bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-181: KLF4 suppresses T-cell acute lymphoblastic leukemia by inhibiting the stress kinase MAP2K7 pathway
Authors: Shen Ye , Park Chun Shik , Suppipat Koramit , Mistretta Toni-Ann , Puppi Monica , Horton Terzah , Rabin Karen , Lacorazza Daniel 
Published: July 2016

Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with the highest incidence of relapse of any pediatric ALL. A minimal two-hit model of leukemogenesis suggests that an initial genetic driver transforms hematopoietic progenitor cells into LICs, whereas a secondary genetic alteration would endow LICs with proliferative and survival advantages. Although most T-ALL patients exhibit activating mutations in NOTCH1, the cooperating genetic events required to accelerate onset of leukemia and worsen disease progression are largely unknown. Here, we show that low levels of the transcription factor KLF4 in children with T-ALL were associated with methylation of its promoter. Consistent with a tumor suppressor function, loss of KLF4 accelerated the development of NOTCH1-induced T-ALL in mice by enhancing the G1-to-S transition and promoting the expansion of leukemia-initiating cells that are responsible for chemoresistance and relapses. Mechanistically, KLF4 represses the gene encoding the kinase MAP2K7, and thus loss of KLF4 activates MAP2K7 and downstream effector JNK both in murine model of T-ALL and lymphoblasts from pediatric patients with T-ALL. Furthermore, pharmacological inhibition of JNK reduced leukemia burden in a xenograft model of human T-ALL and small molecule inhibitors exhibited anti-leukemic properties in patient-derived xenograft cells. In summary, our findings demonstrate a novel tumor suppressor function of KLF4 in a T-ALL mouse model and in pediatric T-ALL and support a model of leukemia inhibition by repression of the stress kinase MAP2K7 and its downstream targets JNK, c-JUN, and ATF2. In addition, our study provides proof-of-principle pre-clinical data supporting JNK inhibition as a potential targeted therapy for T-ALL and prompts future studies in high-risk T-ALL patients with refractory and relapsed disease.
Citation Format: Ye Shen, Chun Shik Park, Koramit Suppipat, Toni-Ann Mistretta, Monica Puppi, Terzah Horton, Karen Rabin, Daniel Lacorazza. KLF4 suppresses T-cell acute lymphoblastic leukemia by inhibiting the stress kinase MAP2K7 pathway. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-181.
Abstract LB-197: Bispecific T-cell engagers: evaluation of circulating tumor-associated antigen levels and pharmacokinetics
Authors: Gilbert Amy E. , Avilion Ariel , Doherty David , Li Shyun , Bailis Julie , Rock Dan 
Published: July 2016

Abstract
Immunotherapeutic approaches to activate patient T cells against cancer have emerged as a promising clinical strategy for many cancer types. One critical consideration for immune activating therapies is to establish efficacious and tolerable dosing limits. The conveyed estimate of the predicted therapeutic window could be impacted by presence of circulating tumor associated antigen. Here we evaluate a Bi-specific T cell Engager (BiTE®) directed against CD3 and CDH19, a type II cadherin overexpressed &gt;60% of melanomas. Because, to our knowledge, the shedding of CDH19 was unknown we developed an immunoassay to detect soluble CDH19 (sCDH19) in the serum of human donors and patients with metastatic melanoma. Utilizing our immunoassay to detect sCDH19, we measured elevated levels of sCDH19 in the serum of metastatic patients relative to normal donors. Additionally, the potency of this BiTE® using T-cell dependent cellular cytotoxity assays was measured. We next incorporated the range of sCDH19 amounts in patients along with BiTE® potency and present desired pharmacokinetic profiles of this therapeutic. In sum, we report that sCDH19 is present in the circulation of patients with metastatic melanoma and evaluate the impact of sCDH19 on BiTE® pharmacokinetics and human dose projections.
Citation Format: Amy E. Gilbert, Ariel Avilion, David Doherty, Shyun Li, Julie Bailis, Dan Rock. Bispecific T-cell engagers: evaluation of circulating tumor-associated antigen levels and pharmacokinetics. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-197.
Abstract LB-203: Development of a nonclinical model for the assessment of oncology therapy-induced cardiomyopathy
Authors: Hemkens Michelle , Cardenas Samantha , Frey Jessica , Hirakawa Brad , Koza-Taylor Petra , Wang Jianying , Butler Paul 
Published: July 2016

Abstract
With the increasing number of people surviving cancer, patients and doctors are becoming equally focused on the quality of life in survivorship as they are on fighting cancer. Consequently, cardio-oncology has emerged as a new clinical discipline with focus on both the stratification of patients at risk and therapies that pose a cardiovascular risk, eg molecularly targeted therapies including tyrosine kinase inhibitors (TKI). Therefore, nonclinical research should strive not only to detect preclinical drug-induced changes in cardiac structure or function, but also to understand the relevance of these cardiotoxic effects to humans. As is typical for new disciplines, there is an unmet need for early and predictive tools to identify both of these factors. Currently, preclinical assessment of cardiovascular toxicity consists of repeat-dose in vivo toxicity studies focused primarily on histopathological endpoints; additional measures, such as cardiac function and biomarkers of cardiac injury, are not routinely assessed in these studies. Furthermore, analysis of these studies suggests that using young and healthy, drug-naïve animals do not adequately translate the TKI-induced cardiomyopathy phenotype; therefore, new nonclinical models are needed to address this gap. The developed model would ideally be used to assess the preclinical cardiotoxicity of proposed oncology therapies, but may also have utility in assessing cardioprotective therapies for use in cardio-oncology. This poster will propose a new model for studying cardio-oncology nonclinically that includes myocardial transcriptional signatures, strain echocardiography imaging, and pharmacologic (dobutamine) stress challenge. In general, rats with radiotelemetry were treated with vehicle or low dose doxorubicin (2 mg/kg/week IP) for 1 month. Cardiac structure and function at rest and during stress were assessed using strain echocardiography in concert with a weekly dobutamine infusion. Circulating blood biomarkers of cardiac toxicity (eg, NTproBNP, NTproANP, cTropin, and miR-208) were collected weekly and at necropsy. At the end of the study, samples of cardiac tissue were taken from the ventricular apex and were submitted for transcriptional profiling along with standard histopathology. These data as well as recent publications give high confidence in developing a rodent model predictive of drug-induced cardiomyopathy.
Citation Format: Michelle Hemkens, Samantha Cardenas, Jessica Frey, Brad Hirakawa, Petra Koza-Taylor, Jianying Wang, Paul Butler. Development of a nonclinical model for the assessment of oncology therapy-induced cardiomyopathy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-203.
Abstract LB-204: Neoadjuvant Ezh2 inhibition amplifies an inflammatory program and sensitizes Kras-driven NSCLC to anti-NF-κB inhibition
Authors: Serresi Michela , Siteur Bjorn , Cesaroni Matteo , Proost Natalie , Hulsman Danielle , van Lohuizen Maarten , Gargiulo Gaetano 
Published: July 2016

Abstract
Kras mutant non-small cell lung cancer (NSCLC) is a leading cause of death but has limited therapeutic options. We investigated the impact of Polycomb repressive complex 2 (PRC2) inhibitors as single agent or as neoadjuvant treatment for subsequent anti-inflammatory therapy. Using orthotopic grafts, we show that Kras cells highly expressing the PRC2 enzymatic component Ezh2 display sensitivity to its inhibition. Ezh2 inhibition leads to transcriptional amplification of an inflammatory program involving NF-kB. Pharmacological inhibition of Ezh2 rerouted Kras tumor progression towards exploiting PRC2/NF-kB target genes as inferred by in vivo RNAi screen but also enhanced the response of Kras NSCLC to a combination of Nimesulide and Bortezomib. These data suggest that low PRC2 levels in Kras-driven NSCLC promote an epigenetic switch, providing a rationale for exploring a novel therapeutic option in which Ezh2 simultaneously acts as biomarker for therapeutic decision and as a neoadjuvant target for therapy.
Citation Format: Michela Serresi, Bjorn Siteur, Matteo Cesaroni, Natalie Proost, Danielle Hulsman, Maarten van Lohuizen, Gaetano Gargiulo. Neoadjuvant Ezh2 inhibition amplifies an inflammatory program and sensitizes Kras-driven NSCLC to anti-NF-κB inhibition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-204.
Abstract LB-226: The effect of cabozantinib to temozolomide and bevacizumab in patients with heavily pretreated relapsed uterine leiomyosarcoma
Authors: Ikeda Sayaka , Kudoh Kazuya , Sasaki Naoki , Takano Masashi , Goto Tomoko , Kikuchi Ryoko , Kita Tsunekazu , Sakamoto Masaru , Susumu Nobuyuki , Aoki Daisuke , Kouta Hiroko , Kikuchi Yoshihiro 
Published: July 2016

Abstract
Background: Although uterine leiomyosarcoma (ULMS) has been treated with adriamycin, dacarbazine, ifosfamide, gemcitabine, docetaxel, et al, the effect is not satisfactory. We have reported the effect of temozolomide (T) combined with bevacizumab (B) in heavily pretreated relapsed ULMS. In this study, we evaluated the effects of addition of cabozantinib (C) to T and B.
Methods: From 2009 to 2015, total 18 patients (pts) with heavily pretreated relapsed ULMS were enrolled. They were treated with T (80mg/body/day) and B (2mg/kg; days 1, 8 and 15, q4 weeks). Since 2013, we expected better efficacy, nine pts out of 18 pts were treated by adding C (140mg/body/week) which is a c-MET inhibitor (TB, n = 9, CTB, n = 9). Treatment was continued until disease progression and/or unmanageable toxicities. The response and adverse events were evaluated using the response evaluation criteria in solid tumors (RECIST), and common terminology criteria for adverse events (CTCAE) version 3.0.
Results: As shown in Table, three (18%) of 17 pts had complete response (CR), two (12%) had partial response (PR) and eight (47%) had stable disease (SD) for at least three months. The response rate (RR; CR+PR) and clinical benefit rate (CBR; CR+PR+SD&gt;3mo) were 29% and 76%, respectively. The median progression-free survival was 9.6 (3 - 58) months. When compared CTB with TB, CBR was better in CTB (87.5% vs 67%), but the median administration cycles and progression free interval were not improved. Two peritoneal perforation were observed in CTB.
Conclusions:
Not only TB but also CTB showed remarkable effect in heavily pretreated relapsed ULMS. These results warrant further prospective and randomized studies. nCRPRSDPDRR(%)CBR(%)TB/CTB1732842976TB921333367CTB811512587.5
Citation Format: Sayaka Ikeda, Kazuya Kudoh, Naoki Sasaki, Masashi Takano, Tomoko Goto, Ryoko Kikuchi, Tsunekazu Kita, Masaru Sakamoto, Nobuyuki Susumu, Daisuke Aoki, Hiroko Kouta, Yoshihiro Kikuchi. The effect of cabozantinib to temozolomide and bevacizumab in patients with heavily pretreated relapsed uterine leiomyosarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-226.
Abstract LB-227: Truncal activating MAPK and PI3K pathway alterations and exceptional response to dual pathway inhibition in anaplastic thyroid cancer
Authors: Gibson William J. , Ruan Daniel T. , Paulson Vera A. , Barletta Justine A. , Hanna Glenn J. , Kraft Stefan , Calles Antonio , Nehs Matthew , Moore Francis , Taylor-Weiner Amaro , Wala Jeremiah , Zack Travis , Lee Thomas , Fennessy Fiona , Alexander Erik , Thomas Tom , Jäne Pasi , Garraway Levi , Carter Scott , Beroukhim Rameen , Lorch Jochen , Van Allen Eliezer 
Published: July 2016

Abstract
Background: Anaplastic thyroid carcinoma (ATC) is among the most aggressive solid tumors, with a uniformly fatal prognosis. No effective systemic therapies exist. We document a case in which a patient with anaplastic thyroid carcinoma (ATC) failed to respond to either mTOR or combined RAF/MEK inhibition, but experienced a dramatic response when both drug regimens were combined.
Methods and Results: Nine biopsies of the tumor were obtained between diagnosis and autopsy. Multi-region whole-exome sequencing revealed truncal BRAF and PIK3CA mutations, which are known to activate the MAPK and PI3K/AKT pathways respectively. We performed the largest meta-analysis of ATC to date and found a 7.4% co-occurrence of MAPK and PI3K pathway alterations in ATC. We analyzed 5,255 cancer exomes in the Cancer Genome Atlas (TCGA) to determine whether similar cancer genomes occurred outside of anaplastic thyroid carcinoma. We identified 11 tumors with BRAF V600E and non-silent PIK3CA mutations. These results indicate that this genotype occurs in other cancers and may predict response to combined therapy.
Conclusions and future directions: We have identified a patient with ATC who had a dramatic response to combined inhibition of the MAPK and PI3K pathways, whereas neither MAPK inhibition nor PI3K inhibition alone was sufficient to produce tumor regression. These observations suggest that MAPK and PI3K/MTOR pathway blockade represents an effective dual therapy aimed at the founding oncogenic lesions in a subset of ATC.
Citation Format: William J. Gibson, Daniel T. Ruan, Vera A. Paulson, Justine A. Barletta, Glenn J. Hanna, Stefan Kraft, Antonio Calles, Matthew Nehs, Francis Moore, Amaro Taylor-Weiner, Jeremiah Wala, Travis Zack, Thomas Lee, Fiona Fennessy, Erik Alexander, Tom Thomas, Pasi Jäne, Levi Garraway, Scott Carter, Rameen Beroukhim, Jochen Lorch, Eliezer Van Allen. Truncal activating MAPK and PI3K pathway alterations and exceptional response to dual pathway inhibition in anaplastic thyroid cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-227.
Abstract LB-235: IGF-1R/mTOR blockade and mechanisms of resistance in Ewing sarcoma
Authors: LAMHAMEDI CHERRADI Salah-Eddine , Menegaz Brian , Ramamoorthy Vandhana , Ludwig Joseph 
Published: July 2016

Abstract
Ewing sarcoma (ES), the second most common bone cancer in adolescents and young adults, is dependent upon the insulin-like growth factor receptor 1 (IGF-1R) and mammalian target of rapamycin (mTOR) cell-signaling axis for malignancy, survival, and metastasis. Therapies co-targeting IGF-1R and mTOR have demonstrated remarkable, although ephemeral, clinical responses in a subset of ES patients. However, the mechanisms of resistance and applicable strategies for overcoming drug resistance to IGF-1R/mTOR blockade are still undefined.
To elucidate predominant mechanism(s) of acquired drug resistance, while identifying synergistic drug combinations that improve clinical efficacy, we generated ES cell lines resistant to IGF-1R or mTOR targeted therapy. Two small-molecule inhibitors of IGF-1R were chosen, NVP-ADW-742 (IGF-1R-selective) and OSI-906 (a dual IGF-1R/insulin receptor alpha [IR-α] inhibitor). Chronic ridaforolimus exposure led to mTOR-resistant ES cell lines. Reverse phase protein lysate arrays (RPPA) revealed proteomic changes linked to IGF-1R/mTOR resistance and selected proteins were validated using in vitro cell-based assays, xenografts, and human clinical samples.
Novel mechanisms of resistance (MOR) occurred in NVP-ADW-742-, OSI-906-, and ridaforolimus-resistant cells. Of particular clinical relevance given OSI-906's ongoing phase 1b/2 clinical trials, the MOR varied depending upon whether IGF-1R or both IGF-1R and IR-α were targeted. Key proteomic alterations present in vitro also occurred in ES xenografts and human tumor specimens exposed to these agents. Novel synergistic drug combinations (e.g., inhibitors of Mnk and mTOR) were identified in vitro that are currently undergoing prospective validation.
In conclusion, we discovered new druggable targets expressed by chemo-resistant ES cells, xenografts, and relapsed human tumors. Joint suppression of these newfound targets with IGF-1R or mTOR enhanced the antineoplastic effect of IGF-1R/mTOR blockade and suggests the need for in vivo validation.
Citation Format: Salah-Eddine LAMHAMEDI CHERRADI, Brian Menegaz, Vandhana Ramamoorthy, Joseph Ludwig. IGF-1R/mTOR blockade and mechanisms of resistance in Ewing sarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-235.
Abstract LB-238: Direct targeting of oncogenic transcription factors using next-generation oligonucleotides as a novel therapeutic strategy for translocation-positive sarcomas
Authors: Slotkin Emily , Spraggon Lee , Hmeljak Julija , Martelotto Luciano , Somwar Romel , de Stanchina Elisa , Cartegni Luca , Ladanyi Marc 
Published: July 2016

Abstract
Many sarcoma subtypes including Ewing sarcoma (ES), alveolar rhabdomyosarcoma (ARMS), synovial sarcoma (SS), and desmoplastic small round cell tumor (DSRCT), are driven by oncogenic chimeric transcription factors. Outcomes for these diseases remain unacceptably poor despite intensification of standard therapies. Although these translocation positive sarcomas possess well-defined oncogenic drivers, as transcription factors that lack intrinsic enzymatic activity, they have been considered undruggable. We have developed a two-tiered pre-clinical therapeutic program 1) creating and characterizing faithful in vitro and in vivo models of these rare malignancies and 2) designing next generation antisense oligonucleotides (ASOs) to directly target the oncogenic chromosomal translocations underlying these multiple sarcoma subtypes. As proof of principle, we present here the program experience with DSRCT, a rare sarcoma for which there has been an overwhelming paucity of both biological tools for pre-clinical investigation, as well as clinical therapeutic options. We have extensively characterized two new DSRCT cell lines harboring the characteristic oncogenic EWSR1-WT1 t(11;22)(p13;q12) fusion, and have used these tools to develop orthotopic xenograft models. Utilizing these accurate model systems we have designed and evaluated a series of ASO compounds directly targeting the EWSR1-WT1 translocation product. Among the series of ASOs developed, we identified D2A, a selective and potent inhibitor of EWSR1-WT1. In vitro, we have shown D2A to abolish the EWSR1-WT1 fusion product with exquisite specificity in a dose-dependent fashion. D2A similarly exhibits efficacy in vivo, with anti-tumorigenic activity in our pre-clinical models resulting in an 80% reduction in xenograft tumor growth. With the aid of authentic in vitro and in vivo modeling systems, this ASO platform has wide-ranging implications for both biological as well as therapeutic advances.
Citation Format: Emily Slotkin, Lee Spraggon, Julija Hmeljak, Luciano Martelotto, Romel Somwar, Elisa de Stanchina, Luca Cartegni, Marc Ladanyi. Direct targeting of oncogenic transcription factors using next-generation oligonucleotides as a novel therapeutic strategy for translocation-positive sarcomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-238.
Abstract LB-239: Induction of therapeutic soluble decoy EGFR variants by antisense manipulation of RNA processing
Authors: Park Jeong Eun , Spraggon Lee , Cartegni Luca 
Published: July 2016

Abstract
Activation of the receptor tyrosine kinase (RTK) signaling pathways represents a key aspect of tumorigenesis in a broad range of human cancers. Thus, targeting of pathogenic RTKs, mainly with small molecule inhibitors and antibodies, has become an attractive therapeutic approach for cancer therapy. However, resistance by multiple mechanisms, including mutational re-activation of RTK signaling, activation of alternative RTK pathways, EMT transition and others, inevitably occurs over time.
We recently identified a number of novel secreted soluble decoy RTKs isoforms (sdRTKs) generated by an U1-snRNP-dependent alternative intronic polyadenylation mechanism. We therefore developed a novel antisense-based method to effectively activate the expression of these sdRTKs, both in vitro and in vivo. This leads to the generation of endogenous dominant negative variants of RTKs, which can specifically affect the signaling of pathogenic RTKs and therefore provides a novel cancer therapy approach.
Employing specific antisense compounds designed to activate intronic polyA sites, we are able to induce natural truncated EGFR variants that encode its extracellular ligand-binding domain but lack the intracellular signaling domain. These compounds thus can inhibit EGFR signaling by a three fold-mechanism: 1) removal of FL receptor, 2) sequestration of ligands and 3) non-productive dimerization with residual receptors. They are therefore designed to affect signaling both of targeted cells and of bystanders.
Here we will show that, using this approach, we can target EGFR signaling both in vitro and in tumors. Importantly, with this method we can bypass the emergence of resistance typically seen with targeted drug treatments. Further development of this methodology will therefore provide the basis for an exciting novel approach to targeting and inhibiting oncogenic EGFR signaling and other pathways in a variety of cancers.
Citation Format: Jeong Eun Park, Lee Spraggon, Luca Cartegni. Induction of therapeutic soluble decoy EGFR variants by antisense manipulation of RNA processing. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-239.