bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4116: Rapid imaging of tumor cell death in vivo using C2Am
Authors: Neves Andre A. , Brindle Kevin M. 
Published: August 2018

Abstract
Cell death is an important target for imaging the early response of tumors to treatment. We describe here the validation of C2Am, a phosphatidylserine-binding agent based on the C2A domain of synaptotagmin-I, for detecting tumor cell death in vivo.
Methods: The capability of (99m)Technetium-, (111)Indium-labelled or near- infrared fluorophore-labelled derivatives of C2Am for imaging tumor cell death was evaluated in implanted and genetically engineered [Fig.1] mouse models of lymphoma and in a human colorectal xenograft, using single photon CT (SPECT) and planar near-infrared fluorescence imaging, respectively [1,2].
Results: (99m)Tc-C2Am and (111)In-C2Am showed favorable biodistribution profiles, with predominantly renal clearance and low nonspecific retention in the spleen and liver at 24 h after probe administration. (99m)Tc-C2Am and (111In)-C2Am generated tumor-to-muscle ratios in drug-treated tumors of 4.3× and 2.2×, respectively, at 2 h and 7.3× and 4.1×, respectively, at 24 h after administration. A fluorophore-labelled C2Am derivative also showed predominantly renal clearance and high specificity and sensitivity for detecting low levels of tumor cell death (&lt;5%). There was a significant correlation (R=0.9) between fluorescently labelled C2Am binding and histologic markers of cell death (cleaved caspase-3); no such correlation was observed with a site-directed mutant of C2Am that does not bind phosphatidylserine (iC2Am).
Conclusions: Given the favorable biodistribution profile of radiolabelled C2Am derivatives, and their ability to produce rapid and cell death-specific image contrast, these agents have potential for clinical translation, particularly as PET tracers. We have initiated GMP manufacture and toxicology studies required for a Phase 1 trial.
References:
[1] Neves AA, Xie B, Fawcett S, Alam IS, Witney TH, de Backer MM, Summers J, Hughes W, McGuire S, Soloviev D, Miller J, Howat WJ, Hu DE, Rodrigues TB, Lewis DY, Brindle KM. Rapid Imaging of Tumor Cell Death In Vivo Using the C2A Domain of Synaptotagmin-I. (2017) J Nucl Med. 58:881-887.
[2] Xie B, Tomaszewski MR, Neves AA, Ros S, Hu DE, McGuire S, Mullins SR, Tice D, Sainson RCA, Bohndiek SE, Wilkinson RW, Brindle KM. Optoacoustic Detection of Early Therapy-Induced Tumor Cell Death Using a Targeted Imaging Agent. (2017) Clin Cancer Res. 23:6893-6903.
Citation Format: Andre A. Neves, Kevin M. Brindle. Rapid imaging of tumor cell death in vivo using C2Am [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 4116.
Abstract 412: 8p12 amplification pattern dictates FGFR1 dependency in squamous cell lung cancer
Authors: Malchers Florian , Attekum Martijn Henricus van , Peifer Martin , Thomas Roman Kurt 
Published: August 2018

Abstract
Squamous cell lung cancer (SQLC) is the second most common lung cancer subtype after adenocarcinoma and accounts for 30% of all lung cancer cases. However, in contrast to adenocarcinoma, SQLC lacks therapeutic targets like activating EGFR mutations, ALK or ROS translocations. Besides immune-checkpoint-inhibition a promising treatment option in SQLC is the recurrent amplification of the tyrosine kinase fibroblast growth factor receptor 1 (FGFR1) within the 8p12-p11 region. Thus, small molecules inhibiting FGFRs have been employed to treat FGFR1-amplified SQLC. However, only about 10% of such FGFR1-amplified tumors respond to single agent inhibitor therapy. To investigate the mechanism of FGFR inhibitor resistance in 8p12-p11 amplified SQLC we performed deep genomic and transcriptome sequencing on 53 FGFR1 amplified samples including primary tumors (n=33), patient derived xenografts (n=13) and cell lines (n=7). For 22 of these samples the response to FGFR inhibition was known. We detected frequent breaks within NSD3 (n=3), also known as WHSC1L1, favoring the expression of NSD3-short, which is known to enhance MYC expression. Furthermore, the amplification pattern for all samples was compatible with a breakage-fusion-bridge (BFB) mechanism, showing chromosomal telomeric losses, copy number, and frequent intrachromosomal head to head and tail to tail breaks. Genomic reconstruction of one sample suggests a tandem duplication followed by a BFB mechanism, implying that the BFB mechanism is a later event in tumor genesis. Intrachromosomal tail to tail fusions within a 400kb region close to the FGFR1 open reading frame, have been detected in 75% of patients with a partial response to FGFR inhibitor therapy (3 of 4 patients). A similar break was detected in the FGFR inhibitor sensitive cell line H1581. All samples, which responded to FGFR inhibition (n=9), demonstrated a centered amplification pattern on NSD3 / FGFR1 and excluded amplification of the adjacent disintigrin and metalloproteinase family members (ADAM) genes. In contrast, the main amplification peak of the non-responding samples (n = 13) was centered on ADAM family members, corresponding to an increase in ADAM expression. These data suggest strong relevance of these genes for tumor development and growth, and warrant further investigation.
Citation Format: Florian Malchers, Martijn Henricus van Attekum, Martin Peifer, Roman Kurt Thomas. 8p12 amplification pattern dictates FGFR1 dependency in squamous cell lung 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 412.
Abstract 4120: A novel HDAC-targeted probe for triple-negative breast tumor imaging
Authors: Tang Chu , Du Yang , Tian Jie 
Published: August 2018

Abstract
Purpose: Due to lack of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER-2), there was no specific imaging probes can be applied to detect triple-negative breast cancers (TNBCs). Currently, several lines of evidences support that overexpression of histone deacetylases (HDACs) has been associated with TNBC. Here, we sought to develop HDAC-targeted probe for TNBC imaging.
Experimental Design: The pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) was chosen as the targeting ligand, and was labeled with a near-infrared dye IRDye800CW for the development of HDAC-targeted probe IRDye800CW-SAHA. Subsequently, HDAC binding affinity and specificity of probe IRDye800CW-SelSA to TNBC MDA-MB-231 cells was evaluated by HDAC inhibition assay, flow cytometry and confocal laser microscope experiments. Moreover, the in vivo fluorescence molecular imaging (FMI) was performed to monitor the biodistribution and tumor targeting effects of the probe in MDA-MB-231 tumor xenografts.
Results: The fluorescence probe IRDye800CW-SAHA was successfully developed, and conjugating IRDye800CW to SAHA did not alter the HDAC binding affinity. The cellular uptake and the fluorescence intensity of probe on MDA-MB-231 cells were significantly higher compared to normal MCF-10A cells (P &lt; 0.05). Meanwhile, the cellular uptake of probe can be effectively blocked by co-incubation with SAHA. The in vivo imaging results showed that IRDye800CW-SelSA was able to target tumor rapidly, and the tumor to normal tissue (T/N) fluorescence intensity ratio reached the peak around 12 h (T/N = 3.4).
Conclusions: Our study demonstrated that IRDye800CW-SAHA is an efficient probe for the targeted imaging of TNBC and may possess clinical translation in the future.
CT and YD contributed equally to this work
Citation Format: Chu Tang, Yang Du, Jie Tian. A novel HDAC-targeted probe for triple-negative breast tumor imaging [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 4120.
Abstract 4124: YAP1 fusion proteins mediate oncogenic activity in ependymoma via interaction with TEAD transcription factors
Authors: Pajtler Kristian W. , Okonechnikov Konstantin , Vouri Mikaella , Brabetz Sebastian , Jones David T. , Korshunov Andrey , Capper David , Chavez Lukas , Pfister Stefan M. , Kool Marcel , Kawauchi Daisuke 
Published: August 2018

Abstract
Ependymomas are neuroepithelial tumors of the central nervous system (CNS), presenting in both adults and children but accounting for almost 10% of all pediatric CNS tumors and up to 30% of those in children under 3 years. In a previous study we identified two molecular groups of supratentorial (ST) ependymoma in pediatric patients driven by distinct gene fusions involving either the NF-κB effector RELA or the HIPPO signaling regulator YAP1, designated ST-EPN-RELA and ST-EPN-YAP1, respectively. The lack of adequate models for ST-EPN-YAP1, which predominantly occurs in very young children, has so far hindered the development of effective targeted therapies for these tumors. In an attempt to model this group, the most frequent fusion type, YAP1-MAMLD1, was cloned into a Luciferase-carrying transposable vector. Oncogenicity was subsequently tested using an electroporation-based in vivo gene transfer following injection of the vector into the lateral ventricle of E13.5 wildtype mouse embryos. After birth, YAP1-MAMLD1-expressing tumors, monitored using luciferase-based in vivo bioluminescence imaging, developed rapidly with 100% penetrance, indicating that the fusion alone is sufficient to initiate tumors. To further investigate the role of this fusion in human EPNs, we performed YAP1 ChIP-seq analyses on human ST-EPN-YAP1 and ST-EPN-RELA primary tumors. Despite similar gene expression levels of YAP1 in both molecular groups, our comparative analyses found that putative binding sites of TEADs, transcriptional factors interacting with YAP1, were significantly enriched in identified YAP1 peaks in ST-EPN-YAP1. In vivo validation further confirmed that interaction between YAP1-MAMLD1 and TEADs is crucial for oncogenicity of the fusion, since prevention of YAP1-TEAD binding did not result in tumor formation. Thus, targeting the YAP1-TEAD interaction might represent a promising therapeutic approach for this devastating infant disease.
Citation Format: Kristian W. Pajtler, Konstantin Okonechnikov, Mikaella Vouri, Sebastian Brabetz, David T. Jones, Andrey Korshunov, David Capper, Lukas Chavez, Stefan M. Pfister, Marcel Kool, Daisuke Kawauchi. YAP1 fusion proteins mediate oncogenic activity in ependymoma via interaction with TEAD transcription factors [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 4124.
Abstract 4127: A tumor evolution screen in zebrafish identifies PlexinA1 as a driver of metastasis and growth in human rhabdomyosarcoma
Authors: Welker Alessandra M. , Hayes Madeline N. , Tang Qin , Langenau David M. 
Published: August 2018

Abstract
Relapse and metastasis are major clinical problems facing patients with rhabdomyosarcoma (RMS), a devastating pediatric malignancy of the muscle. Alveolar Rhabdomyosarcoma (ARMS) is characterized by genetic translocations while Embryonal Rhabdomyosarcoma (ERMS) is characterized by Ras pathway activation. Treatment for either RMS subtype requires surgical resection, chemotherapy, and radiation with overall poor prognosis for patients with high-risk features including metastasis and relapse. Thus, there is great interest in elucidating key molecular pathways and genetic factors that are involved in continued RMS growth and tumor maintenance. In the Langenau lab, we utilize a powerful transgenic zebrafish model of kRASG12D- induced ERMS and have recently developed a p53-/- (null) zebrafish model. p53 is one of the most common tumor suppressor genes, and upwards of 1/3 of RMS patients have mutations or Loss-of-Heterozygosity (LOH) of this locus. This model accurately mimics the molecular underpinnings and histopathology of human ERMS and has been used to discover molecular pathways that drive relapse. Using our tp53-/- (null) zebrafish along with large-scale cell transplantation assays, we have assessed metastatic potential of our ERMS tumors following serial passaging and acquisition of new driver mutations. Specifically, we performed a tumor evolution screen using serial engraftment of ERMS into recipient fish followed by RNA sequencing to discover novel pathways that are associated with elevated tumor growth and metastasis. Plexin A1 was one of our top hits in this screen, being expressed at &gt;8 fold in metastatic lesions of the zebrafish and expressed in &gt;80% of human RMS. Plexins are a large family of receptors for transmembrane, secreted and GPI-anchored semaphorins. Knockdown of PLXNA1 decreased human ERMS cell proliferation, increased differentiation and impaired anchorage-independent growth and migration. Collectively, our data supports the hypothesis that PLXNA1 is an important moderator of tumor growth in a large fraction of human RMS and likely regulates local invasion and metastasis. This work will provide much needed data for discovery of novel therapeutically-actionable pathways for relapsed ERMS and likely inform future treatment for high-risk patients.
Citation Format: Alessandra M. Welker, Madeline N. Hayes, Qin Tang, David M. Langenau. A tumor evolution screen in zebrafish identifies PlexinA1 as a driver of metastasis and growth in human rhabdomyosarcoma [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 4127.
Abstract 4133: Increased I2PP2A compromises TP53 function by stabilizing MDM2 in Shh medulloblastoma
Authors: Wei Yun , Maximov Victor , Kenney Anna 
Published: August 2018

Abstract
Medulloblastoma is the most common malignant pediatric brain tumor. Currently, the standard therapy comprising radiation, surgery and chemotherapy “cures” about 70% of medulloblastoma patients. However, these aggressive and non-differential treatment modalities cause lifelong side effects in patients. Medulloblastoma patients are classified into four different subgroups based on transcriptional and molecular profiles, namely WNT, SHH, Group 3, and Group 4. The SHH subgroup accounts for approximately 30% of all medulloblastoma cases and is further subcategorized into TP53 wild type and TP53 deficient subtypes. The importance of TP53 status in SHH medulloblastoma patients has been recently recognized by the association between TP53 mutation and poor prognosis for these patients. However, research findings illustrating TP53 signaling in preclinical models of SHH medulloblastoma are quite limited. Apart from the fact that TP53 mutation is associated with poor survival, 80% of medulloblastoma cases are TP53 wild type. TP53 protein is a tumor suppressor which acts as a checkpoint protein for all types of cells. Cancer cells either mutate TP53 gene or employ other mechanisms such as overexpressing MDM2 to compromise TP53 protein function. Therefore we hypothesize that TP53 function is compromised by highly active MDM2 in TP53 wild type Shh medulloblastoma.
Using the SmoA1 mouse model, which closely recapitulates human SHH medulloblastoma, we aim to investigate whether TP53 signaling has been disrupted in Shh medulloblastoma. Surprisingly, we observed relatively higher TP53 protein levels in tumor tissue lysates as compared to that in neighboring normal cerebellum using SmoA1 mice. However, MDM2, the major suppressor of TP53, showed higher phosphorylation at Ser166, which would stabilize MDM2, resulting in degradation of newly-produced TP53 protein. We also found significantly increased protein levels of I2PP2A, an endogenous inhibitor of phosphatase 2A, which can dephosphorylate MDM2 at Ser166. Using COG112, a small molecule inhibitor of I2PP2A, we showed the reactivation of PP2A, concurrent with a decrease of p-MDM2 and an increase of TP53 in a time-dependent manner. From these experiments, we conclude that 1) TP53 pathway is functional in our SmoA1 mouse model; 2) I2PP2A upregulation could be the reason for rapid degradation of TP53 protein in SmoA1 mice. These findings have translational implications as they suggest that targeting I2PP2A in TP53 wild type SHH medulloblastoma patients could be a method of driving tumor cell death, thus resulting in better clinical outcomes for these patients.
Citation Format: Yun Wei, Victor Maximov, Anna Kenney. Increased I2PP2A compromises TP53 function by stabilizing MDM2 in Shh medulloblastoma [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 4133.
Abstract 4135: c-MYC drives a subset of high-risk pediatric neuroblastoma and is activated through mechanisms including enhancer hijacking and focal enhancer amplification
Authors: Zimmerman Mark W. , Liu Yu , He Shuning , Durbin Adam D. , Abraham Brian J. , Easton John , Shao Ying , Beisi Xu , Zhu Shizhen , Zhang Xiaoling , Li Zhaodong , Weichert-Leahey Nina , Young Richard A. , Zhang Jinghui , Look A. Thomas 
Published: August 2018

Abstract
The amplified MYCN gene serves as an oncogenic driver in approximately 20% of high-risk pediatric neuroblastomas. Here we show that c-MYC itself is a potent transforming gene in a separate subset of high-risk neuroblastoma cases (~10%), based on (i) its upregulation by focal enhancer amplification or genomic rearrangements leading to enhancer hijacking, and (ii) its ability to transform neuroblastoma precursor cells in a transgenic animal model. The aberrant regulatory elements associated with oncogenic c-MYC activation include focally amplified distal enhancers or translocation of highly active enhancers from other genes to within topologically associating domains containing the c-MYC gene locus. The clinical outcome for patients with high levels of c-MYC expression is virtually identical to that of patients with amplification of the MYCN gene, a known high-risk feature of this disease. Together, these findings establish c-MYC as a bona fide oncogene in a clinically significant group of high risk childhood neuroblastomas.
Citation Format: Mark W. Zimmerman, Yu Liu, Shuning He, Adam D. Durbin, Brian J. Abraham, John Easton, Ying Shao, Xu Beisi, Shizhen Zhu, Xiaoling Zhang, Zhaodong Li, Nina Weichert-Leahey, Richard A. Young, Jinghui Zhang, A. Thomas Look. c-MYC drives a subset of high-risk pediatric neuroblastoma and is activated through mechanisms including enhancer hijacking and focal enhancer amplification [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 4135.
Abstract 4136: Marked decrease of BIRC5/Survivin by haploinsufficiency does not inhibit neuroblastoma in transgenic mice: Implications for survivin as a therapeutic target in neuroblastoma
Authors: Dorneburg Carmen , Rasche Volker , Lechel Andre , Katz Sarah-Fee , Debatin Klaus-Michael , Beltinger Christian 
Published: August 2018

Abstract
Overexpression of survivin, a crucial regulator of the mitotic spindle checkpoint with additional antiapoptotic effects, is associated with poor prognosis in neuroblastoma (NB) and other cancers. Thus, survivin is a promising therapeutic target in NB. Transcriptional inhibitors of survivin show preclinical efficacy and have been tested in clinical trials. The results of these trials, however, have been disappointing, due to modest efficacy and unexpected off-target effects. We thus investigated the consequences of marked, yet incomplete decrease of survivin on NB in a novel transgenic mouse model.
To this end, we crossed mice haploinsufficient for survivin with TH-MYCN mice to generate BIRC5+/- MYCN tg/+ mice. These mice developed NB with markedly decreased mRNA and protein expression of survivin. Surprisingly, incidence and latency of the NB that developed in the BIRC5+/- MYCN tg/+ mice were not different from those in the TH-MYCN mice. Growth of tumors was not decreased in BIRC5+/- MYCN tg/+ mice, as assessed by serial MRI imaging, and survival of the mice was not increased. Immunohistochemistry of the NB did not show decreased proliferation (Ki67), increased apoptosis (activated caspase 3) or a change in vascularity (CD31). No difference in copy number variations between the two NB mouse models was discernible using CGH arrays. To determine whether dysfunctional T cells described in mice haploinsufficient for survivin could have masked any loss of aggressiveness of NB cells haploinsufficient for survivin, NB of BIRC5+/- MYCN tg/+ mice were retransplanted into survivin sufficient mice. No difference in tumor incidence, latency and growth was detected.
Taken together, despite a marked decrease in the expression of BIRC5/survivin by haploinsufficiency development and growth of NB were not inhibited. While a further decrease of survivin beyond that seen in haploinsufficiency will inhibit NB, it most likely will also elicit marked side effects, given that survivin is essential for normal cells. Our results cast doubt on the efficacy of inhibitors of survivin expression in NB and call for targeting survivin by alternative approaches, such as inhibiting protein-protein interactions of survivin.
Citation Format: Carmen Dorneburg, Volker Rasche, Andre Lechel, Sarah-Fee Katz, Klaus-Michael Debatin, Christian Beltinger. Marked decrease of BIRC5/Survivin by haploinsufficiency does not inhibit neuroblastoma in transgenic mice: Implications for survivin as a therapeutic target in neuroblastoma [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 4136.