bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C053: BACE1 cleaves EGFR to drive lung adenocarcinoma brain metastasis
Authors: Chafe Shawn C , Zhai Kui , Singh Sheila K 
Published: December 2023

Abstract
Brain metastasis occurs in up to 40% of patients with non-small cell lung cancer (NSCLC). Considerable genomic heterogeneity exists between the primary lung tumour and respective brain metastasis; however, the identity of the genes capable of driving brain metastasis is incompletely understood. Here, we carried out an in vivo genome-wide CRISPR activation (CRISPRa) screen to identify molecular drivers of brain metastasis from a NSCLC patient-derived xenograft model. We discovered activation of the Alzheimer’s disease associated b-site amyloid precursor protein cleaving enzyme 1 (BACE1) led to a significant increase in brain metastasis. Furthermore, BACE1 knockout or inhibition with Verubecestat treatment blocked NSCLC brain metastasis. Mechanistically, we identified BACE1 cleaves an N-terminal fragment of EGFR to activate downstream signalling through MEK and ERK and drive this metastatic phenotype. Together our data highlights the power of in vivo CRISPR screening to unveil novel molecular drivers and potential therapeutic targets of NSCLC brain metastasis.
Citation Format: Shawn C Chafe, Kui Zhai, Sheila K Singh. BACE1 cleaves EGFR to drive lung adenocarcinoma brain metastasis [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C053.
Abstract C071: HBI-2375, a selective inhibitor of MLL1-WDR5 interaction, possesses desirable preclinical characteristics in solid tumors in combination with checkpoint inhibitors and also in leukemias in the future clinical investigations
Authors: Shojaei Farbod , Fang Che , Ricono Jill M , Gillings Mireille 
Published: December 2023

Abstract
MLL1 (mixed lineage leukemia1) interaction with WDR5 (WD repeat domain 5) is critical for its histone methyl transferase (HMT) activity leading to transcriptional regulation of gene expression. MLL1 dysregulation such as its translocation at chromosome 11q23 results in generation of MLL1 fusion genes and leukemia development. Additionally, recent studies indicated a role for MLL1-WDR5 interaction in solid tumors progression via directly affecting cancer cells or by suppression of tumor immunity. Therefore, MLL1-WDR5 interaction is an important target in the discovery of anti-cancer drugs for both leukemia and solid tumors. HUYABIO recently identified HBI-2375 as a selective inhibitor of MLL1-WDR5 interaction. HBI-2375 showed potent inhibition of WDR5 (IC50=4.48 nM) and inhibited MV4-11 cellular proliferation (average IC50=3.15 µM) in CTG assays. In addition, HBI-2375 was stable in liver S9 and whole blood, with moderate to high plasma protein binding rates in multiple species, and acceptable hERG IC50 (17 µM). Furthermore, HBI-2375 displayed reasonable oral PK properties (Cmax, T1/2, AUC, and F%) in mouse and dog. In vivo, HBI-2375 has shown significant dose dependent anti-tumor activity in MV4-11 xenograft AML model along with reduction in methylation of H3K4 in the tumors harvested from the treated animals demonstrating the targeted disruption of HMT activity in cancer cells by HBI-2375. Furthermore HBI-2375 in combination with PD-1 mAb significantly inhibited tumor growth in MC38, colorectal tumor model, and in 3LL lung carcinoma syngeneic tumor models. Flow cytometry and IHC showed significant increase in the infiltration of CD8+ CTLs in the combination group further providing immune-driven mechanisms for greater efficacy of combination therapy. Gene expression analysis also identified genes that are involved in promoting immune system activity in the combination group. Therefore, HBI-2375 may represent a first-in-class MLL1-WDR5 inhibitor in the clinic.
Citation Format: Farbod Shojaei, Che Fang, Jill M Ricono, Mireille Gillings. HBI-2375, a selective inhibitor of MLL1-WDR5 interaction, possesses desirable preclinical characteristics in solid tumors in combination with checkpoint inhibitors and also in leukemias in the future clinical investigations [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C071.
Abstract C082: SCD1 is a potent therapeutic target in MYC-amplified group 3 medulloblastoma
Authors: Custers Stefan , Escudero Laura , Suk Yujin , McKenna Dillon , Gwynne William , Chaudhry Iqra , Chan Jeremy , Quaile Andrew , Moffat Jason , Venugopal Chitra , Montenegro-Burke Rafael , Singh Sheila 
Published: December 2023

Abstract
Medulloblastoma (MB) is the most common pediatric brain tumor comprising of four subgroups: WNT, SHH, Group 3 (Gp3) and Group 4 (G4). Improved Standard of care has led to a greatly improved patient survival. However, 30% of patients still succumb to the disease and survivors are plagued with lifelong neuro-cognitive and neuro-developmental disorders. MYC amplified G3MB is a highly aggressive subgroup with a high frequency of metastasis and recurrence, leading to a bleak prognosis. Molecular understanding of G3MB is lacking and improved treatment options are urgently needed. Recent studies suggest a role for reprogrammed lipid metabolism, especially at recurrence. Here, we utilized comparative profiling of the G3MB and neural stem cells (NSC) lipidome with liquid chromatography-mass spectrometry (LC-MS). We identified a class of lipids whose differential abundance in G3MB renders these tumor cells sensitive to chemical inhibition of their biosynthesis. Pharmacological and genetic inhibition of the rate limiting enzyme of the de novo lipid synthesis pathway, Stearoyl-CoA Desaturase-1 (SCD1), completely abolishes self-renewal and proliferation in vitro, while supplementing cell culturing media with Oleic Acid (OA) fully restores these effects. Genetic knockout of SCD1 in G3MB cells significantly prolongs survival and reduced tumor burden in vivo. Moreover, administration of CAY10566, a SCD1 specific small molecule inhibitor significantly prolongs survival in vivo as well. RNA-seq, lipidomic and metabolomic analyses of G3MB treated with CAY10566 or DMSO is being employed to unravel SCD1-mediated mechanisms. Together, these data suggest that enzymes regulating lipid metabolism in G3MB represent potential targets for therapeutic translation.
Citation Format: Stefan Custers, Laura Escudero, Yujin Suk, Dillon McKenna, William Gwynne, Iqra Chaudhry, Jeremy Chan, Andrew Quaile, Jason Moffat, Chitra Venugopal, Rafael Montenegro-Burke, Sheila Singh. SCD1 is a potent therapeutic target in MYC-amplified group 3 medulloblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C082.
Abstract C097: Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma
Authors: Singh Sheila , Gwynne William , Suk Yujin , Chan Jeremy , Qualie Andrew , Escudero Laura , Brown Kevin , Venugopal Chitra , Moffat Jason , Montenegro-Burke Rafael 
Published: December 2023

Abstract
Background: MYC-amplified group 3 (G3) medulloblastoma (MB) represents a clinically aggressive subgroup of MB that is defined by leptomeningeal metastases, disease recurrence and particularly poor survivorship in comparison to other MB subgroups. There is an urgent need for a more thorough molecular understanding of G3 MB to develop more effective therapeutic modalities that will improve the durability of remission.
Methods: We mapped the functional G3 MB metabologenomic landscape via parallel genome-wide CRISPR-Cas9 screening and untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomics. The tractability of potential therapeutic targets was assessed using patient-derived orthotopic preclinical models of G3 MB. Transcriptomics, functional genomics, and metabolomics were employed to discern a mechanism whereby inhibition of DHODH (dihydroorotate dehydrogenase), which is a mitochondrial-bound enzyme that facilitates de novo pyrimidine biosynthesis, selectively impairs G3 MB tumor cell fitness.
Results: Untargeted metabolomic profiling shows enrichment of de novo pyrimidine biosynthesis and depletion of salvage pyrimidine intermediates in G3 MB tumor cells in comparison to neural stem cells (NSC), which are the prospective cell-of-origin of MB. In agreement with reprogrammed nucleotide metabolism, DHODH was identified as a corresponding ‘druggable hit’ in the genetic screen. We demonstrate that genetic or pharmacological inhibition of DHODH selectively targets G3 MB brain tumor initiating cells (BTIC) while sparing normal NSC. We further show that MYC-amplified G3 MB tumors harbor subgroup-specific transcriptomic signatures that delineate enrichment of de novo pyrimidine biosynthesis, which sustains c-Myc activity via a metabolite-protein interaction.
Significance: Despite clear evidence favoring an altered metabolic landscape in MYC-driven cancers, there have been few reports into the role of metabolic reprogramming in MYC-amplified G3 MB. This metabolic vulnerability is hence not exclusive to MB and has recently been identified in other primary brain malignancies; current efforts are focused on establishing relevant biomarkers that will facilitate clinical translation.
Citation Format: Sheila Singh, William Gwynne, Yujin Suk, Jeremy Chan, Andrew Qualie, Laura Escudero, Kevin Brown, Chitra Venugopal, Jason Moffat, Rafael Montenegro-Burke. Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C097.
Abstract C106: Identification of nucleic acid drug candidates against mesenchymal transition and its application to breast cancer and glioblastoma cells
Authors: Yoshikawa Kiyotsugu , Takahashi Rei 
Published: December 2023

Abstract
Cancer stem-like cells (CSLC) have a feature of epithelial-mesenchymal transition (EMT) responsible for tumor heterogeneity and therapeutic resistance. To identify molecular targets of CSLC, we underwent shRNA screening for epithelialization of MDA-MB-231 mesenchymal breast cancer cell line with novel EMT/MET dual reporter system and identified 2 shRNAs (shP1 and shH1) which reverse EMT in mesenchymal breast cancer as well as glioblastoma cells. While mesenchymal breast cancer cells undergo adipogenic differentiation upon PPAR gamma activation, shP1-induced epithelialization suppresses adipogenic differentiation. Of the two shRNAs, the shH1 strongly inhibited their growth, indicating shH1-specific sequence has a therapeutic potential for nucleic acid therapeutics. Metabolome/transcriptome analyses of immortalized human mammary epithelial cells (HMLE) undergoing EMT in the presence of absence of H-Ras oncogene revealed global metabolic change upon EMT, including reduced glycolysis, increased shunting to pentose phosphate pathways, shift in TCA, and increased glutathione biosynthesis. Ras-mesenchymal CSLC cells overcame the effects of EMT on glycolysis and acquired hybrid metabolic state. In summary, we have revelaed metabolic plasticity of mesenchymal cancer cells and identified nucleic acid drug candidates against mesenchymal transition.
Citation Format: Kiyotsugu Yoshikawa, Rei Takahashi. Identification of nucleic acid drug candidates against mesenchymal transition and its application to breast cancer and glioblastoma cells [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C106.
Abstract C111: A novel human monoclonal antibody targeting active ADAM10 demonstrates anti-tumor effects in colorectal cancer
Authors: Mashati Pargol , Sun Dan , Reino Eduardo Garcia , Blandino Jessica A. , Mason Ben , Saha Nayanendu , Nikolov Dimitar B. , Premsrirut Prem 
Published: December 2023

Abstract
Colorectal cancer (CRC) is the third most diagnosed cancer in the USA and accounts for more than 600,000 deaths annually worldwide, primarily due to relapse with highly aggressive, chemo-resistant disease characterized by poorly differentiated cancer cells with stem cell-like properties. A common signature of these chemo-resistant tumors is dysregulation of Notch receptor signaling, as well as upregulation of its metalloprotease activator, ADAM10. Although small molecule inhibition of either Notch or ADAM10 has been shown to produce potent anti-tumor effects, these therapeutic strategies have failed in clinical trials primarily due to systemic toxicities, especially cytotoxic effects on the gastrointestinal tract and musculoskeletal system, highlighting the need for development of more targeted approaches. We have previously demonstrated that ADAM10 predominantly exists in an inhibited state in normal tissues but is activated in tumor cells through a conformational change in the extracellular domain, thus providing a potential target for tumor-specific modulation of ADAM10 activity. Here, we look to characterize a novel human monoclonal antibody agent (1H5) that selectively targets an exposed extracellular region of activated ADAM10 on tumor cells. We previously demonstrated that treatment with a murine version of the antibody (8C7), specific for the activated form of both mouse and human ADAM10, conferred a significant reduction in tumor burden against human CRC cell lines in cell culture and transplants in xenograft models, and relapse was prevented when 8C7 was combined with chemotherapy. Here, we demonstrate that the 1H5 monoclonal antibody effectively reduces cell viability in numerous colorectal cancer cell lines in vitro and induces marked tumor regression in established xenograft models through inhibition of Notch signaling. Through the use of additional genetic tools combined with in vitro and in vivo models, our preclinical study aims to fully evaluate 1H5 as novel therapeutic agent to treat aggressive colorectal cancer. We aim to propel this novel agent toward clinical-stage development.
Citation Format: Pargol Mashati, Dan Sun, Eduardo Garcia Reino, Jessica A. Blandino, Ben Mason, Nayanendu Saha, Dimitar B. Nikolov, Prem Premsrirut. A novel human monoclonal antibody targeting active ADAM10 demonstrates anti-tumor effects in colorectal cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C111.
Abstract C137: Tumor-selective, chaperone-mediated targeting of ERK5 (MAPK7)
Authors: Foley Kevin P , Yang Xiangcai , Yin Wei , Xu Mengmeng , Wang Mingkai , Ding Qinglin , Dai Yan , Zhou Haoxin , Tusa Ignazia , Menconi Alessio , Lombardi Zoe , Tubita Alessandro , Prince Thomas L , Wang Guoqiang , Rovida Elisabetta , Ying Weiwen 
Published: December 2023

Abstract
Extracellular signal-regulated kinase 5 (ERK5 or MAPK7) belongs to the mitogen-activated protein kinase family and has been associated with a wide range of cellular functions, including cell proliferation, migration, differentiation and survival. ERK5 has also been implicated in the onset and progression of several types of cancer. Importantly, studies comparing pharmacological inhibition versus genetic deletion or knockdown of ERK5 have revealed that it also possesses kinase activity-independent functions, suggesting that an ERK5 protein degrader approach may be required to completely block all ERK5-regulated signaling. To this end, we have explored applying Chaperone-mediated Protein Degradation (CHAMP) technology to target ERK5 protein. CHAMPs are heterobifunctional small molecules that mediate protein degradation by inducing proximity between a target protein and the HSP90 chaperone complex, resulting in target ubiquitination and degradation by the proteasome. Due to HSP90 being highly activated in cancer cells, CHAMPs also preferentially accumulate in tumors relative to normal tissues, resulting in an improved therapeutic index versus typical inhibitors. In order to chemically induce ERK5 degradation, CHAMP compounds were synthesized by covalently coupling ERK5- and HSP90-binding moieties through a short linker. CHAMP treatment of cancer cell lines resulted in formation of an ERK5-CHAMP-HSP90 ternary complex and subsequent proteasome-dependent ERK5 degradation. This in turn resulted in inhibition of ERK5 downstream signaling, leading to cell growth inhibition, cell cycle arrest and apoptosis in a panel of cancer cell lines. Further, in mouse xenograft models, CHAMPs displayed prolonged pharmacokinetics in tumors relative to plasma and normal tissues and strongly inhibited tumor growth at tolerated doses. Based on these findings, ERK5-targeted CHAMPs represents a promising new approach to disrupt the entire function of ERK5 for the of treatment cancer.
Citation Format: Kevin P Foley, Xiangcai Yang, Wei Yin, Mengmeng Xu, Mingkai Wang, Qinglin Ding, Yan Dai, Haoxin Zhou, Ignazia Tusa, Alessio Menconi, Zoe Lombardi, Alessandro Tubita, Thomas L Prince, Guoqiang Wang, Elisabetta Rovida, Weiwen Ying. Tumor-selective, chaperone-mediated targeting of ERK5 (MAPK7) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C137.
Abstract C140: BI 1810631 is a novel EGFR wild-type sparing, HER2-selective small molecule inhibitor that efficiently blocks HER2 mutant-driven lung cancer
Authors: Neumüller Ralph A. , Wilding Birgit , Scharn Dirk , Baum Anke , Augsten Martin , Waizenegger Irene , Kohsaka Shinji , Santoro Valeria , Chetta Paolo , Woelflingseder Lydia , Popow Johannes , Gerlach Daniel , Ettmayer Peter , Gerstberger Thomas , Fuchs Julian , Treu Matthias , Zahn Stephan , Pearson Mark , Petronczki Mark , McConnell Darryl B. , Kraut Norbert , Solca Flavio 
Published: December 2023

Abstract
Here we report pre-clinical characterization of the clinical compound BI 1810631, a HER2 specific, EGFR wild-type-sparing tyrosine kinase inhibitor (TKI). BI 1810631 has shown early signs of clinical activity in patients carrying tumors with HER2 aberrations [NCT04886804], mainly comprising HER2 mutations (Heymach et al. 2023). In non-small cell lung cancer, activating mutations in HER2 are found in 2-4% of patients and predominantly cluster in exon 20 within the tyrosine kinase domain (TKD), of which the most frequent variant is A775_G776insYVMA. Studies across tumor cell lines and xenograft mouse models show that BI 1810631 is a potent and selective inhibitor of HER2-driven oncogenic signaling. Compound-mediated reduction of cell growth and survival was observed in mutant HER2 driven Ba/F3 cell systems, in human tumor cell lines in vitro and translated into tumor regressions in a genome-engineered HER2-YVMA mutant xenograft model. The in vivo efficacy of BI 1810631 was further confirmed in HER2 exon 20 mutant patient-derived tumor models. Corresponding biomarker studies in vitro and in vivo showed modulation of pharmacodynamic markers, corroborating the on-target mechanism of action of the compound. These findings demonstrate that HER2 mutations can be effectively addressed by BI 1810631 and support the ongoing and future clinical trials.
Citation Format: Ralph A. Neumüller, Birgit Wilding, Dirk Scharn, Anke Baum, Martin Augsten, Irene Waizenegger, Shinji Kohsaka, Valeria Santoro, Paolo Chetta, Lydia Woelflingseder, Johannes Popow, Daniel Gerlach, Peter Ettmayer, Thomas Gerstberger, Julian Fuchs, Matthias Treu, Stephan Zahn, Mark Pearson, Mark Petronczki, Darryl B. McConnell, Norbert Kraut, Flavio Solca. BI 1810631 is a novel EGFR wild-type sparing, HER2-selective small molecule inhibitor that efficiently blocks HER2 mutant-driven lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C140.
Abstract C171: Immune desert microenvironment is associated with poor outcome in Wilms tumors
Authors: Su Xiaoping , Malouf Gabriel 
Published: December 2023

Abstract
Background: Presence of anaplasia is a potent marker for adverse outcome in patients with Wilms tumors with diffuse anaplasia (DAWT). Patients with WT with focal anaplasia (FAWT) are considered as intermediate risk. Besides TP53 mutations thought to arise in anaplastic components, the crosstalk between genomic alterations and immune landscape remains unknown.
Methods: We performed whole-exome and/or RNA sequencing on genomic DNA derived from 12 matched tumor-normal WTs and extended analysis in an independent dataset of 9 cases. TP53 mutations and tumor infiltrating lymphocytes (TILs: CD3, CD4 and CD8) were also assessed. Validation was performed using TARGET-WT (n=96) and GEO-WT (n=12) cohorts. Prognostic role of TILs was investigated in another 55 pre-treated WTs.
Results: TP53 (50%) and DROSHA (33.3%) were the sole recurrent mutations identified. TP53 mutations occurred in mutually exclusive manner with chromatin-modifying genes which were altered in both FAWT (100%) and DAWT (33.3%). Microenvironment analysis revealed a reproducible immune desert WTs with poor outcome that enriched in DAWT cases and TP53 mutation, which mirrored the inversion of CD4:CD8 ratio in TP53-mutated comparing to TP53-wild tumors (P=0.003). Immune desert WTs were also characterized by overexpression of DNA repair pathways, PRC2, HDCA, and polycomb targets of EZH2, leading to higher sensitivity to HDCA inhibitor of vorinostat. Additionally, the immunophenotypes were tightly associated with replication stress subtypes; WTs with high replication stress were susceptible to ATR and WEE1 inhibitors. High ratio of CD4/CD8 was considered as independent recurrence-free and overall survival factors for WTs (both P&lt;0.05).
Conclusions: Our results reveal that WT with anaplastic features are characterized by either TP53 alterations or chromatin-modifying genes. These data implicate TP53 as a tumor cell-intrinsic driver of an immune desert phenotype, in contrast with adult TP53 tumors. TP53 inactivation might therefore causes epigenetic deregulation across cancer sites, and has implications for immunotherapy.
Citation Format: Xiaoping Su, Gabriel Malouf. Immune desert microenvironment is associated with poor outcome in Wilms tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C171.