tbuckley/cabot-search huggingface dataset:
Abstract 3518: Piperlongumine, a novel treatment option to overcome BRAF inhibitor resistance in melanoma
Authors: Sharavan Ramachandran, Neel Fofaria, Sanjay Srivastava
Journal: Cancer Research (2018)

Abstract Tumor cell metabolism is a hallmark of chemoresistance and its role has been well-defined in BRAF inhibitor resistance in melanoma. Melanoma cells are highly proliferative and are shown to develop addiction towards the metabolic pathways like glycolysis and mitochondrial respiration to meet energy demands. Melanoma cells predominantly utilize cytosolic aerobic glycolysis or Warburg effect to develop resistance towards BRAF inhibitors (vemurafenib and dabrafenib). Our observations indicated that vemurafenib resistant cells possessed 1.5 fold higher extra-cellular acidification rate (ECAR), an indicator of glycolysis when compared to sensitive cells. We also observed that STAT3, a known regulator of glycolysis was up-regulated in A375 and SKMEL28 BRAF inhibitor resistant cells when compared to the parental cell line. In addition, LDH-A, a key glycolytic enzyme was significantly overexpressed in A375 vemurafenib resistant cells when compared to its parental counterpart. Consequently, we observed that vemurafenib and dabrafenib treatment induces the expression of STAT3 in A375 and SKMEL-28 melanoma cells. Our results showed that piperlongumine inhibits the survival of A375 vemurafenib resistant (A375VR) melanoma cells. Our observations indicated that the combination of piperlongumine with vemurafenib and dabrafenib shows synergistic effects by suppressing 75% - 85% of cell survival when compared to vemurafenib/dabrafenib and piperlongumine (25% - 45%) treatment alone in A375 and SKMEL-28 BRAF inhibitor resistant melanoma cells. Moreover, the combination of piperlongumine with vemurafenib or dabrafenib induced 2-8 fold apoptosis when compared to vemurafenib/dabrafenib and piperlongumine treatment alone in A375 and SKMEL-28 BRAF inhibitor resistant melanoma cells. Piperlongumine treatment reduced the ECAR (glycolysis) in a concentration dependent manner after 12h of treatment in A375VR cells and suppressed nearly 50% of ECAR parameters glycolysis and glycolytic capacity. Treatment of A375VR cells with piperlongumine for 48h inhibited the expression of LDH-A and its upstream regulators pSTAT3 (Y705), β-catenin, c-Myc and HIF-1α as evaluated by western blot. In addition, oral administration of piperlongumine and vemurafenib combination suppressed 86% of tumor growth when compared to vemurafenib treatment. Taken together, our study thus indicate that piperlongumine potentiates the effects of BRAF inhibitors by inhibiting Warburg effect and its upstream regulators. [Supported in part by R01 grant CA129038, awarded to (S.K.S) by the National Cancer Institute. Citation Format: Sharavan Ramachandran, Neel Fofaria, Sanjay Srivastava. Piperlongumine, a novel treatment option to overcome BRAF inhibitor resistance in melanoma [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 3518.
Abstract 5199: Microenvironmental control of breast cancer subtype elicited by paracrine platelet-derived growth factor-CC signaling
Authors: Matteo Bocci, Michael Bartoschek, Pernilla Roswall, Kristian Pietras
Journal: Cancer Research (2018)

Abstract Aim: Breast tumors of the basal-like, hormone receptor-negative subtype, remain an unmet clinical challenge, as patients exhibit the highest recurrence rate, the shortest time to recurrence and the worst overall survival rate due to a paucity of therapeutic targets. Also, as tumors develop, the surrounding microenvironment co-evolves into an activated state through continuous paracrine communication, creating a dynamic signaling circuitry that promotes malignant progression. Thus, novel treatment approaches that also include the targeting of stromal components are urgently required. Methods: We used experimental mouse models of cancer (transgenic, syngeneic, human cell lines and patient-derived xenografts) for knockout studies and preclinical trials, immunostaining, in vitro assays, western-blot, gene expression analysis and RNA-sequencing, patient cohorts, data mining and bioinformatics analysis. Results and discussion: We identified a paracrine crosstalk between cancer cells expressing platelet-derived growth factor (PDGF)-CC and cancer-associated fibroblasts (CAFs) expressing the cognate receptors in human basal-like mammary carcinomas. In translational efforts, we found that PDGF-CC expression in the malignant epithelium of breast cancer was associated with a hormone receptor-negative state. We then generated a mouse model to characterise the functional role of PDGF-CC in tumorigenesis. Moreover, we identified and validated factors secreted by CAFs to maintain a basal-like phenotype, e.g. Stanniocalcin (STC)-1, Hepatocyte Growth Factor (HGF) and Insulin Growth Factor Binding Protein (IGFBP)-3. Genetic or pharmacological targeting of PDGF-CC in experimental mouse models resulted in the transcriptional reprogramming and conversion of basal-like breast tumors into a luminal-like state characterised by Estrogen Receptor (ER)-α positivity, that conferred sensitivity to endocrine therapy in previously intrinsically unresponsive tumors. Conclusions: Specification of the basal-like subtype of breast cancer is under microenvironmental control and therapeutically actionable in order to achieve sensitivity to endocrine therapy. Our work sheds light on previously unknown mechanisms that define breast cancer subtype and has significant therapeutic implications for patients with basal-like breast tumors. Citation Format: Matteo Bocci, Michael Bartoschek, Pernilla Roswall, Kristian Pietras. Microenvironmental control of breast cancer subtype elicited by paracrine platelet-derived growth factor-CC signaling [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 5199.
Abstract 5060: Exosomes derived from HIV-infected T cells promote cancer cell growth and progression via the HIV TAR RNA
Authors: Lechuang chen, Zhimin Feng, Hong Yue, Scott Sieg, Bingcheng Wang, Alex Y. Huang, Ge Jin
Journal: Cancer Research (2018)

Abstract Background: Residual and persistent HIV replication plays key roles in the development and progression of non-AIDS-defining cancers (NADCs), including head and neck as well as lung cancers. However, the underlying mechanisms remain elusive. HIV-infected T cells produce immunologically active exosomes to influence intercellular communication and regulate immune response at both local and distant sites, thus potentially contribute to enhanced risk for tumorigenesis. We investigated the role of exosomes derived from HIV-infected T cells in growth and progression of head and neck cancer (HNC) and lung cancer cells. Methods: Exosomes were isolated from conditioned media of HIV-1-infected J1.1 cells and non-infected control Jurkat cells using the ultracentrifugation protocol. Exosomes were validated by western blotting for tetraspanins (CD9, CD63 and CD81) and transmission electron microscope. The acetyl-CoA acetylcholinesterase (AChE) enzyme activity was used to quantify exosomes. HNC cells UM-SCC-104, TR146, HSC3, SCC9 and lung cancer cells NCI-H1299, NCI-H1437 were treated with exosomes for cell growth, migration and gene expression in vitro and in vivo. Exosome HIV RNA was determined by quantitative RT-PCR. Results: Exosomes isolated from HIV-1-infected T cells, but not those from normal control T cells, significantly stimulated HNC and lung cancer cell proliferation, migration and invasion in vitro. Exosomes purified from plasma of HIV-positive individuals also stimulated proliferation of cancer cells. HNC and lung cancer cells co-inoculation with exosomes from HIV-1-infected T cells into nude mice promoted tumor growth compared to those from non-HIV control T cells. Mechanistically, we found that the HIV trans-activation response (TAR) element RNA, which exists in excess of other HIV RNAs in exosomes from HIV-1-infected T cells, enhanced cancer cell proliferation and stimulated EGF- and TLR3-inducible gene expression. The TAR RNA mutant with nucleotide replacements in the loop/bulge region failed to induce gene expression. Moreover, co-transfection of the TAR RNA aptamer blocked induction of gene expression induced by HIV-positive T-cell exosomes. Conclusion: HIV TAR RNA-containing exosomes derived from HIV-1-infected T cells promote growth and progression of NADCs through interaction with EGFR and TLR3. Citation Format: Lechuang chen, Zhimin Feng, Hong Yue, Scott Sieg, Bingcheng Wang, Alex Y. Huang, Ge Jin. Exosomes derived from HIV-infected T cells promote cancer cell growth and progression via the HIV TAR RNA [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 5060.
Abstract 1256: Lynch syndrome premalignancy upregulates immune checkpoints independently from neoantigen and mutational rates
Authors: Kyle Chang
Journal: Cancer Research (2018)

Abstract Colorectal carcinomas in Lynch syndrome (LS) patients arise in a background of mismatch repair deficiency that leads to the accumulation of high numbers of mutations and neoantigens, thus causing infiltration by abundant tumor-infiltrating lymphocytes, a unique immune profile with upregulation of immune checkpoints, and response to immunotherapy. However, there is still a knowledge gap with regards to the level of immune activation and the assessment of mutation and neoantigen rates in LS premalignancy. We performed whole transcriptomic analysis using next-generation sequencing in a total of 28 colorectal polyps (26 tubular adenomas and 2 hyperplastic polyps) from 21 patients diagnosed with LS (n=11) and FAP (n=10) as comparators and a model of mismatch repair proficient colorectal premalignancy.Overall, LS polyps presented with low mutational and neoantigen rates but displayed a strinking immune activation profile characterized by CD4 T-cells, proinflammatory (TNF, IL12) and checkpoint molecules (LAG-3 and PD-L1). This immune profile was independent of mutational rate, neoantigen formation, and MMR status. In addition, we identified a small subset of LS polyps with high mutational and neoantigen rates that were secondary to accumulation of indels enriched for deregulation of DNA damage repair pathways (ATM and BRCA1 signaling). Our findings challenge the canonical model, based on the observations made in carcinomas, that emphasizes a dependency of immune activation on the acquisition of high levels of mutations and neoantigens, thus opening the door to the implementation of immune checkpoint inhibitors and vaccines for cancer prevention in Lynch syndrome. Citation Format: Kyle Chang. Lynch syndrome premalignancy upregulates immune checkpoints independently from neoantigen and mutational rates [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 1256.
Apoptosis Induced by Inhibition of Cyclic AMP Response Element–Binding Protein in Vascular Smooth Muscle Cells
Authors: TomotakeTokunou, ReiShibata, HisashiKai, ToshihiroIchiki, TakashiMorisaki, KaeFukuyama, HirokiOno, NaokoIino, SatokoMasuda, HiroakiShimokawa, KensukeEgashira, TsutomuImaizumi, AkiraTakeshita
Journal: Circulation (2003)

Background— The balance between apoptosis and proliferation of vascular smooth muscle cells (VSMCs) is believed to contribute to the vascular remodeling process. Cyclic AMP response element–binding protein (CREB) is a critical transcription factor for the survival of neuronal cells and T lymphocytes. However, the role of CREB in blood vessels is incompletely characterized. Methods and Results— Nuclear staining with Hoechst 33258 or propidium iodine showed an increase in apoptotic cells with activation of caspase-3 in VSMCs infected with adenovirus expressing the dominant-negative form of CREB (AdCREBM1). Basal expression of Bcl-2 and Bcl-2 promoter activity were decreased by infection with AdCREBM1. Immunohistochemistry revealed that CREB was mainly induced and activated in the neointimal α-smooth muscle actin–positive cells of rat carotid artery after balloon injury. Infection with AdCREBM1 suppressed neointimal formation (intima-media ratio) by 33.8% after 14 days of injury, which was accompanied by an ...
Abstract 575: Prediction of genomic instability in triple-negative breast cancer patients utilizing a CTC phenotype classifier
Authors: Adam Jendrisak, Nadia Ebrahim, Angel Rodriguez, Jerry Lee, Ramsay Sutton, Yipeng Wang, Mark Landers, Ryan Dittamore
Journal: Cancer Research (2018)

Abstract Background: Genomic scars and HRD gene mutations are biomarkers for PARP inhibitor (PARPi) and platinum agent therapy response in breast cancer. Tests for these markers are usually performed by next-generation sequencing (NGS) of tumor tissue or circulating tumor DNA (ctDNA) and have limitations such as sample accessibility/availability and under-sampling due to inter/intratumor heterogeneity. Previously we predicted genomic instability (GI) using CTC phenotypic features without the use of NGS in metastatic castration-resistant prostate cancer (mCRPC) pts with high accuracy (&amp;gt;76%) (ASCO 2016). In addition, patients with phenotypically predicted GI (pGI) CTCs had significantly better PSA responses on abiraterone + veliparib (92%) vs. abiraterone alone (23%) (ESMO 2016), and also responded better to platinum agents vs. taxane agents (ESMO 2017). Here, we sought to develop and analytically validate an algorithm for predicting CTC pGI in TNBC. Methods: Training set: 521 CTCs from 26 mCRPC pts were detected with the Epic Sciences CTC platform and analyzed for 19 phenotypic digital pathology features, including protein expression and cell morphology. The same CTCs were single-cell sequenced for the number of large-scale transitions (LSTs) as an indicator of GI. A linear regression algorithm to predict GI by CTC phenotype was developed, cross validated, and utilized to generate a CTC pGI score. Test set: 114 CTCs from 8 TNBC blood samples, median of 8 CTCs/pt, were sequenced for GI and phenotypically predicted for pGI. Results: Analytical cutoff for GI (8.74) was determined in the mCRPC training set by separation of a binomial distribution low vs. high GI scores. pGI cutoff (8.74) was set the same as GI. The training set performance was: sensitivity = 69%, specificity = 83%, accuracy = 77%. In the TNBC test set, pGI vs. GI demonstrated: sensitivity = 86%, specificity = 92%, accuracy = 88%. Conclusions: Previous studies showed that pGI was an analytically validated biomarker with clinical utility to predict PARPi or platinum therapy response in mCRPC pts. Here we show the same test concept can be applied to TNBC. Further analytical validation in a larger cohort is ongoing. The ability to identify PARPi/platinum sensitivity using an IF CTC staining method for CTC phenotype without the use of NGS will help to stratify patients more rapidly, at reduced cost, and aid in the acceleration of drug development. Citation Format: Adam Jendrisak, Nadia Ebrahim, Angel Rodriguez, Jerry Lee, Ramsay Sutton, Yipeng Wang, Mark Landers, Ryan Dittamore. Prediction of genomic instability in triple-negative breast cancer patients utilizing a CTC phenotype classifier [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 575.
Abstract LB-284: Engineering a hypermutant mouse model of NSCLC to modulate immune response
Authors: Olivia C. Smith, Peter M. Westcott, David A. Canner, William M. Rideout, Arjun Bhutkar, Mary C. Beytagh, Tuomas Tammela, Tyler E. Jacks
Journal: Cancer Research (2018)

Abstract Immune checkpoint inhibitors are an exciting new class of cancer therapy with unprecedented response rates, and have shed light on the importance of understanding the immune context of tumors. Despite achieving durable clinical responses for a subset of patients, immune checkpoint therapies produce variable response rates, even within tumor type, suggesting a need for improved understanding of the tumor-immune cell axis. Recent clinical trials using checkpoint blockade against CTLA-4 and PD-1 have underscored the relevance of tumor mutational landscapes in predicting these response rates. For example, non-small cell lung cancer (NSCLC) patients with high mutational burden and PD-L1 expression respond better to anti-PD-1 treatment than those with high PD-L1 expression alone. While genetically engineered mouse models (GEMMs) of cancer are powerful platforms for testing new therapies, existing models fail to recapitulate the mutational burden and signatures of human cancers, limiting their ability to model relevant immune responses. We have therefore used CRISPR-Cas9 to knockout the DNA mismatch repair (MMR) gene Msh2 in the widely-used Kras and P53 mutant (KP) GEMM of NSCLC. Specifically, lentivirus expressing a short guide RNA (sgRNA) targeting Msh2, and Cre-recombinase, is delivered intra-tracheally into KP mice carrying a Cas9 allele. Whole-exome sequencing reveals elevated mutational burdens in Msh2KO tumors, as compared to non-targeted controls, and mutational signatures characteristic of MMR deficient human tumors. Histological characterization indicates elevated T cell infiltration of Msh2KO tumors at early time points, while tumors at later stages show minimal infiltration and appear like immune “cold” human tumors. Our future efforts will test checkpoint blockade therapies combined with immunogenic chemotherapy to facilitate neo-antigen presentation in late stage tumors. Development and characterization of this “hypermutant” model should prove valuable for future preclinical development of immunotherapies in NSCLC. Citation Format: Olivia C. Smith, Peter M. Westcott, David A. Canner, William M. Rideout, Arjun Bhutkar, Mary C. Beytagh, Tuomas Tammela, Tyler E. Jacks. Engineering a hypermutant mouse model of NSCLC to modulate immune response [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 LB-284.
Abstract 16843: Protease-Activated Receptor 4 Improves Cardiac Function in Models of Viral, Ischemic and Dilated Cardiomyopathy
Authors: SilvioAntoniak, NigelMackman
Journal: Circulation (2014)

Introduction: Cardiomyocytes are a major source of protease-activated receptor 4 (PAR4), in the heart. PAR4 activation facilitates a unique signaling pathway in cardiomyocytes through the epidermal growth factor receptor (EGFR) and src kinase in vitro. EGFR signaling is known to mediate survival of cardiomyocytes and enhance antiviral pathways. Hypothesis: Here, we investigated if cardiac PAR4 mediates protective effects in three different heart failure models in vivo. Methods: PAR4-/- mice and wild-type (WT) littermates were compared in models of viral, ischemic or dilated cardiomyopathy. Cardiac injury was analyzed by cardiac troponin I (cTnI) ELISA. Gene expression analyses were performed with ELISA and RT-PCR. Changes in heart dimension and function were evaluated by echocardiography. Results: PAR4 expression was protective in a coxsackievirus B3 (CVB3) viral cardiomyopathy model. PAR4-/- mice had higher cTnI plasma levels compared to WT mice 8d post infection with 10^5 plaque forming units of CVB3 (c...
Abstract 21168: Heart Failure With Preserved Ejection Fraction (HFpEF) Outcomes After Same Hospital Readmission versus Different Hospital Readmission
Authors: Nilay V Patel, ShilpKumar Arora, Sera Sabhrawal, Varun Kumar, Byomesh Tripathi, Ekta Aneja, Kriti Sharma, Mihir Dave, Neil Patel, Sam Setarah, Vishwa Kondoor, Abhishek Mishra, Subir Bhatia, Bhaskar Bharadwaj, Smit Patel, Priti Malik, Umesh Gidwani, Radha Gopalan
Journal: Circulation (2017)

Introduction: Heart failure with preserved ejection fraction(HFpEF) is a syndromemwith limited treatment modalities. Our control over 30 day readmissions and readmission outcomes is limited. Methods: HCUP’s Nationwide Readmissions Database (NRD) from 2013-14 was used for HFpEF related hospitalizations using ICD-9- CM diagnostic code:428.3x in primary diagnosis field. 30-day readmissions were identified and classified into two groups: same-hospital readmissions and different-hospital readmissions. A comparative analysis was conducted focused on three metrics - mortality, length of stay (LOS) and cost of hospitalization. We used hierarchical two-level modeling and propensity score matching to adjust for confounders. Results: Of the 94,988 readmitted patients (age &amp;gt;65 years: 79%, Females: 61.45%) - 76,665 (80.70%) to the same hospital and rest to different hospitals. After adjusting extensive list of confounders, same hospital readmission was associated with better outcomes including in hospital mortality (OR: 0.73, 95% CI: 0.66 - 0.80, p&amp;lt;0.001), LOS (Days: -1.14, 95% CI: -1.31 - -0.97, p&amp;lt;0.001), Cost of care ($: -4208, 95% CI: - 4681 - -3734, p&amp;lt;0.001). For validation of our results, we ran propensity score matching, showed similar results - in hospital mortality (6.23% vs 8.07%), LOS (6.30 ± 0.08 vs 7.47 ± 0.095), Cost of care (14042.7 ± 215.7 vs 18685.4 ± 279.2). Post hoc high-risk subgroup analysis were conducted and showed similar results (Figure). Number needed to treat (for mortality) was 74 patients. Up to ~ 100 million dollars could have been saved over 2 years. Conclusions: Considering scale of problem and limited option to prevent worse outcomes, Simple interventions such as redirecting patient to same hospital as previous admission would be beneficial.
Gynecomastia as a rare symptom in ß-HCG-positive giant-cell tumor of bone GCTOB.
Authors: Arp Klaus Blum
Journal: Journal of Clinical Oncology (2015)

e21501 Background: Extragonadal germcell tumors (EGGCT) in men are a rare form of testicular cancer. They produce the same tumor-markers as testicular cancer, but they have a poor prognosis by IGCCCG . A ß-HCG-positive tumor in men close to the spine is always suspicious of being EGGCT. ß-HCG has hormonal properties and can cause gynecomastia. Giant-cell tumors of bone (GCTOB) are predoninantly found close to the joints of long bones. They ususally to not express any specific tumor-markers and grow by regional destruction. When located at the sacrum patients often can not be cured surgically but need neoadjuvant or palliative therapy using Denosumab. Methods: A 47-year old man presented with painful gynecomastia. An elevation of ß-HCG of 11,7 mIU/ml (norm: < 5) led to urological ultrasound wihout signs for NSGCT or EGGCT. A CT-scan of the thorax and abdomen showed a presacral tumor of 5,5 by 8cm While ventraly smooth it destroyed the ventral sacrum entering the neuroforaminae. A CT-guided biopsie seen be a reference-pathologist showed no markers for a germ cell tumor, excluded a possibly chordoma and showed a giant cell tumor. With hindsight the patient recalled backpain for three years, increasing obstipation for four month and the resection of a giant cell tumor from the right arm at the age of 16. After biopsy obstipation and backpain increased due to fast progression. Results: In this case of an unresectable giant-cell tumor there was a partial response to Denusumab 120 mg s.c. on day 1,8,15 continued monthly with Calcium and Vitamin D added with complete relief of all symptoms within three months. Conclusions: A man presenting with gynecomastia should undergo ultrasound of the testis and a lab-analysis for germcelltumors including AFP, ß-HCG, Estradiol and Prolactin. Even with elevated markers there should be no therapy-decision without a biopsy.