucin-domain containing-protein 3 (Tim-3), and the T-cell immunoreceptor with Ig and ITIM domains (TIGIT). These inhibitory receptors (IRs) are upregulated by TA-specific CD8+T cells in the tumor microenvironment (TME) while their respective ligands are expressed by antigen-presenting cells (APCs) and tumor cells. Circulating TA-specific CD8+ T cells and CD8+ tumor-infiltrating lymphocytes (TILs) that coexpress PD-1, TIGIT and Tim-3 exhibit different levels of T-cell dysfunction. Dysfunctional/exhausted CD8+ TILs are not totally inert and can exhibit cytolytic functions but are likely kept in check by multiple inhibitory pathways that can be targeted by immune checkpoint blockade. TIGIT is an attractive target for the next-generation immune checkpoint blockade for several reasons. First, it is highly expressed by the majority of CD8+ TILs together with PD-1. Second, the TIGIT ligands, CD155/PVR, and CD112, are highly expressed in the TME by melanoma cells and APCs. Third, dual PD-1/TIGIT blockade augments the expansion and function of human TA-specific CD8+ T cells in vitro and promotes tumor rejection in animal models. Fourth, TIGIT also acts in Tregs and NK cells to regulate antitumor immune responses. CD8+ TILs in melanoma and other solid tumors downregulate the costimulatory molecule DNAM-1/CD226, which competes with TIGIT for binding to the same ligands CD155 and CD112. Therefore, in addition to the TIGIT-mediated T-cell intrinsic inhibitory effects, the downregulation of CD226 expression by CD8+TILs in the TME also contributes to impede T-cell responses to melanoma. Collectively, our findings provide the rationale for dual PD-1/TIGIT blockade together with therapeutic strategies to counteract CD226 downregulation in the TME to improve the clinical benefits of single PD-1 blockade in patients with melanoma and other solid tumors.
Citation Format: Joe-Marc Chauvin, Mignane Ka, Ornella Pagliano, Julien Foucade, Carmine Menna, Diwakar Davar, John Kirkwood, Vijay Kuchroo, Ana Anderson, Alan Korman, Hassane Zarour. Next targets for immune checkpoint blockade in melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA02.
Abstract IA11: The War on Melanoma: Oregon’s early detection experiment
Authors: Leachman Sancy A. , Lapidus Jodi , Sonmez Kemal , Heath Michael , Detweiler-Bedell Brian , Detweiler-Bedell Jerusha , Berry Elizabeth G. , Stoos Elizabeth 
Published: June 2022

Abstract
Early detection of melanoma has several advantages over treatment of late-stage disease. Cure rates are higher, disfigurement is reduced, both short-term and long-term side effects from unnecessary systemic therapies are avoided, and most importantly, a large number of lives of individuals who would never have responded to these treatments in the first place are saved. Early detection is also likely to reduce the overall cost of care because early-stage treatments are far less expensive than those used in advanced disease. Despite the potential benefits of screening and early detection, relatively few prospective interventional studies have been performed to objectively demonstrate effectiveness or quantify the effects. However, multivariate data do show that a basic awareness of skin health and appearance (not requiring specialized knowledge of melanoma features) is associated with early detection of melanoma. The purpose of the War on Melanoma research study is to prospectively test whether a statewide early-detection campaign can improve melanoma outcomes. We will compare three objective metrics before and after the intervention (the education campaign): (1) melanoma knowledge in the general public by survey of a representative population sample; (2) state cancer registry data on stage, mortality, etc.; and (3) cost information from an all-claims, all-payers database. We hypothesize that there will be an increase in melanoma-specific knowledge in the general public, an improved prognosis at the time of diagnosis, and a decrease in melanoma mortality in Oregon compared to two control states (Utah and Washington). We will also quantify the difference in cost of care for melanoma before and after the campaign and will determine if these costs are associated with knowledge levels and/or prognostic/mortality data. These results will provide a model for future early-detection campaigns in other states or for other cancers, by providing evidence for the impact of public health education.
Citation Format: Sancy A. Leachman, Jodi Lapidus, Kemal Sonmez, Michael Heath, Brian Detweiler-Bedell, Jerusha Detweiler-Bedell, Elizabeth G. Berry, Elizabeth Stoos. The War on Melanoma: Oregon’s early detection experiment [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA11.
Abstract IA24: Are there nonimmune targets in the BRAFV600 WT melanoma patient?
Authors: Sosman Jeffrey A. 
Published: June 2022

Abstract
Molecular targeting of melanoma beyond the BRAFV600 mutation has been a frustrating and largely unsuccessful pursuit. The dominant driver in many of these cases is the gain of function NRAS mutations, while a smaller subset are in part driven by NF1 loss of function genetic alterations, and lastly a subset (WT) with a variety of mutations, most of which activate the MAPK pathway such as mutations in c-Kit, MEK, KRAS, HRAS, and alternate non-V600 BRAF mutations. This effort has concentrated on the inhibition of the activated MAPK pathway with MEK inhibitors and targeted NRAS tumors, which make at least 1/3 of the non-BRAF V600 mutant melanoma. As a single agent this approach has been disappointing, but preclinical data support the need for combination therapy, including MEK inhibition with inhibition of alternate pathways such as the PI3/Akt pathway, the cell cycle pathway with CDK4/6 inhibitors, or MDM2 inhibitors to restore functional p53 driven apoptosis. These approaches have been frequently plagued by significant toxicity. Many of these approaches continue to be pursued in the clinic in the hope that different schedules will be more effective and less toxic. An obvious target has been inhibition of downstream pERK which has shown some limited clinical activity. Attacking other pathways looks promising, including targeting mitotic kinases, such as PLK1 and Aurora kinase A. Either inhibiting autophagy or enhancing Bim-directed apoptosis is also under investigation. Finally, we now have a better understanding about the interaction between the targeted agent and the tumor microenvironment. Preclinical and clinical studies show that MEK inhibition can actually enhance the T-cell response at the site of the tumor by selectively eliminating naïve T cells; CDK4/6 inhibition can influence PD-L1 expression and induce retroviral sequences, which then induce an inflammatory (hot) tumor microenvironment. On the other hand, there is further evidence that the microenvironment may be critical for targeted therapy to be effective. This supports an approach combining targeted agents with immune checkpoint inhibitors even in BRAF WT melanoma. While immunotherapy approaches dominate treatment of BRAF WT melanoma, it is critical that we do not lose focus on defining targets, developing better agents, and learning to administer them by an optimal schedule.
Citation Format: Jeffrey A. Sosman. Are there nonimmune targets in the BRAFV600 WT melanoma patient? [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA24.