bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B12: Synergistic anticancer activity of Aurora A kinase and MDM2 antagonists in melanoma
Authors: Vilgelm Anna E. , Pawlikowski Jeff S. , Liu Yan , Oriana E. Hawkins , Tyler A. Davis , Weller Kevin P. , Horton Linda W. , McClain Colt M. , Ayers Gregory D. , Turner David , Essaka David C. , Stewart Clinton F. , Sosman Jeffrey A. , Kelley Mark C. , Ecsedy Jeffrey A. , Johnston Jeffrey N. , Richmond Ann 
Published: July 2015

Abstract
Senescence-inducing therapies can block proliferation of malignant cells and promote anti-tumor immune activity. However, the risk of tumor relapse remains high due to the long lifespan of senescence cells with potential to escape senescence. Here our preclinical studies demonstrate that combining a senescent-inducing aurora kinase A (AURKA) inhibitor alisertib (MLN8237) with an MDM2 antagonist [(-)-nutlin 3a] effectively induces robust p53 activation in senescent Tp53WT tumors accompanied by: 1) tumor cell proliferation arrest; 2) mitochondrial depolarization and tumor cell apoptosis; and 3) tumor cell clearance via CCL5-, CCL1- and CCL9-mediated recruitment of anti-tumor leukocytes. This combined therapy shows adequate bioavailability and low toxicity to the host in the mouse model. Moreover, the prominent preclinical response of patient-derived melanoma tumors to the co-targeting of MDM2 and AURKA provides rationale for further investigation of alisertib and MDM2 inhibitors.
Citation Format: Anna E. Vilgelm, Jeff S. Pawlikowski, Yan Liu, E. Hawkins Oriana, A. Davis Tyler, Kevin P. Weller, Linda W. Horton, Colt M. McClain, Gregory D. Ayers, David Turner, David C. Essaka, Clinton F. Stewart, Jeffrey A. Sosman, Mark C. Kelley, Jeffrey A. Ecsedy, Jeffrey N. Johnston, Ann Richmond. Synergistic anticancer activity of Aurora A kinase and MDM2 antagonists 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 B12.
Abstract B18: Non-thermal plasma, tirapazamine, and gap junctions: A novel approach to melanoma therapy through ROS induction
Authors: Zucker Shoshanna N. , Higley Cory , Koch Zethan , Goli Haneesha , Casey Peter , Francis Akeem , Burke Kevin , Zirnheld Jennifer 
Published: July 2015

Abstract
Melanoma cells typically have high levels of superoxide anion which may increase their susceptibility to cell death by reactive oxygen species (ROS). We have used this information to establish a system whereby melanoma cells are saturated with ROS through treatment with non-thermal plasma (NTP). NTP is formed from a mixture of highly charged helium and atmospheric gases to emit a total of 45 molecular species, many of which are ROS. We have recently demonstrated that NTP causes selective apoptotic cell death of melanoma cells as compared to normal skin keratinocytes when plated in co-culture. Since tumors flourish under low oxygen (hypoxic) conditions, we tested the effects of NTP under hypoxia. In order to enhance the effects of NTP, we combined this therapy with the experimental anticancer drug, tirapazamine, which promotes cell toxicity through DNA damage only under hypoxic conditions. The question then remains as to how to increase the target area of melanoma therapy. Our previous studies have demonstrated that gap junctions act via the bystander effect to enable the passage of cell-death promoting signals by NTP. We utilized stably transfected 1205Lu metastatic melanoma cells that express three different levels of gap junctions: endogenous low levels, increased levels through expression of connexin 43, or an absence of gap junctions due to expression of a dominant negative mutant connexin 43. We have shown that the cells with the mutant connexin 43 showed increased invasive potential as well as enhanced expression of HIF1α. The combination therapy with NTP and tirapazamine under hypoxic conditions caused a synergistic effect which increased cell death in all cells, yet was most apparent in the 1205Lu cells overexpressing the functional gap junctions. In addition, the target area of the NTP torch was dramatically increased under these conditions. This suggests that the ROS generated by NTP and tirapazamine induced the bystander effect and promoted the spreading of cell death signals well beyond the area of the plasma treatment. These results are indicative a novel future approach to melanoma therapy through selective ROS induction and modification of gap junction phenotype.
Citation Format: Shoshanna N. Zucker, Cory Higley, Zethan Koch, Haneesha Goli, Peter Casey, Akeem Francis, Kevin Burke, Jennifer Zirnheld. Non-thermal plasma, tirapazamine, and gap junctions: A novel approach to melanoma therapy through ROS induction. [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 B18.
Abstract B20: Design, synthesis and SAR studies of novel survivin inhibitors with potent antiproliferative properties
Authors: Xiao Min , Wang Jin , Lu Yan , Miller Duane D. , Li Wei 
Published: July 2015

Abstract
A series of novel survivin inhibitors were designed and synthesized based our recently reported compound UC-112. All the new analogs were tested against several cancer cell lines including multidrug-resistant melanoma cancer cell lines. The in vitro results showed that several compounds had excellent antiproliferative activity with IC50 values within nanomolar range. Mechanism of action of those new analogs was investigated by Western blot assay. The study confirmed that the new analogs acted by selectively suppressing survivin with the similar mechanism as the parent compound UC-112. Those new analogs represent promising agents that can be further developed for selective anticancer treatment.
Citation Format: Min Xiao, Jin Wang, Yan Lu, Duane D. Miller, Wei Li. Design, synthesis and SAR studies of novel survivin inhibitors with potent antiproliferative properties. [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 B20.
Abstract B24: A phosphoproteomic comparison of oncogenic BRAF and MKK1/2 inhibition in human melanoma
Authors: Stuart Scott , Houel Stephane , Wang Nan , Old William , Ahn Natalie 
Published: July 2015

Abstract
The purpose of this study was to use phosphoproteomics to gain insight into the different clinical responses to BRAF inhibition, MKK1/2 inhibition, and combined BRAF/MKK inhibition. Experiments were designed to test whether BRAF inhibition may affect a distinct subset of targets that MKK1/2 inhibition does not and whether BRAF and MKK1/2 inhibitors work additively or synergistically when used in combination. To this end, we employed a SILAC-based method to quantify changes in the phosphoproteome of WM239A melanoma cells treated with a clinically relevant BRAF inhibitor (PLX4032; 10μM) or MEK1/2 inhibitor (AZD6244; 10μM) inhibitor. Phosphopeptides were enriched by titanium dioxide prior to fractionation on an electrostatic repulsion-hydrophilic interaction chromatography (ERLIC) column. In a set of three biological replicate experiments, we quantified changes at 23,986 phosphosites on 4,722 proteins. We identified 1,356 phosphosites that decreased in abundance, and 341 that increased in abundance, in response to treatment with either PLX4032 or AZD6244. The overwhelming majority of phosphosites were responsive to both inhibitors. Of the phosphosites that decreased in abundance, 13 responded only to PLX4032, suggesting that certain targets are regulated by BRAF but not MKK1/2. In contrast, we failed to identify any phosphosites that responded only to AZD6244. To determine whether the therapeutic benefit of combined BRAF and MKK1/2 inhibition may be a result of drug synergy, we treated cells either with a single inhibitor or with a combination of AZD6244 and PLX4032, each at submaximal doses (30 nM). We then compared the magnitude of the responses observed with the combination treatment to those observed for each drug alone. Comparison of observed versus predicted changes at 6,463 phosphosites demonstrated that the primary effect of the two inhibitors is additive. Taken together, we show that the combination of BRAF and MKK1/2 inhibitor leads to predominantly additive interactions, and that the BRAF inhibitor has a potential for regulating phosphorylation events that are not targeted by MKK1/2 inhibitor.
Citation Format: Scott Stuart, Stephane Houel, Nan Wang, William Old, Natalie Ahn. A phosphoproteomic comparison of oncogenic BRAF and MKK1/2 inhibition in human 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 B24.
Abstract B29: Differential effects of BRD4 inhibition on uveal melanoma cells with Gnaq/11 mutations
Authors: Ambrosini Grazia 
Published: July 2015

Abstract
Uveal melanoma (UM) represents the most common intraocular malignancy, and there are no effective treatments for this aggressive disease. Nearly 80% of UM is characterized by oncogenic mutations in G protein subunits Gnaq and Gna11, and 70% have extra copies of the oncogene MYC.
Chromatin regulators have become attractive targets for cancer therapy. In particular, the BET-bromodomain inhibitor JQ1 has shown selective inhibition of c-Myc expression, followed by the suppression of c-Myc-dependent target genes. Treatments of UM cell lines with JQ1 showed that the Gnaq/Gna11 mutant cells were the most sensitive to BET inhibition with induction of cell death, while the cells without the mutations underwent cell cycle arrest in G1.
Microarray analysis of UM cells revealed that several genes were differentially regulated by JQ1 treatment in Gnaq/11 mutant cells, with the downregulation of c-Myc, of the anti-apoptotic protein Bcl-2, and DNA repair proteins Rad51 and Brca1. While depletion of each of these genes did not affect cell viability, the concomitant silencing of Rad51 and Bcl-2 represented the minimal requirement to mimic the apoptotic effects of JQ1. As opposed to hematopoietic cancer cell lines, c-Myc depletion did not seem to play a major role in inhibiting the growth of these cells.
Furthermore, the treatment with JQ1 resulted in significant antitumor activity in a mouse xenograft model of uveal melanoma with Gnaq mutation.
Our results suggest the potential therapeutic use of BET bromodomain inhibitors for treating uveal melanoma with Gnaq/Gna11 mutations.
Citation Format: Grazia Ambrosini. Differential effects of BRD4 inhibition on uveal melanoma cells with Gnaq/11 mutations. [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 B29.
Abstract B39: Exome sequencing in primary melanoma identifies novel drivers of melanoma progression
Authors: Montagnani Valentina , Benelli Matteo , Apollo Alessandro , Gerlini Gianni , Borgognoni Lorenzo , Stecca Barbara 
Published: July 2015

Abstract
Melanoma is the most malignant and lethal among skin cancers, due to its high infiltration and invasion ability and resistance to therapy. Whereas early stages melanoma can be cured in the majority of cases by surgical excision, metastatic melanoma is a highly lethal condition. The most frequent known oncogenic mutation in melanoma is BRAF-V600E and several full exome sequencing studies have revealed numerous other alterations (Wei et al, 2011; Nikolaev et al, 2011; Stark et al, 2011; Krauthammer et al, 2012). A crucial issue in understanding melanoma progression is to identify which mutations are specifically involved in making an individual melanoma competent for metastatic spread. It is well established that this behavior is highly correlated with histological features, such as the thickness of the primary tumor and the mitotic index. Here we performed full exome sequencing of 5 thin (&lt;1mm in thickness) and 5 thick (&gt;4mm in thickness) primary melanomas compared to matched-normal DNA. We confirmed recurrent somatic mutations in known melanoma-related genes, including BRAF, c-KIT, EGFR, PPP6C, MLL3 and several components of the glutamate signaling. In addition, we discovered mutations in genes not previously linked to this tumor, such as CSMD1, FGFR4 and components of the Hedgehog (HH) signaling pathway. In particular, in a thick melanoma we found an novel activating mutation in the transcription factor GLI1, one of the final effectors of the HH signaling. Notably, in the only 3 thick melanomas that produced metastasis, we identified candidate metastasis-driving mutations in six genes (ADAMTS6, ADAMTS7, CHD9, MLL3, NALCN and TSC2). Interestingly, we identified several regions of focal somatic copy-number alterations (SCNAs) that were altered at significantly higher frequency in thick compared to thin melanomas. Several gene families are comprised among these regions of focal SCNAs, including components of Notch, HH and Wnt/ß-catenin signaling pathways, BRAF, c-MYC and its cofactor PIM1, several ADAMs, EGFR and the HOX genes. Our preliminary results identify potential drivers of melanoma progression, enhancing our understanding of the genomic complexity underlying melanoma.
Citation Format: Valentina Montagnani, Matteo Benelli, Alessandro Apollo, Gianni Gerlini, Lorenzo Borgognoni, Barbara Stecca. Exome sequencing in primary melanoma identifies novel drivers of 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 B39.
Abstract IA12: Preclinical models for targeting oncogenic Ras signaling in cancer
Authors: Shannon Kevin 
Published: July 2015

Abstract
Somatic RAS mutations occur in 30% of human cancers, and are common in both melanoma and hematopoietic cancers. Importantly, whereas KRAS mutations predominate in epithelial cancers, NRAS is mutated much more often in melanoma and hematopoietic cancers. The most obvious therapeutic strategy for cancers with RAS mutations – developing specific inhibitors of the mutant protein – is extremely challenging due to the very high affinity of Ras for GTP, structural considerations of the Ras/GTPase activating protein (Ras/GAP) molecular switch, and the loss of normal enzymatic activity as a consequence of oncogenic RAS mutations. Given these issues, most recent drug discovery efforts have focused on inhibiting downstream biochemical targets of mutant Ras such as Raf, MEK, and Akt with many compounds undergoing clinical evaluation. We have exploited strains of mice that recapitulate endogenous expression of cancer-associated RAS alleles or NF1 inactivation to model human hematologic cancers and to conduct biologic and preclinical studies. In particular, we have deployed the MOL4070LTR retrovirus as an insertional mutagen to generate genetically heterogeneous transplantable myeloid and lymphoid leukemias characterized by hyperactive Ras signaling. We utilize cohorts of mice that are engrafted with the same primary leukemias for preclinical testing. In this presentation, I will focus on three biologic and therapeutic questions related to NRAS in tumorigenesis: (1) loss of the normal NRAS allele in cancers with oncogenic NRAS mutations; (2) responses of primary Nras mutant leukemias to MEK and PI3 kinase inhibitors; and, (3) potential strategies for selectively targeting oncogenic N-Ras in cancer.
Note: This abstract was presented as part of the Joint Session: Clinical Science Interactions between Melanoma and Hematologic Malignancies with the AACR Special Conference: Hematologic Malignancies: Translating Discoveries to Novel Therapies held September 20-23, 2014 in Philadelphia, PA.
Citation Format: Kevin Shannon. Preclinical models for targeting oncogenic Ras signaling in cancer. [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 IA12.
Abstract IA15: Adoptive T cell therapy with CAR modified T cells: We have a model A Ford, can we build a Ferrari?
Authors: Brentjens Renier 
Published: July 2015

Abstract
Recently published reports support the novel approach of treating cancer with patient derived T cells genetically modified to express artificial T cell receptors, termed chimeric antigen receptors (CARs), targeted to tumor associated antigens. To this end, initial clinical trial outcomes of patients with relapsed B cell acute lymphoblastic leukemia (B-ALL) treated with T cells genetically modified to express a CAR specific to the CD19 antigen demonstrate that this approach is a very promising therapeutic intervention which potentially may dramatically alter the standard of care in this disease. In contrast far more modest clinical responses were seen in patients with relapsed low grade B cell malignancies including chronic lymphocytic leukemia (CLL) and B cell non-Hodgkins lymphomas (NHL). The etiologies of discordant clinical outcomes between B-ALL and CLL/NHL patients treated with CD19 targeted CAR T cells remains a subject of conjecture although the tumor microenvironment is a strong focus for further investigation. To this end, we will present novel data on a next generation of CAR T cells, termed “armored CAR” T cells genetically designed to enhance persistence, anti-tumor efficacy, and an ability to overcome an immune suppressive tumor microenvironment through further genetic modification. Promising preclinical studies utilizing various “armored CAR” T cell approaches and their role in future clinical trials will be discussed as well as the relevance of these findings to the extrapolation of this technology from hematologic tumors to far more prevalent solid tumor malignancies.
Note: This abstract was presented as part of the Joint Session: Clinical Science Interactions between Melanoma and Hematologic Malignancies with the AACR Special Conference: Hematologic Malignancies: Translating Discoveries to Novel Therapies held September 20-23, 2014 in Philadelphia, PA.
Citation Format: Renier Brentjens. Adoptive T cell therapy with CAR modified T cells: We have a model A Ford, can we build a Ferrari? [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 IA15.
Abstract IA19: Response and resistance PD-1 pathway blockade
Authors: Topalian Suzanne L. 
Published: July 2015

Abstract
Melanoma is a genetically complex cancer harboring a multitude of somatic mutations for potential targeting by the immune system. However, melanoma cells can co-opt normal immune tolerance mechanisms to evade elimination. The immunoglobulin-like molecule PD-L1 (B7-H1), expressed by many melanomas in situ, creates a protective shield against immune attack. PD-L1 is a ligand for the programmed death-1 (PD-1) receptor expressed on activated T and B cells, and it delivers an inhibitory signal to suppress antitumor immunity. Blocking the PD-1:PD-L1 interaction can rejuvenate anti-melanoma immunity and mediate tumor regression. Multicenter clinical trials of blocking antibodies against PD-1 (nivolumab, pembrolizumab) or PD-L1 (BMS-936559, MPDL3280A, MEDI4736) have been undertaken. In an early phase trial of biweekly nivolumab administration, durable objective tumor regressions and disease stabilization were observed among 31% and 7%, respectively, of 107 patients with advanced treatment-refractory melanoma. Median overall survival in this trial was 17 months. Partial tumor regressions that are durable and persist after drug discontinuation suggest that PD-1 blockade can reset the balance between the immune system and melanoma. In some patients, “mixed” tumor regressions or initial disease progression followed by regression suggest that tumor lesions separated anatomically or chronologically may be immunologically heterogeneous. Durable objective tumor regressions reported in clinical trials of various antibodies blocking the PD-1 and PD-L1 immune checkpoints validate the importance of targeting this pathway in melanoma therapy. Ongoing investigations into pharmacodynamics and potential biomarkers of response are designed to reveal the basis for immunological heterogeneity among different patients, and among diverse tumor sites in individual patients, to enable the optimal clinical development of these drugs.
Supported by research grants from Bristol-Myers Squibb, the National Institutes of Health, Stand Up 2 Cancer, the Barney Family Foundation, the Laverna Hahn Charitable Trust, Moving for Melanoma of Delaware, and the Melanoma Research Alliance.
Citation Format: Suzanne L. Topalian. Response and resistance PD-1 pathway blockade. [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 IA19.
Abstract IA20: Targeting AMPK signaling in melanoma
Authors: Zheng Bin 
Published: July 2015

Abstract
Biguanides, such as the diabetes therapeutics metformin and phenformin, have demonstrated anti-tumor activity both in vitro and in vivo. The energy-sensing AMP-activated protein kinase (AMPK) is known to be a major cellular target of biguanides. We have previously reported that AMPK signalling is attenuated by BRAFV600E in melanoma through phosphorylation of LKB1, a major upstream kinase of AMPK. More recently, we have also discovered that BRAF is directly phosphorylated by AMPK, leading to impaired BRAF-KSR1 association and MEK-ERK signalling (Mol Cell, 2013, 52:161). Based on this crosstalk between the AMPK and BRAF signaling pathways, we investigated the anti-tumor effects of combining phenformin with a BRAF inhibitor PLX4720 on the proliferation of BRAF mutated melanoma cells in vitro and on BRAF-driven tumor growth in vivo. Co-treatment of BRAF mutated melanoma cell lines with phenformin and PLX4720 resulted in synergistic inhibition of cell viability, compared to the effects of the single agent alone. Moreover, treatment with phenformin significantly delayed the development of resistance to PLX4720 in cultured melanoma cells. Biochemical analyses showed that phenformin and PLX4720 exerted cooperative effects on inhibiting mTOR signaling and inducing apoptosis. Noticeably, phenformin selectively targeted subpopulations of cells expressing JARID1B, a marker for slow cycling melanoma cells. In contrast, PLX4720 selectively targeted JARID1B negative cells, which represents the majority of cells in the tumors, and spared the JAR1D1B-positive slowing cycling population. Finally, in contrast to their use as single agents, the combination of phenformin and PLX4720 induced tumor regression in both nude mice bearing melanoma xenografts and in a genetically engineered BRAFV600E/PTENnull-driven mouse model of melanoma. These results strongly suggest that significant therapeutic advantage may be achieved by combining AMPK activators such as phenformin with BRAF inhbitors for the treatment of melanoma.
Citation Format: Bin Zheng. Targeting AMPK signaling 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 IA20.