bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2898: Inhibition of HDAC6 as a novel targeted therapy in breast cancer
Authors: Zeleke Tizita Z. , Putcha Preeti , Yu Jiyang , Califano Andrea , Silva Jose M. 
Published: August 2018

Abstract
The identification and use of biomarkers is critical to guided clinical care. Cancer treatment has made use of many biomarkers to determine which therapeutic avenues are adequate for each patient. For example, the use of Trastuzumab is intimately linked to the presence of HER2/NEU amplification in breast cancers. Previous work from our group established the importance of HDAC6 in maintaining the homeostasis of inflammatory breast cancer cells (IBC). We also reconstructed the HDAC6 regulon using gene expression profile signatures from over 900 primary breast cancers to obtain a biomarker that guide the use of HDAC6 inhibitors towards the right patient group. This method identified a regulon of 162 transcripts as a set of transcriptional targets whose expression is affected by HDAC6 master regulator activity. Finally, the expression of all transcripts that are co-regulated by HDAC6 in the breast cancer samples were integrated into a single score termed as the HDAC6 score. Through this work, we established that HDAC6 score is associated with cancer cell response to HDAC6 inhibitor ACY1215.
HDAC6, one of eighteen deactylases, is distinct from all other HDACs as it is located mainly in the cytosol and has non-chromatin substrates such as α-tubulin and HSP90. HDAC6 inhibitors have gained a lot of momentum in the clinic for hematological malignancies and our computational analysis has also revealed that these tumors also exhibit a high HDAC6 score. Therefore, by identifying the HDAC6 score for tumors, we can widen the scope of using HDAC6 inhibitors to a wide range of cancers.
Our increasing understanding of tumor biology has led to the use of combinatorial therapies to fully benefit from cancer therapy. This project will encompass the use of combinatorial therapy containing HDAC6 inhibitors and paclitaxel to demonstrate an increased potential in treating breast cancer. These studies will closely mirror the clinical trial that we are undertaking with our collaborators from Acetylon where metastatic breast cancer patients are being treated using HDAC6 inhibitor ACY1215 in combination with nab-paclitaxel (NCT02632071). This project aims to provide the frame work to utilize for the first time the HDAC6 score as a marker for identifying tumors that will be most susceptible to HDAC6 inhibition in the clinic.
Citation Format: Tizita Z. Zeleke, Preeti Putcha, Jiyang Yu, Andrea Califano, Jose M. Silva. Inhibition of HDAC6 as a novel targeted therapy in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2898.
Abstract 2899: Antitumor activity of CIGB-300, a peptide CK2 inhibitor, in breast cancer models
Authors: Gottardo Maria F. , Capibianco Carla S. , Sidabra Johanna E. , Perera Yasser , Perea Silvio , Alonso Daniel F. , Farina Hernan G. 
Published: August 2018

Abstract
CK2 is a serine-threonine kinase that has been involved in growth, proliferation and cell apoptosis. CK2 has a constitutive expression and it has more than 300 substrates. In recent years, CK2 became an interesting target for anticancer therapies. Inhibition of CK2 showed antitumor activity in different types of cancer. Because breast cancer is one of the main tumor types in which CK2 is overexpressed, we focus on the effect of CK2 inhibition as a modulator of key features of breast cancer cell biology. The aim of the present study was to evaluate the role of inhibition of CK2 by CIGB-300 in murine and human mammary carcinoma cell lines. For this purpose, we evaluated the action of CIGB-300 on viability, apoptosis, cell cycle, clonogenic capacity and migration using three different breast tumor cell lines, MCF7 (positive for estrogen, progesterone and HER2-neu receptors), MDA MB 231 (representative of triple negative tumors) and F3II, a murine mammary carcinoma. As compared the potential of CK2 inhibition in these models we included another chemical inhibitor of the enzyme, CX-4945. Our results showed that CIGB-300 reduced the viability of MDA MB 231 (IC50=120 μM) and MCF-7 (IC50=140 μM) (p&lt;0.05, ANOVA). We observed that in both human and murine cell lines CIGB-300 exerts a pro-apoptotic action (TUNEL assay, p&lt;0.05, χ2) and arrest cell cycle. We also found that the inhibition of CK2 by CIGB-300 decreased the clonogenic capacity and migration of F3II, MCF-7 and MDA-MB-231 (p&lt;0.05, ANOVA). In vivo studies using the syngeneic F3II breast cancer model in BalB/c mice showed a decrease in the number of lung metastases in mice treated systemically with CIGB-300 after primary tumor surgery (Mann Whitney test, p&lt;0.05). However, CK2 inhibition did not affect the growth of local recurrences. Also, intravenous administration of CIGB-300 decreased lung metastasis development of F3II cells. These results demonstrate an antimetastatic effect of CIGB-300 in a systemic inoculation model after surgical removal of primary tumors. In this work we demostrated the antitumor effect of CIGB-300 in breast cancer models such as those reported in myeloid leukemia, lung and cervix and head cancer.
Citation Format: Maria F. Gottardo, Carla S. Capibianco, Johanna E. Sidabra, Yasser Perera, Silvio Perea, Daniel F. Alonso, Hernan G. Farina. Antitumor activity of CIGB-300, a peptide CK2 inhibitor, in breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2899.
Abstract 2903: A novel compound induces synthetic lethality for p53 mutations in osteosarcoma cells
Authors: Iwakuma Tomoo , Parrales Alejandro , McDonald Peter , Roy Anuradha , Braun Mitchell W. , Schoenen Frank J. , Wang Jenna , Rogers Steve , Broward Melinda , Bruns Tyce , Anant Shrikant , Dixon Dan A. , Meyer Fred , Chastain Katherine M. , Thamm Douglas H. , Weir Scott J. , Neville Kathleen , Fulbright Joy M. 
Published: August 2018

Abstract
Osteosarcoma is the second-highest cause of cancer-related death in children and adolescents. Despite advances in chemotherapy and surgery, the survival rate for metastatic osteosarcoma remains below 30% for the last three decades. Discovery of new chemotherapy agents would be crucial for improving outcomes of osteosarcoma patients. Here, using high-throughput screening, we have found a new compound, called 2-{2-[(3,5-dimethoxybenzyl)sulfanyl]-1,3-thiazol-4-yl}-N-(2-thienylmethyl)acetamide (referred to as KU0171032), as an inducer of apoptosis in various canine and human osteosarcoma cells. This compound shows minimal effects on non-transformed osteoblast and fibroblast cells. Intriguingly, KU0171032-induced apoptosis is more robust in osteosarcoma cells having mutant p53 or null for p53, as compared to cells with wild-type p53. Knockdown of wild-type p53 in U2OS and SJSA-1 cells significantly enhances sensitivity to KU0171032 with increase in DNA damage and caspase-3 cleavage. Moreover, KU0171032 significantly reduces in vivo tumor growth of osteosarcoma cells with p53 knockdown or carrying mutant p53. Our results strongly suggest that KU0171032 shows synthetic lethality with p53 mutations in osteosarcoma cells. Given that loss of p53 activity is frequent event in many cancer types including osteosarcoma while normal cells usually retain wild-type p53, this compound could be used to develop novel therapeutic strategies that capitalize on vulnerabilities in osteosarcoma and other types of cancer.
Citation Format: Tomoo Iwakuma, Alejandro Parrales, Peter McDonald, Anuradha Roy, Mitchell W. Braun, Frank J. Schoenen, Jenna Wang, Steve Rogers, Melinda Broward, Tyce Bruns, Shrikant Anant, Dan A. Dixon, Fred Meyer, Katherine M. Chastain, Douglas H. Thamm, Scott J. Weir, Kathleen Neville, Joy M. Fulbright. A novel compound induces synthetic lethality for p53 mutations in osteosarcoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2903.
Abstract 2923: BET inhibitors synergize with HDAC inhibitors and downregulate expression of interferon response genes in glioblastoma
Authors: Gusyatiner Olga , Pham Minh Diêu Thanh , Lei Yvonne , Park Jungyeon , Bady Pierre , Delorenzi Mauro , Hegi Monika 
Published: August 2018

Abstract
Glioblastoma (GBM) is the most aggressive brain tumor in adults with a median overall survival of only 15 months. Despite multiple attempts, single agent therapies have failed in clinical trials and new strategies for combination treatments are urgently needed.
Here, our aim was to predict rational combination therapies with BET inhibitors (BETi) that target bromodomain and extra-terminal tail (BET) proteins and are currently evaluated as anti-cancer drugs. In order to identify BETi-induced vulnerabilities in cancer relevant pathways that may be targeted with a second drug, we obtained differential expression profiles of glioma sphere lines (GS-lines) treated with the BETi JQ1. Gene set enrichment analysis revealed several significantly disturbed pathways that included IFN-alpha response genes and signatures of response to histone deacetylase inhibitors (HDACi).
In order to validate the observed down regulation of the interferon response gene signature, we primed the GS-lines with IFN-alpha and confirmed that interferon-stimulated genes (ISGs), such as MX1, OAS1, and CD274 are down regulated after a 4-hour exposure to JQ1. Importantly, the levels of pSTAT1 in the nucleus remained unchanged upon JQ1 treatment, suggesting that JQ1 was acting directly on the transcriptional level of ISGs and not on the canonical JAK-STAT pathway. Similar results were obtained in adherent GBM cell lines that constitutively express ISGs. Moreover, in U87MG orthotropic xenografts in mice, a single i.p. injection of JQ1 downregulated OAS1 and CD274 expression. Currently we are studying the mechanism of how BETi represses transcription of ISGs by chromatin immuno-precipitation.
Finally, we show that HDACi and JQ1 synergize to reduce cell viability of GS-lines in vitro. Further experiments will test HDACi and BETi drug combinations in mouse orthotopic xenografts of GS-lines.
Citation Format: Olga Gusyatiner, Minh Diêu Thanh Pham, Yvonne Lei, Jungyeon Park, Pierre Bady, Mauro Delorenzi, Monika Hegi. BET inhibitors synergize with HDAC inhibitors and downregulate expression of interferon response genes in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2923.
Abstract 2925: Tandem targeting of poly (ADP-ribose) polymerase (PARP) and epidermal growth factor receptor (EGFR) as a novel strategy for enhancing radio- and chemosensitivity of refractory tumors
Authors: Rupp Martin , Mouhri Zhor Senhaji , Stochaj Ursula , Jean-Claude Bertrand 
Published: August 2018

Abstract
Poly (ADP-ribose) polymerase (PARP) inhibitors are a novel therapeutic approach for the selective targeting of tumours with BRCA1/2 hereditary deficiencies. BRCA1/2 are two key proteins involved in homologous recombination (HR) repair. Although the therapeutic benefit of PARP inhibitors has now been proven in the clinic in patients with BRCA1/2 mutations, much effort has been deployed to expand the use of PARP inhibitors beyond tumours harbouring inherited deficiencies in HR- mediated DNA repair. Several combination modalities with agents that can induce HR deficiency and exploit the concept of “contextual synthetic lethality” have been reported for PARP inhibitors. Here we exploited the contextual synthetic lethality between PARP and the epidermal growth factor receptor (EGFR) to design and synthesize a novel dual EGFR targeted PARP inhibitor, termed ZSMR06. The results showed that: a) ZSMR06 is capable of inhibiting EGFR and PARP in whole cells in the nanomolar range (36-63 nM); b) it was selectively potent against BRCA2 mutant and EGFR expressing isogenic cells; c) as monotherapy, ZSMR06 was extremely potent with growth inhibitory activities superior to that of an equimolar combination of olaparib (a clinical PARP inhibitor) and gefitinib (a clinical EGFR inhibitor) in a large panel of tumour cell lines; d) ZSMR06 strongly potentiated the effect of temozolomide (TMZ) and induced significantly stronger (p&lt;0.05-0.001) growth inhibition than olaparib + TMZ combination in cells expressing O6-methylguanine-DNA methyltransferase (MGMT), an enzyme that confers a robust resistance to TMZ; e) ZSMR06 selectively potentiated TMZ on EGFR expressing cells; f) it was able to strongly sensitize bladder cancer cells to radiation (DMF50= 2.96-9.5). These results in toto showed that ZSMR06 due to its dual mechanism of action is capable of behaving as a strong potentiator of TMZ and radiation in resistant cells. Its potency in non-BRCA1/2 mutant tumour cells indicates that it may be the first prototype of hybrid molecules capable of expanding the use of PARP inhibition beyond BRCA1/2 mutations.
Citation Format: Martin Rupp, Zhor Senhaji Mouhri, Ursula Stochaj, Bertrand Jean-Claude. Tandem targeting of poly (ADP-ribose) polymerase (PARP) and epidermal growth factor receptor (EGFR) as a novel strategy for enhancing radio- and chemosensitivity of refractory tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2925.
Abstract 2955: A radiomic-based MRI phenotype is uniquely associated with hypermutated genotype in gliomas
Authors: Hassan Islam , Kotrotsou Aikaterini , Matsuoka Carlos Kamiya , Alfaro-Munoz Kristin D. , Elshafeey Nabil , Shafei Nancy El , Zinn Pascal O. , Groot John F. de , Colen Rivka R. 
Published: August 2018

Abstract
INTRODUCTION Hypermutation is the excessive accumulation of DNA mutation in cancer cells. This specific hypermutated genotype has been reported in low and high grade gliomas, specifically post-temozolomide treatment and is associated with treatment-resistance. Herein, we sought to identify an imaging-based signature for hypermutated gliomas using a radiomics-based approach.
MATERIALS AND METHODS In this IRB-approved retrospective study, we analyzed a total of 101 patients with primary gliomas from the University of Texas MD Anderson Cancer Center. Next generation sequencing (NGS) platforms (T200 and Foundation 1) were used to determine the Mutation burden status in post-biopsy (stereotactic/excisional). Patients were dichotomized based on their mutation burden; 77 hypomutated (&lt;30 mutations) and 24 hypermutated (&gt;=30 mutations or &lt;30 with MMR gene or POLE/POLD gene mutations). Radiomic analysis was performed on the conventional MR images (FLAIR and T1 post-contrast) obtained prior to tumor tissue surgical sampling; and a total of 2480 rotation-invariant radiomic features were extracted using: (i) the first-order histogram and (ii) grey level co-occurrence matrix. The Maximum Relevance Minimum Redundancy technique was used to select the most relevant radiomic features. ROC analysis and leave-one-out cross-validation (LOOCV) were used to assess the performance of the Support Vector Machine (SVM) classifier as and AUC, Sensitivity, Specificity, and p-value were obtained.
RESULTS We found 100 radiomic features that can discriminate between hypermutated versus hypomutated gliomas, AUC 96.3% (CI: 90.2%-98.9%), Sensitivity 100%, Specificity 95%, p-value=3.769e-6.
CONCLUSION Hypermutated gliomas has a unique radiomic quantitative signature that can be used to predict mutation burden regardless of tumor grade or histopathology.
Citation Format: Islam Hassan, Aikaterini Kotrotsou, Carlos Kamiya Matsuoka, Kristin D. Alfaro-Munoz, Nabil Elshafeey, Nancy El Shafei, Pascal O. Zinn, John F. de Groot, Rivka R. Colen. A radiomic-based MRI phenotype is uniquely associated with hypermutated genotype in gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2955.
Abstract 2956: Mechanisms of resistance for osimertinib for patients with EGFR-mutant lung cancer: MD Anderson Cancer Center single institution experience with osimertinib resistance
Authors: Le Xiuning , Negrao Marcelo Vailati , Nilsson Monique , Robichaux Jacqulyne , Roarty Emily , Rinsurongkawong Waree , Glisson Bonnie , Zhang Jianjun , Heymach John V. 
Published: August 2018

Abstract
PURPOSE: Osimertinib was initially approved for treating epidermal growth factor receptor (EGFR) T790M positive non-small cell lung cancer (NSCLC), and recently is moving forward as the first-line treatment for EGFR sensitizing mutation positive NSCLC. However, the types and frequencies of resistance mechanisms to osimertinib have been incompletely described, and currently there are no guidelines for managing these patients. We evaluated clinical and genetic characteristics of patients who received osimertinib for EGFR-mutant NSCLC. We also provide treatment experience after progression on osimertinib.
PATIENTS AND METHODS: Using the MD Anderson Lung Cancer Moon Shot GEMINI database, we identified patients treated with osimertinib and performed clinical outcome analysis. Molecular profiling analysis was performed at the time of progression when available.
RESULTS: Eighty two patients were identified. Median PFS on osimertinib was 8.8 months (95% CI, 6.7 to 10.9). Fifty three of the 82 patients had disease progression on osimertinib. Among them, 30 had molecular profiling upon progression. Other than two cases with germline T790M, 11 cases preserved and 17 cases lost T790M mutation. In T790M preserved cases, tertiary mutations of C797S (5 cases) and L792H (2 cases) in EGFR gene, as well as MET amplification (4 cases), were the most common mechanisms of resistance. In T790M lost cases, 12 cases were without known resistance mechanisms. Upon progression, osimertinib was continued in 34 of 51 patients and 17 (50%) of them received local consolidation radiation. The osimertinib continued patients had longer PFS2 compared to the patients who discontinued on osimertinib upon first progression.
CONCLUSION: T790M loss is common (61%) in osimertinib resistance cases. In T790M-preserved cases, tertiary mutation within EGFR was the most common mechanism of resistance. MET amplification was observed in both T790M preserved and loss cases. In T790M loss cases, the mechanisms of resistance were mostly EGFR independent, highlighting the importance of understanding T790M-negative resistance mechanisms in the osimertinib era.
Citation Format: Xiuning Le, Marcelo Vailati Negrao, Monique Nilsson, Jacqulyne Robichaux, Emily Roarty, Waree Rinsurongkawong, Bonnie Glisson, Jianjun Zhang, John V. Heymach. Mechanisms of resistance for osimertinib for patients with EGFR-mutant lung cancer: MD Anderson Cancer Center single institution experience with osimertinib resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2956.
Abstract 298: Identifying mechanisms of anti-apoptotic adaptation to enhance BAX activation and overcome resistance to apoptosis
Authors: Lopez-Arroyo Andrea G. , Gavathiotis Evripidis 
Published: August 2018

Abstract
The BCL-2 protein family includes both pro- and anti-apoptotic proteins, which have a central role in regulating apoptosis during tumor formation and in response to chemotherapy. Cancer cells can evade apoptosis through upregulation of the BCL-2 anti-apoptotic proteins and/or the downregulation or inhibition of the BCL-2 pro-apoptotic proteins. BAX is a crucial pro-apoptotic BCL-2 family protein that upon activation translocates from the cytosol to the mitochondria to execute mitochondrial outer membrane permeabilization, the “point of no return” for mitochondrial apoptosis. BH3 mimetics, small molecules that have been developed to bind specific anti-apoptotic BCL-2 proteins, such as Venetoclax, have shown efficacy in hematologic cancers but generally are less effective in solid tumors. Here we explored a panel of non-small cell lung cancer (NSCLC) cell lines for elucidating their mechanism of anti-apoptotic adaptation and identify novel therapeutic strategies to overcome resistance to apoptosis. We used the BH3 profiling approach in NSCLC cell lines, as a tool to understand addiction to specific BCL-2 family members, and identified cells that depend on one or more anti-apoptotic proteins for their survival. Furthermore, these cell lines have low expression levels of the activators BH3-only proteins suggesting that downregulation of BH3-only proteins could be a second apoptotic block. Using size-exclusion chromatography of cytosolic cellular extracts we found that NSCLC cell lines contain BAX in dimeric conformation, which is previously characterized to provide resistance to BAX activation, suggesting that this could be a third factor increasing the apoptotic threshold. Our laboratory recently developed a lead BAX activator small molecule, BTSA1, that mimics BIM BH3 helix and interacts with the BAX activation site inducing apoptosis in vitro and in vivo in hematological cancers. We hypothesized that availability of increased amounts of cytosolic BAX monomers in addition to direct BAX activation by BTSA1 would be sufficient to broadly overcome resistance to apoptosis in NSCLC cells. To systematically identify such mechanisms, we have performed combinatorial high-throughput screens using a library of FDA-approved and investigational chemotherapeutic drugs. We identified drugs that significantly enhanced apoptosis when are combined with direct BAX activation. Our work highlights three different mechanisms of anti-apoptotic adaptation and resistance in NSCLC and provides novel pharmacological strategies that may lead to effective therapies for cancer patients.
Citation Format: Andrea G. Lopez-Arroyo, Evripidis Gavathiotis. Identifying mechanisms of anti-apoptotic adaptation to enhance BAX activation and overcome resistance to apoptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 298.