bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P175: Investigating inositol polyphosphate-4-phosphatase, type II (INPP4B) signaling and role in acute myeloid leukemia
Authors: Chen Keyue , Genc Gizem E. , Woolley John F. , Lee Daniel K.C. , Botelho Roberto J. , Salmena Leonardo 
Published: December 2021

Abstract
Acute myeloid leukemia (AML) is an aggressive clonal stem cell disorder characterized by invasion of bone marrow, impaired hematopoiesis and accumulation of functionally immature myeloblasts. Our previous studies demonstrated that the expression level of the lipid phosphatase, INPP4B, is associated with poor outcomes in AML. To gain an understanding of the role of Inpp4b in AML progression, we performed RNA sequencing on Inpp4b+/+ and Inpp4b−/− MLL-AF9 leukemias. Analysis of RNA sequencing data revealed that a disproportionately large number of lysosomal gene transcripts are decreased in Inpp4b−/− leukemias; these include cathepsins and lysosomal specific proteases responsible for proteolysis. This discovery provided evidence supporting a potential role for INPP4B in the lysosomal pathway. To validate these findings, immunofluorescence staining of the lysosomal protein LAMP1 was performed, which revealed a greater number of lysosomes in U2OS cells overexpressing INPP4B, and a decrease in lysosome number upon siRNA knockdown of INPP4B. Subsequently the DQ-BSA staining was used to assess INPP4B’s effect on lysosomal function. In both U2OS and the leukemia cells, we observed that INPP4B expression is positively associated with the proteolytic activity of lysosomes. Currently we are testing the role of INPP4B expression on sensitivity to lysosomal inhibitors; Lys05, Chloroquine, and Mefloquine. Overall, we aim to uncover how INPP4B expression in AML controls lysosomal mechanisms and biology and to test putative therapeutic strategies to exploit this pathway.
Citation Format: Keyue Chen, Gizem E. Genc, John F. Woolley, Daniel K.C. Lee, Roberto J. Botelho, Leonardo Salmena. Investigating inositol polyphosphate-4-phosphatase, type II (INPP4B) signaling and role in acute myeloid leukemia [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P175.
Abstract P176: Discovery and development of novel covalent inhibitors of the YAP-TEAD transcription activity
Authors: Guo Shirley , Huang Cindy , Begley C. Glenn , Bishop Michael J. , Cao Ping 
Published: December 2021

Abstract
TEAD (TEA domain transcription factor) is a transcription factor. As a major effector of the Hippo signaling pathway, TEAD is reported to be responsible for cell proliferation, apoptosis, and stem cell self-renewal. Emerging evidence has shown that TEADs play a prominent role in the development, progression, and metastasis of cancers such as mesothelioma, liposarcoma, pancreatic, etc. Small-molecule inhibitors of TEADs could be a novel targeted therapy for multiple cancers. Using its proprietary chemoproteomic platform IMTACTM (Isobaric Mass Tagged Affinity Characterization), BridGene has screened its unique covalent library against live-cell proteomes. Three distinct series of hits, with MCS Tanimoto Coefficients at ~0.3 between any two series, were identified for TEAD proteins with nanomolar affinity and high proteomic selectivity. The covalent interactions between the hit and TEAD proteins were confirmed using orthogonal fluorescence-based experiments. Mass Spec analysis and mutagenesis experiments identified the site of modification within the central lipid (palmitate) binding pocket of TEAD1. Multiple novel and potent small molecule inhibitors were obtained with good druggability. Several functional assays were established to measure inhibition of TEAD-YAP transcription activity/disruption including Luciferase assay in MCF7-Luc, CTG (cell-titer Glo), and ELISA. When evaluated in vitro, BridGene’s TEAD inhibitors exhibited anti-proliferative properties against NF2-deficient mesothelioma cell lines (NCI-H226, NF2-/-) with low nM IC50, but had little effects on in NF2 wildtype cancer cell lines (NCI-H2452, NF2+/+) or HepG2 cell line. In an ELISA assay, BridGene’s small molecules can potently disrupt TEAD-YAP protein-protein interaction in cells. In MCF7-TEAD1 luciferase reporter cells, compounds showed single-digit nM potency in disrupting TEAD downstream gene expression. BridGene is developing covalent TEAD inhibitors to treat multiple cancers that are dependent on TEAD activity, including mesothelioma, cholangiocarcinoma, liposarcoma, pancreatic cancer, etc. With their high potency and proteomic selectivity, these TEAD inhibitors can potentially act as single-agent therapy, or work in combination with other care agents to treat multiple cancers.
Citation Format: Shirley Guo, Cindy Huang, C. Glenn Begley, Michael J. Bishop, Ping Cao. Discovery and development of novel covalent inhibitors of the YAP-TEAD transcription activity [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P176.
Abstract P178: RBM39 degradation leads to exceptional responses in high-risk neuroblastoma by targeting the spliceosome
Authors: Yang Jun 
Published: December 2021

Abstract
Genome-wide studies of thousands of human tumors have revealed dysregulated pre-mRNA splicing as a critical pathway in tumorigenesis, which may consequently create vulnerabilities for cancer cells. Indeed, C-MYC-dependent cancers are specifically susceptible to perturbation of spliceosome function. The MYC oncogenes (C-MYC, MYCN, and MYCL1), which are known transcriptional drivers of large numbers of genes, are among the most common genetic abnormalities in human cancer. We found that neuroblastoma, a MYC-driven cancer characterized by splicing dysregulation and spliceosomal dependency, requires splicing factor RBM39 for survival. Indisulam, a “molecular glue” that selectively recruits RBM39 to the CRL4-DCAF15 E3 ubiquitin ligase for proteasomal degradation, is highly efficacious against neuroblastoma, leading to exceptional responses in multiple high-risk disease models, without overt toxicity. Genetic depletion or indisulam-mediated degradation of RBM39 induces significant genome-wide splicing anomalies and cell death. Mechanistically, the dependency on RBM39 and high-level expression of DCAF15 determine the exquisite sensitivity of neuroblastoma to indisulam. Our data indicate that targeting the dysregulated spliceosome by precisely inhibiting RBM39, a vulnerability in neuroblastoma, is a valid therapeutic strategy. In summary, our study has validated the mechanism by which “molecular glues” targeting RNA binding proteins can be exploited for drug development in cancer, and has a broad impact on understanding of the splicing dependency of MYC-driven cancers and the identification of novel therapeutic approaches against them.
Citation Format: Jun Yang. RBM39 degradation leads to exceptional responses in high-risk neuroblastoma by targeting the spliceosome [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P178.
Abstract P182: VRK1 is a novel synthetic lethal target in VRK2-methylated glioblastoma
Authors: Shields Julie , Meier Samuel R. , Engel Justin , Bandi Madhavi , Dam Ferdinez Maria L. , Zhang Wenhai , Zhao Shan-chuan , Zhang Minjie , Choi Ashley , Yu Yi , Pan Xuewen , McMillan Brian , Williams Brett , Sjin Robert Tjin Tham , Whittington Douglas , Wilker Erik , Huang Alan , Li Fang , Emmanuel Natasha 
Published: December 2021

Abstract
Synthetic lethality — the genetic interaction that causes cell death when two genetic deficiencies co-occur but cell survival when each deficiency occurs alone — can be co-opted for cancer therapeutics. A pair of paralog genes is among the most straightforward synthetic lethal interactions by virtue of their redundant function in the cell. Here we demonstrate a paralog synthetic lethality by targeting VRK1 in VRK2-methylated glioblastoma multiforme (GBM). VRK2 is silenced by methylation in about two-thirds of GBM, an aggressive cancer with few available targeted therapies. Genetic knockdown of VRK1 in VRK2-null or VRK2-methylated cells leads to cell death via cell cycle arrest in G2M and subsequent DNA damage. The lethality is dependent on the kinase activity of VRK1 and is rescued by ectopic VRK2 expression. Knockdown of VRK1 leads to robust tumor growth inhibition in VRK2-methylated glioblastoma xenografts in vivo. These results suggest that inhibiting VRK1 kinase activity could be a viable cancer therapeutic in VRK2-methylated glioblastoma.
Citation Format: Julie Shields, Samuel R. Meier, Justin Engel, Madhavi Bandi, Maria L. Dam Ferdinez, Wenhai Zhang, Shan-chuan Zhao, Minjie Zhang, Ashley Choi, Yi Yu, Xuewen Pan, Brian McMillan, Brett Williams, Robert Tjin Tham Sjin, Douglas Whittington, Erik Wilker, Alan Huang, Fang Li, Natasha Emmanuel. VRK1 is a novel synthetic lethal target in VRK2-methylated glioblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P182.
Abstract P184: Anti-tumor efficacy of an MMAE conjugated antibody targeting cell surface TACE/ADAM17-cleaved Amphiregulin in breast cancer
Authors: Lofgren Kristopher A. , Sreekumar Sreeja , Jenkins Edmund C. , Ernzen Kyle J. , Kenny Paraic A. 
Published: December 2021

Abstract
The Epidermal Growth Factor Receptor ligand, Amphiregulin, is a key proliferative effector of estrogen receptor signaling in breast cancer and also plays a role in other malignancies. Amphiregulin is a single-pass transmembrane protein proteolytically processed by TACE/ADAM17 to release the soluble EGFR ligand, leaving a residual transmembrane stalk that is subsequently internalized. Here, we report the development of an antibody drug conjugate, GMF-1A3-MMAE, targeting an AREG neo-epitope revealed following ADAM17-mediated cleavage. The antibody does not interact with uncleaved Amphiregulin, providing a novel means of targeting cells with high rates of Amphiregulin shedding. Using fluorescent dye conjugation, we demonstrated that the antibody is internalized by cancer cells in a manner dependent on the presence of cell surface cleaved Amphiregulin. Antibodies conjugated with monomethyl auristatin E (MMAE) were cytotoxic in vitro and induced rapid regression of established breast tumor xenografts in immunocompromised mice. We further demonstrate that these antibodies recognize the Amphiregulin neo-epitope in formalin fixed paraffin embedded tumor tissue, suggesting their utility as a companion diagnostic for patient selection.
Citation Format: Kristopher A. Lofgren, Sreeja Sreekumar, Edmund C. Jenkins, Kyle J. Ernzen, Paraic A. Kenny. Anti-tumor efficacy of an MMAE conjugated antibody targeting cell surface TACE/ADAM17-cleaved Amphiregulin in breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P184.
Abstract P217: The next generation PARP inhibitor AZD5305 is active in a broad range of pre-clinical models of ovarian cancer
Authors: Dellavedova Giulia , Decio Alessandra , Staniszewska Anna , Leo Elisabetta , Giavazzi Raffaella , Bani Maria Rosa 
Published: December 2021

Abstract
Since the approval of poly (ADP-ribose) polymerase inhibitors (PARPi) for BRCA-mutated ovarian cancer patients, different PARPi have been developed and have shown efficacy in homologous recombination deficient (HRD) tumours. These first-generation drugs inhibit both PARP1 and PARP2 (as well as other PARP family members) and present undesirable adverse effects, such as haematological and intestinal toxicity, that restricted their use especially in combination with already poorly tolerated chemotherapeutic agents. Here, patient-derived ovarian cancer xenografts (OC-PDXs) were used i) to evaluate the dose response efficacy of AZD5305, a next generation, potent and selective PARP1 inhibitor and ii) to investigate the effect of the combination with carboplatin, a standard-of-care treatment for ovarian cancer patients. AZD5305 was administered orally (po) once daily (QD) for 8 weeks as monotherapy (0.1, 1 and 10 mg/kg) and in combination with carboplatin (CPT) dosed intravenously (35 mg/kg; Q7x4). Two BRCA1 mutated (HOC106 and HOC107) and a BRCA wild-type (HOC84) OC-PDXs (all TP53 mutated) were implanted subcutis and the effect of treatments on tumour growth evaluated. AZD5305 dosed at 0.1, 1 and 10 mg/kg to mice bearing HOC106 tumours, inhibited tumours growth in a dose dependent manner. Administered in combination at 0.1 and 1 mg/kg, AZD5305 potentiated the effect of carboplatin, causing a significant and sustained regression of HOC106 tumours. The anti-tumour efficacy was also evident against the PARPi-resistant OC-PDX HOC107, whereby the tumour growth was inhibited by AZD5305 at 1 and 10 mg/kg dose. Combined with carboplatin, AZD5305 stabilized the growth of HOC107 tumours at doses as low as 0.1 mg/kg that on its own was not effective. As expected, none of the treatments affected the growth of the BRCA wild-type HOC84 (PARPi and carboplatin resistant OC-PDX). Overall, AZD5305 a next generation PARP1-selective inhibitor and trapper, shows improved efficacy and tolerability in combination with chemotherapy compared to first generation, PARP1/2 inhibitors, making it a promising clinical candidate for the treatment of ovarian cancer.
Citation Format: Giulia Dellavedova, Alessandra Decio, Anna Staniszewska, Elisabetta Leo, Raffaella Giavazzi, Maria Rosa Bani. The next generation PARP inhibitor AZD5305 is active in a broad range of pre-clinical models of ovarian cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P217.
Abstract P231: Multigenomic characterization of context-dependent alternative splicing in normal and neoplastic cells
Authors: McMillan Elizabeth A. , Sriram Krishna , Creger Emily , Merkwirth Carsten , Pippa Raffaella , Pedraza Melinda , Do Long , Deshmukh Vishal , Bossard Carine , White Michael A. 
Published: December 2021

Abstract
Alternative pre-mRNA splicing (AS) supports the dynamic and regulated diversification of cells by allowing the production of multiple distinct proteins from individual genes. Dysregulated AS is commonly associated with human malignancies, producing pathological proteomes that underpin disease initiation, progression, and emergence of therapy resistance. The CDC2-like kinases (CLKs) and dual-specificity tyrosine-regulated kinases (DYRKs) are thought to govern the efficiency and specificity of AS by directly phosphorylating serine/arginine-rich splicing factors (SRSFs) and thereby influencing pre-mRNA splice junction selection. Cirtuvivint (SM08502) is a first-in-class small molecule ATP-competitive inhibitor of CLK/DYRK kinases. To directly evaluate the contribution of these kinases to AS profiles, changes in AS following treatment with cirtuvivint followed by high-depth RNAseq analysis across &gt;25 cell lines representing 7 tumor lineages were evaluated. Both baseline and drug-induced changes in AS events (ASEs) were measured using a multivariate analysis of transcript splicing (rMATS). Pan-CLK/DYRK inhibition was found to affect a minority of baseline ASEs, leaving the majority of spliceosome activity intact in all samples. However, the magnitude and quantity of detected drug-induced alterations were larger in a sample of tumor cells from a patient compared with adjacent non-tumorigenic cells. Moreover, most ASEs sensitive to pan-CLK/DYRK inhibition were tumor type-specific irrespective of selective presence at the gene level. Multi-omics data integration revealed sensitivity to cirtuvivint was associated with alterations in splicing genes and that drug-induced ASEs were significantly associated with disease-promoting biology across lineage and oncogenic driver contexts. Perturbed splicing of the AR-V7 variant in treatment-resistant prostate cancer and MDM2 in p53 wild-type cancers were prominent examples. These observations indicate vulnerabilities to CLK-DYRK regulated splicing span a wide range of oncogenic contexts with potential to be therapeutically addressed with pan CLK/DYRK inhibitors.
Citation Format: Elizabeth A. McMillan, Krishna Sriram, Emily Creger, Carsten Merkwirth, Raffaella Pippa, Melinda Pedraza, Long Do, Vishal Deshmukh, Carine Bossard, Michael A. White. Multigenomic characterization of context-dependent alternative splicing in normal and neoplastic cells [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P231.
Abstract P242: Preclinical efficacy landscape of the pan-CLK/DYRK inhibitor Cirtuvivint (SM08502)
Authors: Bossard Carine , Creger Emily , McMillan Elizabeth A. , Merkwirth Carsten , Ibanez Maureen , Bhat Deepti , Stewart Josh , Eastman Brian , Mak Chi-Ching , Deshmukh Vishal , White Michael A. 
Published: December 2021

Abstract
A monumental challenge facing cancer therapy is the vast mechanistic diversity of tumors among and even within cancer patients. This severely limits the number of patients that respond to any given therapy and the durability of responses that do occur. Deep phenotypic profiling of almost 9000 patient samples indicates perturbation of alternative pre-mRNA splicing (AS) is often a root cause of cancer. This offers an extraordinary opportunity to restore health through normalization of AS in diseased tissue. The bottleneck to progress has been finding and drugging the right targets. The CLK/DYRK kinases modulate AS efficiency and specificity, and therefore, targeting them offers the potential to address this bottleneck. The isoquinoline cirtuvivint is a potent ATP-competitive inhibitor of the Cdc2-like kinases (CLK1-4) and the dual-specificity tyrosine phosphorylation-regulated kinases (DYRK1-4), with activity against only a minimal number of the remaining members of the CMGC-family kinases or the kinome as a whole. Cellular target engagement assays indicated biological IC50s below 0.06 μM across the CLK/DYRK target class. Thus, cirtuvivint has utility for robust chemical evaluation of the overarching contribution of CLK/DYRK family activity to tumor biology in general and context- dependent AS in particular. To help assess the breadth and depth of CLK/DYRK dependencies in human cancers, the consequences of pan-CLK/DYRK inhibition on growth and survival of 154 cancer cell line models, 46 PDX models, and 43 CDX models were tested. EC50s in cell viability assays ranged from 0.014 to 0.73 μM in culture with strong effects observed in subsets of cell lines across all lineages tested. Molecular profiles associated with high sensitivity to cirtuvivint included somatic mutations in the RBM10 splicing factor. Tumor growth inhibition assays with daily dosing at exposures about 2X below the MTD resulted in significant disease control (≥75% TGI) in 15/46 PDX and 18/43 CDX models. Together, these results indicate broad cancer relevance, at least in the preclinical setting, and are consistent with a common reliance on CLK/DYRK-dependent alternative splicing among otherwise highly mechanistically heterogeneous disease.
Citation Format: Carine Bossard, Emily Creger, Elizabeth A. McMillan, Carsten Merkwirth, Maureen Ibanez, Deepti Bhat, Josh Stewart, Brian Eastman, Chi-Ching Mak, Vishal Deshmukh, Michael A. White. Preclinical efficacy landscape of the pan-CLK/DYRK inhibitor Cirtuvivint (SM08502) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P242.
Abstract P245: Synergistic effect of combination of pemigatinib with enfortumab vedotin (EV) in human bladder cancer models
Authors: Hess Rodrigo A. , Truong Lisa , Chadderton Antony , Frascella Michelle , Hall Leslie , Koblish Holly 
Published: December 2021

Abstract
Bladder cancer is among the most prevalent cancers worldwide, with urothelial carcinoma accounting for approximately 90% of cases. Until recently, poor overall survival after chemotherapy combined with immune checkpoint blockade therapies for patients with advanced urothelial carcinoma highlighted the need for new therapies. Although data supports the use of targeted therapies, such as FGFR inhibitors, recent advances in the treatment of bladder cancer are changing the landscape. Enfortumab vedotin (EV) is an antibody drug conjugate (ADC) consisting of an anti-Nectin-4 antibody conjugated to monomethyl auristatin E, which specifically delivers the auristatin payload to Nectin-4 high-expressing urothelial carcinomas. While activity and durability of response from both monotherapy trials as well as combination with pembrolizumab are favorable, additional treatment options might be required for either patients not responding to treatment or those who might develop resistance. Importantly, FGFR activation through rearrangement or mutation is frequently found in the luminal papillary subtype which also expresses high levels of Nectin-4. Thus, we sought to test the potential of combining pemigatinib and EV in models of human bladder cancer which express both activated FGFR3 and Nectin-4. Our initial analysis show that FGFR3 mutant tumors express high levels of Nectin-4. We further demonstrated that two bladder cancer cell lines RT112/84 (FGFR3-TACC3 fusion) and UM-UC-14 (FGFR3S249C) are sensitive to both pemigatinib and EV in vitro and in vivo. Notably, synergistic anti-tumor effects were observed when pemigatinib was combined with EV in vivo. In addition, combination of pemigatinib with EV significantly improved overall survival when compared to single treatments in these models. Altogether, our data strongly suggest a potential for combination of these therapies in the clinic.
Citation Format: Rodrigo A. Hess, Lisa Truong, Antony Chadderton, Michelle Frascella, Leslie Hall, Holly Koblish. Synergistic effect of combination of pemigatinib with enfortumab vedotin (EV) in human bladder cancer models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P245.