bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B11: Manipulating senescence to combat melanoma initiation and progression
Authors: Pawlikowski Jeff S. , Holmes Malorie , Richmond Ann 
Published: July 2015

Abstract
Senescence has been identified as a tumor suppression mechanism in many premalignant tissues. The most widely studied example is the melanocytic nevus that guards against the onset of melanoma. Senescence therefore acts as a barrier to malignancies and reinforcing this growth-arrested state can be a valuable way to combat tumorigenesis. Accordingly, therapy induced senescence (TIS) has been shown to be a promising approach for treatment of cancer. Here we further study how specific factors govern TIS.
Numerous clinical trials are currently ongoing that inhibit MDM2 or CDK4/6, which regulate the tumor suppressors p53 and RB/p16, respectively. As these tumor suppressors are the master regulators of senescence and senescence is an important mechanism in melanoma initiation, we analyzed the effect of their inhibition in primary melanocytes and transformed melanoma cell lines. As anticipated, we show that upon administration of the MDM2 and CDK4/6 inhibitors (-)-Nutlin-3a (1uM) and PD2991 (8uM, respectively), primary human melanocytes and human melanoma cell lines stop proliferating. While MDM2 and CDK4/6 inhibitors have been shown to induce senescence, we were surprised to find that induction of senescence was not conserved among all cell types studied. Analysis of the cell cycle arrest showed that human melanocytes do not display senescence associated beta-galactosidase activity while melanoma cell lines do stain positive for this marker of senescence. Furthermore, members of the senescence associated secretory phenotype (SASP) are not increased upon MDM2 and CDK4/6 inhibition in primary melanocytes, whereas the same treatment in melanoma cells causes SASP up-regulation in a similar fashion to that triggered by oncogene induced senescence (OIS). The induction of the SASP members was particularly evident upon combined treatment with MDM2 and CDK4/6 inhibitors. These results suggest that TIS may be influenced by the expression of the SASP.
We have previously showed that many members of the SASP whose expression increases with senescence also expressed in metastatic disease. By further evaluating SASP following OIS vs TIS, we may better understand the mechanisms behind existing senescence inducing therapies and define additional routes for pro-senescence cancer therapy. Senescence is a highly complex process that is able to control multiple cell fates, often due in part to the SASP. Consequently, by manipulating the SASP we may be able to regulate melanoma initiation and progression.
Citation Format: Jeff S. Pawlikowski, Malorie Holmes, Ann Richmond. Manipulating senescence to combat melanoma initiation and 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 B11.
Abstract B19: Discovery of novel tubulin inhibitor ABI-274 whose synergistic combination with vemurafenib overcome acquired vemurafenib resistance in BRAF mutated melanoma
Authors: Wang Jin , Chen Jianjun , Miller Duane D. , Li Wei 
Published: July 2015

Abstract
Acquired clinical resistance to BRAF inhibitors such as vemurafenib or dabrafefnib arises frequently after short term of these targeted therapy. We hypothesized that a combined therapy using vemurafenib with a G2/M phase blocking agent will arrest resistant cells and overcome vemurafenib resistance. To test this hypothesis, we performed combination studies using our recently discovered tubulin inhibitor ABI-274 and vemurafenib on both vemurafenib-sensitive cells and a resistant A375RF21 sub line. The combination showed strong synergy in vitro, synergistically arrested cells in G1/G2/M phase, and significantly enhanced cancer cell apoptosis. In vivo co-administration of vemurafenib with ABI-274 showed strong synergistic efficacy in the vemurafenib-resistant xenograft model in nude mice. Overall, these results offer a rational combination strategy to significantly enhance the therapeutic benefit in melanoma patients who inevitably become resistant to current vemurafenib therapy. This work was supported by NIH grants R01CA148706, 1S10OD010678-01 and 1S10RR026377-01.
Citation Format: Jin Wang, Jianjun Chen, Duane D. Miller, Wei Li. Discovery of novel tubulin inhibitor ABI-274 whose synergistic combination with vemurafenib overcome acquired vemurafenib resistance in BRAF mutated 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 B19.
Abstract B28: In vivo ERK1/2 pathway reporting during acquired resistance to combined RAF/MEK inhibition
Authors: Sanchez Ileine , Aplin Andrew 
Published: July 2015

Abstract
The MEK-ERK1/2 signaling pathway is constitutively activated in BRAF V600E/K melanomas. Concurrent BRAF and MEK inhibitor treatment was recently FDA-approved for BRAF V600E melanoma; however, acquired resistance to the drug combination limits durable responses. Our lab has developed a luciferase reporter system that temporally and non-invasively quantitates ERK1/2 activity in mutant BRAF melanoma xenografts. We used this reporter system to examine the temporal kinetics of ERK1/2 activity in vivo upon treatment with combined BRAF/MEK inhibition. Using a 1205Lu reporter system, all established tumors regressed to levels that were not detectable visually. After prolonged treatment with BRAF and MEK inhibitors, only 2 out of 8 mice regrew resistant tumors. In similar experiments with A375 xenografts, only 1 out 12 tumors developed resistance. In 1205Lu tumors, re-activation of the ERK1/2 pathway was evident prior to re-growth. Additionally, cell lines generated from these resistant tumors exhibited elevated levels of ERK1/2 suggesting that resistance to BRAF + MEK inhibitors involves re-activation of ERK1/2 signaling. In comparison to parental cells, resistant cells in vitro displayed reduced levels of apoptosis, increased proliferation, and increased viability in the presence of BRAF plus MEK inhibitor. Furthermore, when removed from drugs, combination-resistant cells showed increased apoptosis and reduced proliferation and viability, suggesting that the resistant lines may be addicted to the dual therapy. RPPA analysis and whole exome sequencing to elucidate mechanisms of resistance are ongoing.
Citation Format: Ileine Sanchez, Andrew Aplin. In vivo ERK1/2 pathway reporting during acquired resistance to combined RAF/MEK inhibition. [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 B28.
Abstract B35: Vinyl sulfone analogues of lysophosphatidylcholine irreversibly inhibit autotaxin and prevent angiogenesis in melanoma
Authors: Murph Mandi , Jiang Guowei , Altman Molly , Wei Jia , Tran Sterling , Nguyen Duy , Alshamrani Ali , Hardman William , Zhang Jianxing , Prestwich Glenn 
Published: July 2015

Abstract
Autotaxin is an enzyme discovered in the conditioned medium of cultured melanoma cells and identified as a protein that strongly stimulates motility. Autotaxin is a unique ectonucleotide pyrophosphatase and phosphodiesterase that facilitates the removal of a choline headgroup from lysophosphatidylcholine to yield lysophosphatidic acid, which is a potent lipid stimulator of tumorigenesis. Thus, autotaxin has received renewed attention because it has a prominent role in malignant progression and represents a promising area of research with significant translational potential. Specifically, we sought to develop active site-targeted irreversible inhibitors as anti-cancer agents. Our goal was to discover agents with therapeutic efficacy in melanoma. For this purpose, we synthesized a set of lysophosphatidylcholine analogs that function as irreversible inhibitors of autotaxin and inactivate the enzyme. The analogs were tested in cell viability assays using multiple cancer cell lines. The IC50 values ranged from 6.74 – 0.39 μM, consistent with a Ki of 3.50 μM for inhibition of autotaxin by the analog CVS-16 (10b). A control compound, GWJ-A-10, which is missing the critical moiety, had little effect on cell viability and did not inhibit autotaxin. In addition, CVS-16 (10b) significantly inhibited melanoma cell wound closure and pore migration (data not presented herein). Most importantly, CVS-16 (10b) significantly inhibited melanoma progression in an in vivo tumor model by preventing angiogenesis. Taken together, this suggests that CVS-16 (10b) is a potent autotaxin inhibitor with significant biological activity, both in vitro and in vivo.
Citation Format: Mandi Murph, Guowei Jiang, Molly Altman, Jia Wei, Sterling Tran, Duy Nguyen, Ali Alshamrani, William Hardman, Jianxing Zhang, Glenn Prestwich. Vinyl sulfone analogues of lysophosphatidylcholine irreversibly inhibit autotaxin and prevent angiogenesis 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 B35.
Abstract B36: The effects of dasatinib in KIT L579P and NRAS Q61K mutant canine melanoma cells
Authors: Lu Lu-Ping , Lin Chen-Si , Liao Albert Taiching 
Published: July 2015

Abstract
Purpose: Malignant melanoma is a common malignant tumor in dog. It is a fatal disease with local invasiveness and frequently metastatic propensity and the poor response has been observed. The aim of this study was to establish the drug-screening platform and used that platform to evaluate small molecular inhibitor, Dasatinib, for therapy of canine melanoma.
Experimental Design: Various phenotypes of eight canine melanoma cell lines, CM01, M1, M3, M4, M5, Pu, C1 and KMeC, were examined in this study. Mutation analysis of kit, Nras and Braf was done by PCR/DNA sequencing. Expression of S100, KIT and KIT downstream signaling cascades NRAS, phospho-ERK and phospho-AKT were evaluated by immunocytochemistry. KMeC, M5 and CM01 cell lines were selected for further evaluation of Dasatinib. Proliferation assay and wound healing assay were performed to assess cell viability and motility in the presence of dasatinib. Cell cycle analysis and Annexin V apoptosis assay were also applied to realize the mechanism of cell death caused by Dasatinib.
Results: Expressions of S100 and KIT were observed in all of the cell lines. NRAS and activated ERK were identified in several cell lines with different expression levels. However, no activated AKT was identified in any cell lines. kit T1736C mutation causing KIT L579P change was detected in M3, KMeC and C1 cells, while Nras C181A mutation causing NRAS Q61K change was found in M5 cell. ERK activity in KMeC (KIT L579P), M5 (NRAS Q61K) and CM01 (KIT & NRAS wild type) cells was down-regulated when Dasatinib was administered. Dasatinib reduced cell viability with the IC50 values of 0.64 μM in KMeC, 0.24 μM in M5 and 0.37 μM in CM01 cells. In wound healing assay, Dasatinib inhibited cell motility in all of the three cell lines. Cell cycle analysis and Annexin V apoptosis assay revealed that the treatment of Dasatinib causes a G1 cell cycle arrest and induction of apoptosis. The analysis of Dasatinib caused signaling change in canine melanoma cell is ongoing.
Conclusions: Various phenotypes of eight canine melanoma cell lines were identified in DNA and protein levels. The NRAS Q61K mutation was first found in canine melanoma. The results showed that KIT L579P mutant type, NRAS Q61K mutant type and wild type canine melanoma cells are sensitive to the treatment of Dasatinib. It caused the reduction of cell viability, and inhibition of motility, moreover, the promotion of G1 cell cycle arrest and cell apoptosis. Dasatinib may potentially be selected as a candidate for therapy of canine melanoma.
Citation Format: Lu-Ping Lu, Chen-Si Lin, Albert Taiching Liao. The effects of dasatinib in KIT L579P and NRAS Q61K mutant canine melanoma cells. [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 B36.
Abstract IA05: Small RNAs reveal nuclear hormone receptor targeting as a novel therapy for melanoma
Authors: Tavazoie Sohail 
Published: July 2015

Abstract
In recent years, numerous genes that drive melanoma metastasis or progression of established metastatic melanoma have been identified. The identification of such genes and their associated pathways have revealed insights into the cellular processes involved in these clinically important events. Our laboratory has found that deregulated expression of microRNAs is a major mechanism by which such gene-expression states that enable metastatic progression are achieved in various solid cancers. In melanoma, we have identified 3 microRNAs (miR-1908, miR-199a5p, and miR-199a3p) to be over-expressed in metastatic sub-populations of human melanoma cells. The expression levels of these microRNAs predict metastatic relapse in primary cutaneous melanomas. These microRNAs convergently target the gene ApoE, which through genetic, molecular, pharmacological, and clinical association analyses, we have identified as a robust suppressor of melanoma metastasis and metastatic progression. We have demonstrated pre-clinical proof-of-concept for the therapeutic activation of ApoE through transcriptional engagement of the Liver-X nuclear hormone receptor (LXR). Oral administration of multiple LXR agonists suppressed the growth of primary and metastatic melanoma in mice. Genetic studies revealed that the effects of LXR agonists are mediated through LXRβ, which elicits these effects through ApoE induction in the stromal and tumoral compartments. LXRβ; agonism suppressed progression in immunocompetent, xenograft, patient-derived xenograft, and genetically initiated melanomas. Moreover, LXRβ agonism exhibited combinatorial efficacy with B-Raf inhibitors and anti-CTLA4 immunotherapy. We provide pre-clinical proof-of-concept for therapeutic activation of nuclear hormone receptors in melanoma.
Citation Format: Sohail Tavazoie. Small RNAs reveal nuclear hormone receptor targeting as a novel therapy for 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 IA05.
Abstract IA27: Combination immunotherapy for melanoma
Authors: Wolchok Jedd D. 
Published: July 2015

Abstract
The past decade has been a period of significant progress in the area of cancer immunotherapy enabled by significant advances in basic science allowing for a better understanding of molecular mechanisms of immune regulation and immune cell dynamics, stressing the importance of close collaboration between basic and translational and clinical scientists. Blockade of CTLA-4 was suggested to be an impactful means to augment tumor immunity based on the pioneering studies of Jim Allison, who hypothesized that impairment of this critical molecular brake would overcome tumor-induced immune suppression and allow for more robust immune response to tumors. In 2011, the US FDA approved ipilimumab for the treatment of metastatic melanoma with two randomized phase 3 trials demonstrating prolongation of overall survival, the first intervention ever to demonstrate this important endpoint in this challenging clinical situation. Investigation of blockade of the PD-1 (programmed death-1) pathway followed very shortly after the efficacy of ipilimumab was observed. PD-1 is a marker on T cells which, while being up-regulated after activation, serves to mark T cells as being exhausted and, when engaging one of its ligands (PD-L1 or -L2), can lower the threshold for apoptosis in T cells. An ever-expanding list of antibodies that block either PD-1 or PD-L1 has entered clinical trials with some currently in phase 3 investigation. It was therefore not completely surprising that PD-1 blockade showed clinical efficacy in melanoma. Given the activity noted with both CTLA-4 and PD-1 blockade and the complementary mechanism of action as well as supportive pre-clinical data, clinical trials are now investigating combination checkpoint blockade. The most mature data has come from a combination of ipilimumab + nivolumab in patients with melanoma and showed an overall response rate of 40% across dose cohorts with over 50% of patients in some cohorts showing rapid and deep (&gt;80% reduction) tumor regressions in the context of manageable toxicity. Responses are generally rapidly apparent and durable. Two-year overall survival rates have been estimated at 79% across all cohorts. Phase 2 and 3 trials of this combination are ongoing.
Citation Format: Jedd D. Wolchok. Combination immunotherapy for 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 IA27.
Abstract IA29: PI3′ -kinase inhibition forestalls the onset of MEK1/2 inhibitor resistance in BRAFV600E/PTENNull melanoma
Authors: Deuker Marian M. , Marsh-Durban Victoria , Phillips Wayne A. , Silva Jillian M. , McMahon Martin 
Published: July 2015

Abstract
Phosphatidylinositide 3′ (PI3′)-lipid signaling promotes the growth of BRAF-mutated melanomas initiated by expression of oncogenic BRAFV600E. Elevation of PI3′-lipid signaling commonly occurs via silencing of the PTEN tumor suppressor, which encodes a PI3′-lipid phosphatase. However mutational activation of PIK3CA, encoding the p110α catalytic subunit of PI3′-kinase (PI3K), or alterations in the PI3′-lipid effectors AKT1-3 have also been observed, albeit infrequently. To characterize the PI3K catalytic isoform dependency of BRAF-mutated melanoma, we utilized a panel of pharmacological isoform-selective PI3K inhibitors in conjunction with melanoma-derived cell lines and genetically engineered mouse (GEM) models of BRAF-mutated melanoma. While BRAFV600E/PIK3CAH1047R mutated melanoma was sensitive to p110α selective blockade, inhibition of BRAFV600E/PTENNull melanoma cell proliferation required combined blockade of p110α, p110δ and p110γ isoforms, and was insensitive to p110β blockade. In GEM models of BRAF-mutated melanoma, PI3K pathway inhibition elicited largely cytostatic effects, and significantly potentiated melanoma regression in response to BRAFV600E pathway-targeted inhibition. Interestingly, an inhibitor of p110α, δ and γ forestalled the onset of MEK inhibitor resistance in a GEM model of BRAFV600E/PTENNull melanoma. Thus, although single agent PI3K inhibition failed to elicit dramatic regression of BRAFV600E expressing melanomas, PI3K inhibitors may be useful in extending the duration of response to BRAFV600E pathway-targeted therapy.
Citation Format: Marian M. Deuker, Victoria Marsh-Durban, Wayne A. Phillips, Jillian M. Silva, Martin McMahon. PI3′ -kinase inhibition forestalls the onset of MEK1/2 inhibitor resistance in BRAFV600E/PTENNull 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 IA29.
Divergent effects of Tlr9 deletion in experimental late venous thrombosis resolution and vein wall injury
Authors: Luke Catherine E. , Elfline Megan , Kittan Nicolai , Allen Ron , Laser Adriana , Oostra Carson , Comerota Anthony , Hogaboam Cory , Kunkel Steven L. , Dewyer Nicholas A. , El-Sayed Osama M. , Henke Peter K. 
Published: July 2015

SummaryDeep-vein thrombosis (DVT) resolves via a sterile inflammatory response. Defining the inflammatory response of DVT may allow for new therapies that do not involve anticoagulation. Previously, we have shown that Toll-like receptor 9 (Tlr9) gene deleted mice had impaired venous thrombosis (VT) resolution. Here, we further characterise the role of Tlr9 signalling and sterile inflammation in chronic VT and vein wall responses. First, we found a human precedent exists with Tlr9 + cells present in chronic post thrombotic intraluminal tissue. Second, in a stasis VT mouse model, endogenous danger signal mediators of uric acid, HMGB-1, and neutrophil extracellular traps marker of citrullinated histone-3 (and extracellular DNA) were greater in Tlr9-/- thrombi as compared with wild-type (WT), corresponding with larger VT at 8 and 21 days. Fewer M1 type (CCR2+) monocyte/macrophages (MØ) were present in Tlr9-/- thrombi than WT controls at 8 days, suggesting an impaired inflammatory cell influx. Using bone marrow-derived monocyte (BMMØ) cell culture, we found decreased fibrinolytic gene expression with exposure to several endogenous danger signals. Next, adoptive transfer of cultured Tlr9+/+ BMMØ to Tlr9-/- mice normalised VT resolution at 8 days. Lastly, although the VT size was larger at 21 days in Tlr9-/- mice and correlated with decreased endothelial antigen markers, no difference in fibrosis was found. These data suggest that Tlr9 signalling in MØ is critical for later VT resolution, is associated with necrosis clearance, but does not affect later vein wall fibrosis. These findings provide insight into the Tlr9 MØ mechanisms of sterile inflammation in this disease process.
Comparative efficacy and safety of anticoagulant strategies for acute coronary syndromes
Authors: Andreotti Felicita , Kołodziejczak Michalina , Schulze Volker , Wolff Georg , Dias Sofia , Claessen Bimmer , Brouwer Marc , Tarantini Giuseppe , Iliceto Sabino , Brockmeyer Maximilian , Kowalewski Mariusz , Lin Yingfeng , Eikelboom John , Musumeci Giuseppe , Lee Leong , Lip Gregory Y. H. , Valgimigli Marco , Berti Sergio , Kelm Malte , Navarese Eliano Pio 
Published: July 2015

SummaryInternational guidelines differ in strengths of recommendation for anticoagulation strategies in acute coronary syndromes (ACS). We performed a comprehensive network meta-analysis (NMA) of randomised controlled trials (RCTs) to investigate the comparative efficacy and safety of parenteral anticoagulants in ACS. MEDLINE, Cochrane, EM-BASE, Google Scholar, major cardiology websites, and abstracts/presentations were searched. Six treatments were identified: 1) unfractionated heparin (UFH) + glycoprotein IIb/IIIa inhibitor (GPI) [UFH+GPI], 2) UFH±GPI, 3) bivalirudin, 4) low-molecular-weight heparins (LMWHs), 5) otamixaban, and 6) fondaparinux. Prespecified outcomes (death, myocardial infarction [MI], revascularisation, major bleeding [MB], minor bleeding, and stent thrombosis [ST]) were evaluated up to 30 days. Forty-two RCTs involving 117,353 patients were included. No significant differences in mortality rates were found among strategies. Compared to UFH+GPI, bivalirudin reduced the odds of MB but increased the odds of ST and MI. LMWHs vs bivalirudin reduced MI risk at the price of MB excess. UFH±GPI significantly increased the odds of MI vs LMWHs, of ST vs UFH+GPI, and of MB vs bivalirudin. Reduced ST risk with otamixaban vs UFH±GPI and vs bivalirudin was offset by a marked 2.5- to four-fold MB excess. Fondaparinux showed an intermediate profile. Results for ST-segment elevation MI were consistent with the overall findings. Early anticoagulant strategies for ACS differ in efficacy and safety, with UFH+GPI and LMWHs reducing ischaemic but increasing bleeding risk, and bivalirudin reducing MB but increases MI and ST. The findings support individualised therapy based on patients´ bleeding and ischaemic risks.