bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2908: PT217, an anti-DLL3/anti-CD47 bispecific antibody, exhibits anti-tumor activity through novel mechanisms of action
Authors: Jia Haiqun(John) , Fang Dorthy , Lobsinger Molly , Long Yan , Chen Kelan , Lam Albert , Guo Yangyang , Selesniemi Kaisa , Wang Ming , Zou Hui 
Published: June 2022

Abstract
Small cell lung cancer (SCLC) is the most lethal subtype of lung cancers with few patients surviving more than 5 years from diagnosis. While SCLC initially responds well to standard chemotherapy treatment, chemotherapy-resistant recurrence is characteristic and available treatment options for recurrent and refractory diseases are limited. Immunotherapy as an alternative or additional treatment has been very successful in treating many cancers, yet it has shown disappointingly limited benefits in SCLC and notable treatment related toxicities have been observed. Delta like 3 (DLL3) is an attractive target for SCLC immunotherapy, as its expression is highly restricted to SCLC and can therefore be used for targeting purposes. On the other hand, CD47 is also strongly expressed on the surface of SCLC cells, where it inhibits macrophage-mediated tumor cell killing. We have developed PT217, a DLL3/CD47 bispecific antibody with effector effect competent Fc to specifically target SCLC cells via two mechanisms. First, PT217 blocks the CD47-SIRPα interaction and stimulates phagocytosis of tumor cells by macrophage. Second, PT217 exhibits robust effector effect (ADCC by NK cells and ADPC by macrophage) mediated by the functional Fc of PT217. Interestingly, it appears that the tumor cells targeted by NK cells are subsequently engulfed by macrophage. Elevated phagocytosis of the tumor cells by macrophages and dendritic cells is expected to increase the presentation of tumor neoantigens that may eventually lead to T cell-mediated killing of tumor cells that do not expression DLL3. In vivo, PT217 demonstrated tumor suppression activity in xenograft mouse models. In addition to the strong tumor killing activity, PT217 also demonstrated good safety profile in NHP studies. Furthermore, PT217 exhibits regular mAb-like manufacturability in process development and CMC. We expect to initiate a phase 1 trial to target SCLC in the first half of 2022.
Citation Format: Haiqun(John) Jia, Dorthy Fang, Molly Lobsinger, Yan Long, Kelan Chen, Albert Lam, Yangyang Guo, Kaisa Selesniemi, Ming Wang, Hui Zou. PT217, an anti-DLL3/anti-CD47 bispecific antibody, exhibits anti-tumor activity through novel mechanisms of action [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2908.
Abstract 2922: Targeting triple negative breast cancer with a VHL recruiting EZH2 protein degrader
Authors: Dale Brandon , Anderson Chris , Park Kwang-su , Kaniskan H. Ümit , Yu Xufen , Jin Jian 
Published: June 2022

Abstract
EZH2 (enhancer of zeste homolog 2) is the main catalytic subunit of the polycomb repressive complex 2 (PRC2) that catalyzes methylation of histone H3K27. EZH2 is overexpressed in a broad spectrum of cancers including prostate, myeloma and lymphoma, and high expression correlates with poor prognosis. However, EZH2 inhibitors, which do not affect EZH2 protein levels, are ineffective at inhibiting growth of TNBC and other breast cancer cell lines with EZH2 overexpression even though they effectively inhibit the catalytic activity of EZH2/PRC2. It has also been shown that overexpression of EZH2 is a major driver for breast cancer development and progression, and knockdown of EZH2 inhibits proliferation of TNBC and other breast cancer cells. These results together suggest that EZH2 overexpression, but not the methyltransferase activity of EZH2, is critical for driving breast cancer progression. Bivalent inhibitor technologies such as PROTACs (proteolysis targeting chimeras) and hydrophobic tagging have been successfully applied to selective degradation of multiple protein targets. CRBN-recruiting (E7) and VHL-recruiting EZH2 (YM281) EZH2 targeting PROTACs have been reported, but do not show potent efficacy in targeting TNBC. Here, we characterize MS8815, a VHL-recruiting EZH2 degrader, that we created. MS8815 displayed nanomolar efficacy at EZH2 degradation and potent in vitro effects on TNBC cell lines, no off-target interactions and utilized the canonical PROTAC mechanism of action. Based on these promising preliminary results, we report MS8815 as the best-in-class EZH2 PROTAC degrader that is able to efficiently degrade EZH2 and kill TNBC cells.
Citation Format: Brandon Dale, Chris Anderson, Kwang-su Park, H. Ümit Kaniskan, Xufen Yu, Jian Jin. Targeting triple negative breast cancer with a VHL recruiting EZH2 protein degrader [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2922.
Abstract 2948: A multimodal, label-free tool for gentle and efficient cell separation
Authors: Travers Kevin , Stevens Chris , Jett Susana , Weaver Suzanne , de Groot Teddy , Ha Stefan , Facer Geoff , Lazaruk Kathy 
Published: June 2022

Abstract
LevitasBio has developed the LeviCell™ platform, a powerful new technology for cell separation and characterization that utilizes magnetic fields to levitate cells. Unlike other methods, cell separation via magnetic levitation does not require dyes, antibodies or specific markers, and the cells are not modified or perturbed in any fashion. However, magnetic levitation also does not preclude the use of these tools to further enhance separation of cells. In its simplest form, magnetic levitation requires only the addition of an inert paramagnetic compound to the media in which the cells are suspended. The cells are subsequently introduced into an externally applied magnetic field while contained within a single-use cartridge, which causes the cells to levitate in solution. The cells’ intrinsic properties, including density and magnetic susceptibility, determine the height to which the cells levitate. As different cell types often have different such properties, they may often levitate to different heights, facilitating their separation. Continuous imaging allows for complete sample analysis and characterization with the benefit of real-time control over the cell separation. The simplicity of magnetic levitation enables cells to be treated gently without use of high pressure or other perturbations that commonly lead to increased cellular stress responses, specific cell type activation, or even cell death. The direct and gentle flow path leads to high yields of live cells even with very low input cell numbers.
This novel cell separation technology enables a variety of applications, including: the enrichment of viable cells from dead/dying cells and debris; separation of different cell types possessing distinct densities; and, in cases where the intrinsic density changes, the separation of differentiated from undifferentiated cells. Given that the levitation chamber is flanked by two magnets on the top and bottom, the levitation technology also inherently allows for the use of magnetic particles to deplete undesired cells within a cell population. Here we illustrate the performance of anti-CD45 antibody-conjugated magnetic particles for CD45+ cell depletion with the LeviCell system. CD45+ depletion rates of greater than 99% are readily obtained across a wide range of total CD45+ input cell numbers, from 105 to 107 total cells. Furthermore, CD45+ cell depletion is performed simultaneously with live cell enrichment, allowing for the collection of a high viability CD45- live cell population.
Citation Format: Kevin Travers, Chris Stevens, Susana Jett, Suzanne Weaver, Teddy de Groot, Stefan Ha, Geoff Facer, Kathy Lazaruk. A multimodal, label-free tool for gentle and efficient cell separation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2948.
Abstract 2950: Coexpression networks of miRNAs and gene transcripts coinciding with lung adenocarcinoma progression and survival
Authors: Young Corey D. , Dammer Eric B. , Griffen Ti'ara L. , Nunez Sha'kayla K. , Dill Courtney , Carey Kaylin M. , Lillard James W. 
Published: June 2022

Abstract
Lung & bronchus cancer is the second most diagnosed cancer, causing the most cancer-related deaths in the United States. A lung and bronchus subtype, NSCLC (non-small cell lung cancer), accounts for over 75% of new lung cancer diagnoses of which lung adenocarcinoma (LUAD) is the most common. Here, we studied the role of microRNAs and the transcriptome expression profile in LUAD prognosis, progression, and overall patient survival. We analyzed RNA-sequence data from a cohort of LUAD patients from The Cancer Genome Atlas (TCGA). The correlations of microRNA gene expression to transcription networks identified by weighted gene co-expression network analysis (WGCNA) were further explored in an upstream regulator/signaling pathway analysis, gene ontology (GO) process enrichment, and differential expression analysis. Mature microRNA abundance was also integrated with the mRNA network via correlation analysis. Our analysis revealed 18 clusters (modules) of highly correlated gene transcripts. The turquoise and red modules were of particular interest, as they were correlated negatively with overall survival, positively with stage 1 status, and negatively to later pathologic stages (3-4). Additionally, high select miRNA correlation to the red module transcripts (e.g., C16Orf89, ADGRF5, CFAP221, and SELENBP1; all with module eigengene correlation rho ≥ 0.75), and to the turquoise module (e.g., DDX39B and LENG8; each with rho ≥ 0.85) suggests these are miRNA-mRNA coregulatory networks of which both the gene products and potentially upstream miRNAs may serve as promising mechanistic targets and prognostic markers for LUAD, meriting further study.
Citation Format: Corey D. Young, Eric B. Dammer, Ti'ara L. Griffen, Sha'kayla K. Nunez, Courtney Dill, Kaylin M. Carey, James W. Lillard. Coexpression networks of miRNAs and gene transcripts coinciding with lung adenocarcinoma progression and survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2950.
Abstract 2956: Superenhancer-drvien SMC4 promote cell growth and proliferation in multiple myeloma
Authors: Jia Yunlu , Zhou Jianbiao , Tan Tze-King , Chung Tae-Hoon , Chen Yongxia , Zhang Enfan , Cai Zhen , Sanda Takaomi , Chng Wee-Joo 
Published: June 2022

Abstract
Background Multiple myeloma (MM) is an incurable malignancy characterized by complex heterogeneous cytogenetic abnormalities. Defined as large clusters of cis-acting enhancers, super-enhancers (SEs) could promote oncogenic transcription to which cancer cells highly addicted. Structural maintenance of chromosome 4 (SMC4) is a core subunit of condensin complexes, which contributes to chromosome condensation and segregation. Here, we identified SMC4 as a novel SE-associated oncogene of myeloma cells, whose functional roles in MM remain largely elusive.
Methods We performed H3K27ac ChIP-seq and RNA-seq on primary MM patient samples, MM cell lines, normal CD138+ plasma cell and lymphoma cell lines as the controls, then the ROSE analysis was used to annotate SEs and their associated genes. THZ1 as a transcriptional CDK7 inhibitor was used to further filter THZ1-responsive genes. Combined analysis of THZ1-sensitive and SE-associated gene uncovered a number of promising MM oncogenes as SMC4. The public data mining, RNA interference, CRISPR/Cas9 gene editing system, overexpression and a variety of cellular functional assays were performed to determine the oncogenic effects of SMC4 on MM malignant. Transcriptome analysis with SMC4 silencing and overexpression, and the underlying molecular mechanism of SMC4 oncogenic role in MM are ongoing.
Results We have demonstrated SMC4 as one of the SE-associated genes specific to MM patient samples and cell lines. SMC4 was related to myelomagenesis with increased expression from MGUS, SMM to MM cases, and overexpression of SMC4 predicted poor overall survival of MM patients, suggesting its clinical relevance. SMC4 silencing in MM cells suppressed cell proliferation and lead to cell apoptosis. Repression of the SMC4-SE region also led to impairment of cell viability and cell growth, consistent with an oncogenic function.
Conclusion In summary, our integrative approached by combing H3H27ac ChIP-seq, RNA-seq and THZ1-sensitive transcripts identified the landscape of SEs and novel oncogenic transcripts as SMC4 in MM. Mapping these acquired SEs and their associated genes may provide novel insight into understanding MM biology, and SMC4 may serve as novel therapeutic targets in MM.
Citation Format: Yunlu Jia, Jianbiao Zhou, Tze-King Tan, Tae-Hoon Chung, Yongxia Chen, Enfan Zhang, Zhen Cai, Takaomi Sanda, Wee-Joo Chng. Superenhancer-drvien SMC4 promote cell growth and proliferation in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2956.
Abstract 2957: Inhibition of epigenetic regulator menin is a novel therapeutic approach for high-risk neuroblastoma
Authors: Chilamakuri Rameswari , Agarwal Saurabh 
Published: June 2022

Abstract
Controlling epigenetic factors such as histone methyltransferases and demethylases has recently emerged as an attractive therapeutic approach for different cancers. KMT2 family protein KMT2A or MLL1 is a H3K4 methyltransferase, which is known to play an essential role in cancer development. MLL1 forms a COMPASS complex to function as an epigenetic regulator and Menin is one of the specific and required binding partner for the activation and function of this epigenetic enzyme. Menin acts as a tumor suppressor protein, and inhibition of Menin-MLL1 interaction has been shown to destabilize the MLL1 epigenetic complex, inhibits H3K4 methyltransferase activity, and hinder the oncogenic potential of various cancers. High-risk neuroblastoma (NB) is the most common extracranial solid pediatric tumor and accounts for almost 15% of all pediatric cancer-related deaths. Recent reports indicate that aberrant activation of epigenetic regulators may drive NB progression and relapse. Therefore, in the present study, we used a specific small-molecule inhibitor, MI-503 to disrupt Menin-MLL1 interaction, and to further understand the role of Menin in pediatric NB. We used different NB cell lines including MYCN-non-amplified (SH-SY5Y, SK-N-AS, CHLA-255) and MYCN-amplified (NGP, LAN-5, IMR-32), and performed cytotoxicity and Colonogenic assays to determine the effect of Menin inhibition on NB proliferation. Results showed that MI-503 significantly inhibits NB proliferation and colony formation capacity in a dose-dependent manner in contrast to controls. Further, we performed apoptosis and cell cycle assays and observed that MI-503 significantly induces apoptosis as detected by the increase of Annexin-V positive early apoptotic cells, and blocks cell cycle progression at the S phase in all NB cell lines tested. Additionally, Western blot assays demonstrated an overall inhibition of H3K3me3 levels in NB cells in response to MI-503. To further determine the effects of Menin inhibition on NB tumor growth, we developed a NB 3D spheroid tumor model that recapitulate in vivo tumor growth for solid tumors. Treatment with MI-503 significantly inhibits spheroidal tumor growth by inducing tumor cell death in a dose-dependent manner. Overall, these data highlight the role of epigenetic regulation, MLL1 complex, and of Menin in NB growth and tumorigenicity. In our future efforts, we will further elucidate the effects of MI-503 and the role of Menin in NB by using in vivo tumor models. Epigenetic inhibitor such as MI-503 holds significant potential for further clinical development and as a novel therapeutic approach for NB.
Citation Format: Rameswari Chilamakuri, Saurabh Agarwal. Inhibition of epigenetic regulator menin is a novel therapeutic approach for high-risk neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2957.
Abstract 2960: KAT6A and ENL form an epigenetic transcriptional control module to drive critical leukemogenic gene expression programs
Authors: Blanco Andres 
Published: June 2022

Abstract
Acute myeloid leukemia (AML) is a poor-prognosis hematological malignancy that is characterized by differentiation blockade and uncontrolled proliferation. Epigenetic programs influence AML cell fate decisions, and their mis-regulation can promote differentiation arrest. Itis therefore of paramount importance to identify the regulators of AML cell differentiation and understand the mechanisms by which they repress myeloid transcriptional programs. Here, we performed a cell-fate selection CRISPR screen for chromatin factors whose inhibition promotes AML cell differentiation. We found that the histone acetyltransferase KAT6A is a critical driver of the differentiation block, and that both genetic and chemical inhibition of KAT6A markedly de-repressed latent myeloid maturation programs, most commonly in MLL-rearranged AML. Inhibition of KAT6A catalytic activity reduced self-renewal, induced cell cycle arrest, and extinguished long-term proliferative capacity of AML cells. Through ChIP-seq, RNA-seq, and extensive analysis of clinical datasets, we found that KAT6A is the likely initiator of a newly-described "writer-reader" module that drives oncogenic gene expression in AML. In this model,KAT6A catalyzes promoter H3K9 acetylation, which is bound by the H3K9ac reader ENL, leading to Super elongation complex (SEC) recruitment and release of paused RNA PolII at oncogenic loci such as MYC. KAT6A is elevated in human AMLs compared to matched normal tissue, and its downregulation correlates with monocytic differentiation transcriptional programs in clinical AML datasets. These findings suggest the potential of targeting both KAT6A and ENL to disrupt this writer-reader module and ablate downstream MYC transcriptional programs inMLL-rearranged AML.
Citation Format: Andres Blanco. KAT6A and ENL form an epigenetic transcriptional control module to drive critical leukemogenic gene expression programs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2960.
Abstract 2984: ARHGAP17, a Cdc42-specific GAP, localizes to invadopodia and regulates their turnover as part of an ARHGAP17/Cdc42/CIP4 complex
Authors: Kreider-Letterman Gabriel , Castillo Abel , Rabino Agustin , Mahlandt Eike K. , Goedhart Joachim , Goicoechea Silvia , Garcia-Mata Rafael 
Published: June 2022

Abstract
One of the hallmarks of aggressive cancer is its ability to invade into surrounding tissues and metastasize. Many invasive cancers form invadopodia, which are protrusive, degradative structures that are regulated by the Rho family of GTPases. Rho GTPases commonly have aberrant activity in invasive cancers caused by changes in their upstream regulators: RhoGEFs and RhoGAPs. We have identified the RhoGAP ARHGAP17 (RICH1/NADRIN) as a negative regulator of invadopodia in triple negative breast cancer. Using confocal and STORM super-resolution microscopy techniques, we show that ARHGAP17 localizes to the regulatory ring surrounding invadopodia where it acts to promote disassembly by decreasing invadopodia lifetime through the inactivation of the Rho GTPase Cdc42. We further support these results in live cells by using a new localization-based Cdc42 biosensor, which reveals that ARHGAP17 suppresses Cdc42 activity specifically at the invadopodia ring. We have also identified the Cdc42 effector CIP4 as part of a complex with ARHGAP17 and Cdc42 that we propose is key in the regulation of invadopodia. Finally, using spheroid and inverse invasion assays, we show that the invadopodia phenotype correlates with increased invasive properties. In conclusion, we have identified ARHGAP17 as a key regulator of invadopodia and invasion in triple negative breast cancer by localizing to invadopodia and inactivating Cdc42 as part of a complex with CIP4. In future studies, we will further characterize the molecular mechanisms that regulate the ARHGAP17/Cdc42/CIP4 complex and their function during invadopodia formation.
Citation Format: Gabriel Kreider-Letterman, Abel Castillo, Agustin Rabino, Eike K. Mahlandt, Joachim Goedhart, Silvia Goicoechea, Rafael Garcia-Mata. ARHGAP17, a Cdc42-specific GAP, localizes to invadopodia and regulates their turnover as part of an ARHGAP17/Cdc42/CIP4 complex [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2984.
Abstract 2996: Pre-activation of autophagy impacts PARP inhibitor sensitivity of prostate cancer cells
Authors: Cahuzac Maxime , Péant Benjamin , Fleury Hubert , Mes-Masson Anne-Marie , Saad Fred 
Published: June 2022

Abstract
Introduction: Advanced prostate cancer (APC) is one of the most common causes of cancer-related mortality in males largely related to the development of resistance to hormonal and chemotherapeutic based regimens. Recently, the PARP inhibitor (PARPi) olaparib was shown to improve progression-free and overall survival in patients with APC although resistance remains a barrier to cure. Therapeutic resistance in cancers can be mediated by autophagy, a cellular recycling process. Here we addressed the role of autophagy in the development of olaparib resistance in APC.
Methods: Autophagy levels and olaparib sensitivity were evaluated in prostate cancer (PC) cell lines (LNCaP, C4-2B and PC-3) by western blots and clonogenic assays, respectively. We introduced a double-tagged (mCherry-GFP) LC3 protein in cells to monitor autophagic flux by confocal microscopy and evaluated the temporal importance of autophagy activation by rapamycin on olaparib sensitivity. We measured cell proliferation (Incucyte), cell cycle (flow cytometry) and DNA repair (microscopy). Finally, we confirmed the role of autophagy in olaparib sensitivity using CRISPR/Cas9 Atg16L1 knockout cell lines.
Results: We found a correlation between the basal level of autophagy and olaparib sensitivity in PC cell lines. PC-3 cells were olaparib resistant and had a higher basal level of autophagy compared to LNCaP and C4-2B cells, which were PARPi sensitive. When autophagy was pre-activated before olaparib treatment, PC cell lines became more resistant by increasing homologous recombination activity. This autophagy-mediated resistance was partially regulated by a balance between SQSTM1 and FLNA protein levels in the nucleus. Inhibition of autophagy or post-activated autophagy prevented development of PARPi resistance.
Conclusion: The autophagic flux is associated with PARPi resistance in PC cell lines by regulating DNA repair. Inhibiting autophagy may lead to new strategies to increase PARPi efficacy. Understanding the role of autophagy in PC progression may lead to strategies that prevent the development of PARPi resistance.
Citation Format: Maxime Cahuzac, Benjamin Péant, Hubert Fleury, Anne-Marie Mes-Masson, Fred Saad. Pre-activation of autophagy impacts PARP inhibitor sensitivity of prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2996.