bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C061: GNL3 promotes prostate cancer growth by regulating androgen receptor protein stability
Authors: Cheung Edwin , Zhang Cuiting 
Published: December 2023

Abstract
Androgen receptor (AR) is a primary driver of prostate cancer growth and development. Changes in AR coregulatoractivity or expression have severe consequences on the development of the disease. Using ChIP-MS, we discover G Protein Nucleolar 3 (GNL3) as a new AR transcriptional coactivator. We show that GNL3 helps the recruitment of AR to chromatin to directly control genes that support prostate cancer growth. We also demonstrate that GNL3 stabilizes AR by protecting it from ubiquitination and proteasomal degradation. We further determine that GNL3 is required for tumor progression by preventing cell-cycle arrest and apoptosis. Moreover, depleting GNL3 causes prostate cancer cells to be more susceptible to AR antagonists. Our work also indicates that Palbociclib, a CDK4/6 inhibitor, can be combined with enzalutamide to suppress cancer cell growth by downregulating AR and GNL3 co-regulated genes. From patient analyses, we observe that GNL3 expression is significantly elevated in many clinical studies. Finally, we reveal an AR-GNL3 gene signature in prostate tumors that is highly expressed and predicts disease recurrence. In summary, our results highlightthat GNL3 is a novel coactivator of AR and a potential target for the treatment of prostate cancer.
Citation Format: Edwin Cheung, Cuiting Zhang. GNL3 promotes prostate cancer growth by regulating androgen receptor protein stability [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 C061.
Abstract C081: Novel and selective inhibitors of KRASG12V
Authors: Bhavar Prashant Kashinath , Surampudi Uday Kumar 
Published: December 2023

Abstract
KRAS is one the most mutated proteins in cancers and are commonly identified in pancreatic adenocarcinoma, colorectal and non-small cell lung cancer. Owing to its role in a different human cancer, KRAS has long been considered as an important therapeutic target in precision oncology. Although KRAS was considered undruggable due to the protein’s structural complexity, recent allele specific inhibitors that covalently bind and trap KRAS in its inactive GDP bound state have demonstrated promising approach for generating anti RAS therapies and is validated by the accelerated approval of Sotorasib and Adagrasib by the FDA for patients with lung cancer. Success of targeting mutant KRASG12C has opened opportunities to tackle other oncogenic KRAS variants such as KRASG12V. KRASG12V mutations occur frequently in multiple tumour histotypes such as adenocarcinoma of Pancreas (~32%), colorectal adenocarcinoma (~20%) and Lung (~19%) and represents a significant unmet medical need. Here we describe preclinical profile of a potent and selective KRASG12V inhibitor VRTX171. VRTX171 is a tool compound that was potent across a KRASG12V mutated cancer cell line and found to be several fold less active in non-KRASG12V mutant cell lines. Using a de novo drug design approach the compound was optimized to offer desired potency with high selectivity over WT KRAS and other KRAS mutant isoforms. Affinity for target protein, was assessed by HTRF based target engagement assay and inhibition of Raf/Mitogen-activated protein kinase (MAPK) pathway was determined using Western blot analysis in multiple cancer cell lines harbouring KRASG12V mutation. In-vivo studies of VRTX171 in Xenograft models harbouring KRASG12V mutations, as single agent as well as in combination with other targeted therapies are under consideration.
Citation Format: Prashant Kashinath Bhavar, Uday Kumar Surampudi. Novel and selective inhibitors of KRASG12V [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 C081.
Abstract C150: Targeted inhibition of homologous recombination and nonhomologous end joining in diffuse intrinsic pontine gliomas to prevent tumor recurrence
Authors: Barravecchia Ivana , Sharma Monika , Teis Robert , Cruz Jeanette , Mumby Rachel , Ziemke Elizabeth , Espinoza Carlos , Magnuson Brian , Ljungman Mats , Koschmann Carl , Whitehead Christopher , Sebolt-Leopold Judith , Galban Stefanie 
Published: December 2023

Abstract
Therapeutic resistance remains a major obstacle to successful clinical management of Diffuse Intrinsic Pontine Glioma (DIPG), a high-grade pediatric tumor of the brain stem. In nearly all patients, available therapies fail to prevent progression. Innovative combinatorial therapies that penetrate the blood-brain barrier and lead to long-term control of tumor growth are desperately needed. We identified mechanisms of resistance to radiotherapy, the standard of care for DIPG. Based on these findings, we rationally designed a brain-penetrant small molecule, MTX-241F, that is a highly selective inhibitor of EGFR and PI3 kinase family members, including the DNA repair protein DNA-PK. Preliminary studies demonstrate that micromolar levels of this inhibitor can be achieved in murine brain tissue and that MTX-241F exhibits promising single-agent efficacy and radiosensitizing activity in patient-derived DIPG neurospheres. Its physiochemical properties include high exposure in the brain, indicating excellent brain penetrance. Since radiotherapy results in double-strand breaks that are repaired by homologous recombination (HR) and non-homologous DNA end joining (NHEJ), we have tested the combination of MTX-241F with an inhibitor of ATM to achieve blockade of HR and NHEJ, respectively, with or without radiotherapy. When HR blockers were combined with MTX-241F and radiotherapy, synthetic lethality was observed, providing impetus to explore this combination in clinically relevant models of DIPG. Our data provide proof-of-concept evidence to support advanced development of MTX-241F for the treatment of DIPG. Future studies will be designed to inform rapid clinical translation to ultimately impact patients diagnosed with this devastating disease.
Citation Format: Ivana Barravecchia, Monika Sharma, Robert Teis, Jeanette Cruz, Rachel Mumby, Elizabeth Ziemke, Carlos Espinoza, Brian Magnuson, Mats Ljungman, Carl Koschmann, Christopher Whitehead, Judith Sebolt-Leopold, Stefanie Galban. Targeted inhibition of homologous recombination and nonhomologous end joining in diffuse intrinsic pontine gliomas to prevent tumor recurrence [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 C150.
Abstract C161: Identification of a reversible selective FGFR2 clinical development candidate with potency against gatekeeper and molecular brake mutations
Authors: Fischer John , Bouhana Karyn , Brizendine Richard , Chicarelli Mark , Fell Brad , Fulton Jennifer , Guarnieri Anna , Haygood Leyla , Jalluri Ravi , Johnson Amber , Koch Keith , Koslov-Davino Erika , Mejia Max , Rieger Rob , Robinson John , Rodriguez Mareli , Sullivan Francis , Wang Yang , Winski Shannon , Wood Silas , Zhou Yeyun 
Published: December 2023

Abstract
Approved FGFR inhibitors have demonstrated responses in patients that harbor FGFR genetic alterations but show reduced activity in patients with gatekeeper and molecular brake mutations. In addition, efficacy of these agents may be reduced due to inhibition of FGFR1 and associated dose-limiting hyperphosphatemia. To address these issues, a novel series of reversible FGFR2 inhibitors with activity against clinically relevant mutations and selectivity over FGFR1 has been identified. The inhibition of FGFR2 phosphorylation in engineered cell lines demonstrated activity toward wild-type FGFR2, molecular brake mutations N549H/K, and gatekeeper mutations V564I/F/L. Selectivity of these inhibitors against FGFR1 could lead to fewer dose limiting toxicities compared to approved FGFR inhibitors. From this series, the identification of the clinical development candidate as a potent selective reversible FGFR2 inhibitor is described. In vivo characterization to be presented includes dose escalating rodent pharmacokinetics (PK), second species PK, and efficacy in AN3 CA tumor bearing mouse models.
Citation Format: John Fischer, Karyn Bouhana, Richard Brizendine, Mark Chicarelli, Brad Fell, Jennifer Fulton, Anna Guarnieri, Leyla Haygood, Ravi Jalluri, Amber Johnson, Keith Koch, Erika Koslov-Davino, Max Mejia, Rob Rieger, John Robinson, Mareli Rodriguez, Francis Sullivan, Yang Wang, Shannon Winski, Silas Wood, Yeyun Zhou. Identification of a reversible selective FGFR2 clinical development candidate with potency against gatekeeper and molecular brake mutations [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 C161.
Abstract IA012: REGN10597: A PD-1-targeted, receptor-masked wild type IL-2 with improved therapeutic window for cancer immunotherapy
Authors: Wu Jiaxi , Bloch Nicolin , Chang Aaron , Bhavsar Ramandeep , Wang Qingqing , Patel Supriya , Garg Vidur , Shakil Hassan , Amatulli Michael , Dudgeon Drew , Yan Yuetian , Wang Shunhai , Ramos Willy , Krueger Pamela , Vazzana Kristin , Crawford Alison , Idun Jacqueline , Decker Corinne , DiLillo David , Chandwani Samira , Huang Tammy , Kirshner Jessica , Guo Chungguang , Macdonald Lynn , Ullman Erica , Hermann Aynur , Olson William , Davis Samuel , Lin John , Smith Eric , Zhang Tong 
Published: December 2023

Abstract
Recombinant IL-2 has been used for the treatment of metastatic melanoma and renal cell carcinoma, and induced complete, durable tumor regression in some patients. ​However, its broader use in cancer immunotherapy has been limited by severe toxicity. Here, we describe the development of REGN10597, a PD-1-targeted, receptor-masked IL-2 immunocytokine with attenuated systemic IL-2 activity but maintained capacity to engage endogenous IL-2Ra on PD-1+ T cells. We will share preclinical data on in vitro characterization as well as in vivo efficacy and toxicity studies of REGN10597.
Citation Format: Jiaxi Wu, Nicolin Bloch, Aaron Chang, Ramandeep Bhavsar, Qingqing Wang, Supriya Patel, Vidur Garg, Hassan Shakil, Michael Amatulli, Drew Dudgeon, Yuetian Yan, Shunhai Wang, Willy Ramos, Pamela Krueger, Kristin Vazzana, Alison Crawford, Jacqueline Idun, Corinne Decker, David DiLillo, Samira Chandwani, Tammy Huang, Jessica Kirshner, Chungguang Guo, Lynn Macdonald, Erica Ullman, Aynur Hermann, William Olson, Samuel Davis, John Lin, Eric Smith, Tong Zhang. REGN10597: A PD-1-targeted, receptor-masked wild type IL-2 with improved therapeutic window for cancer immunotherapy [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 IA012.
Abstract IA013: Integrating natural product samples back into drug screening programs
Authors: O'Keefe Barry R. 
Published: December 2023

Abstract
Natural products have a proven track record in use as anti-cancer agents. As of 2020 natural products (NPs), NP pharmacophores, and NP mimics represent a significant percentage of small molecule-based anti-cancer drugs. However, accessing the potential of NPs in high-throughput screening (HTS) campaigns has been challenging due to the complexity of the crude NP extracts, the time necessary for follow-up isolation efforts, and indefinite capabilities for resupply. This has resulted in NP-based libraries being significantly underrepresented in most recent large-scale HTS programs. The US National Cancer Institute’s Natural Product Extract Repository is one of the world’s largest, most diverse collections of natural products containing &gt;200,000 unique extracts derived from plant, marine and microbial organisms. To address the challenges in screening NPs and encourage increased assay of NP chemical diversity, the NCI created a Program for Natural Product Discovery (NPNPD) which has developed an automated, high-throughput robotics platform that has created 500,000 pre-fractionated NP samples and released them to the public for screening. In addition, automated secondary purification and structure elucidation systems were created that significantly decrease costs and timelines. This presentation will discuss the reasons for, challenges to, and mechanisms by which the NCI is working to increase the pace and efficiency of NP-based drug discovery.
Citation Format: Barry R. O'Keefe. Integrating natural product samples back into drug screening programs [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 IA013.
Abstract LB_A24: Baicalein suppresses tumorigenesis of the ER𝛼 positive of breast cancer cells by targeting multiple signaling pathways
Authors: Xhabija Besa , McLaughlin Aidan J. , Epelle Ibiere Lovelyn , Nielson Tristan H. , Ujeniuc Elisabeta , Duhaini Mariam I. 
Published: December 2023

Abstract
The anti-tumor properties of baicalein, a flavonoid compound, have been extensively documented. However, the specific effects of baicalein on ER𝛼 positive breast cancer cell lines, namely T47-D and MCF-7, are less well-known. In this study, we conducted comprehensive in vitro experiments to elucidate the comparative impacts of baicalein on these two cell lines. Our results demonstrate that baicalein exerts robust anti-cancer effects, inducing morphological changes, reducing colony formation, and inhibiting cell proliferation in both T47-D and MCF-7 cells. These effects were more pronounced at higher concentrations. Additionally, baicalein treatment impeded the migratory capabilities of both cell lines, as shown by wound healing assays. Furthermore, our data show that baicalein triggers apoptosis, leading to an increase in early apoptotic, late apoptotic, and dead cells. This apoptotic process appears to be caspase 3/7-dependent. Interestingly, the pro-apoptotic effects were more potent in T47-D cells, accompanied by significant upregulation of pro-apoptotic genes and downregulation of anti-apoptotic markers. Baicalein treatment also induced oxidative stress and DNA damage, evidenced by an increase in reactive oxygen species (ROS) and phosphorylation of ATM and H2A.X. Importantly, baicalein inhibited the PI3K signaling pathway, a key mediator of cancer progression. Genome-wide transcriptomic analysis revealed significant changes in gene expression patterns, with baicalein treatment causing both upregulation and downregulation of several genes. Pathway analysis revealed that cell cycle and ferroptosis pathways were activated in both cell lines upon baicalein treatment. In conclusion, our findings highlight the potential of baicalein as a therapeutic agent against breast cancer, while also revealing nuanced differences in response between the T47-D and MCF-7 breast cancer cell lines.
Citation Format: Besa Xhabija, Aidan J. McLaughlin, Ibiere Lovelyn Epelle, Tristan H. Nielson, Elisabeta Ujeniuc, Mariam I. Duhaini. Baicalein suppresses tumorigenesis of the ER𝛼 positive of breast cancer cells by targeting multiple signaling pathways [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 LB_A24.
Abstract LB_B03: Lentivirus-induced ALDH1L1 knock-in inhibits proliferation and migration and activates apoptosis of human A549 lung adenocarcinoma cells
Authors: Abdellatef Amira , Krupenko Sergey 
Published: December 2023

Abstract
Lung Adenocarcinoma (LUAD), one of the most common life-threatening malignancies worldwide, represents about 40% of all lung cancers. Human Protein Atlas and OncoLnc database indicate that LUAD tumors have significantly lower mRNA levels of ALDH1L1 (10-formyltetrahydrofolate dehydrogenase, a regulatory enzyme in folate metabolism) than in non-tumor lung tissues. Moreover, higher intratumoral ALDH1L1 expression in LUAD patients correlates with better clinical outcome. These findings raise the question of whether ALDH1L1 knock-in can have a therapeutic effect. As the first step in addressing this question, we knocked-in ALDH1L1 in A549 lung adenocarcinoma cells using the lentiviral delivery. Of note, as most cancer cell lines, A549 cells do not express ALDH1L1. We have constructed the lentiviral vector carrying ALDH1L1 and green fluorescent protein (EGFP) cDNA under the control of CMV and SV40 promoters, respectively. Recombinant lentivirus (Lv-ALDH1L1), generated and packed in HEK293 cells, was used to transduce A549 cells. The efficiency of the transduction was evaluated by monitoring the GFP expression using the fluorescence microscopy of live cells. The expression of ALDH1L1 was determined at the mRNA and protein levels by RT-PCR and western blot assays, accordingly. Our results showed a significant expression of ALDH1L1 mRNA and protein expression in A549 cells carrying the Lv-ALDH1L1 vector. The lentivirus-induced ALDH1L1 elevation produced strong inhibitory effects on cellular proliferation and colony formation under nutrient-rich conditions. Of note, it also induced alterations of cell morphology. To explore the underlying mechanisms of these effects, apoptosis-related markers were examined. Elevated levels of the signal transduction pathways involved in initiating apoptosis; BID, BAX, and BAK in A549 cells transduced with Lv-ALDH1L1 were observed. Furthermore, using the wound healing assay, we showed that ALDH1L1 strongly suppresses the migratory ability of A549 cells. Interestingly, this effect was associated with a robust down-regulation of the actin depolymerizing factor cofilin and its phosphorylated form. Overall, this study demonstrated that lentiviral ALDH1L1 knock-in produces strong anti-tumorigenesis effects in A549 cells. This further suggests that ALDH1L1 should be investigated as a therapeutic drug target in cancer treatment.
Citation Format: Amira Abdellatef, Sergey Krupenko. Lentivirus-induced ALDH1L1 knock-in inhibits proliferation and migration and activates apoptosis of human A549 lung adenocarcinoma 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 LB_B03.
Abstract LB_B07: Probability of negative impact on adherence caused by the most frequent side effects of adjuvant endocrine therapy for premenopausal breast cancer in SOFT and TEXT Trials
Authors: Qurayshah Tariq Hassan AL 
Published: December 2023

Abstract
Background: Regardless of adjuvant chemotherapy, the addition of ovarian function suppression (OFS) to adjuvant endocrine therapy tamoxifen or exemestane in pre-menopausal women with estrogen receptor (ER)-positive breast cancer cause adverse events may affect adherence. Among the 22 targeted adverse events systematically reported in SOFT and TEXT trials, adverse events commonly experienced in exemestane–OFS group (32.3%) and tamoxifen–OFS group (31.0%), compared with tamoxifen alone group (24.6%). Side effects associated with endocrine therapy cause negative impact on adherence. Early discontinuation of endocrine therapy in 22.5%, 19.3%, and 23.7% of the tamoxifen, tamoxifen–OFS, and exemestane–OFS groups, respectively, in SOFT and TEXT trials. This report is intended to evaluate the possible contribution of the 8 most frequently studied side effects that have negative impact on adherence to hormone therapy in breast cancer. Methods: Calculating the probability of negative impact of most frequent endocrine therapy`s side effects (per SOFT-TEXT trials) on adherence per Leanne Fleming et al quantitative systematic review “The impact of medication side effects on adherence and persistence to hormone therapy in breast cancer survivors” Results: Musculoskeletal/joint pain had the most negative impact on the adherence in tamoxifen, tamoxifen–OFS, and exemestane–OFS groups (56%, 63% and 73%, respectively). Average of negative impact of tamoxifen, tamoxifen–OFS, and exemestane–OFS on adherence is 22%, 25% and 27%) Conclusions: The probability of adherence of using tamoxifen alone seems better than tamoxifen–OFS and exemestane–OFS.
Citation Format: Tariq Hassan AL Qurayshah. Probability of negative impact on adherence caused by the most frequent side effects of adjuvant endocrine therapy for premenopausal breast cancer in SOFT and TEXT Trials [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 LB_B07.
Abstract LB_B21: Extracellular RNA signatures of mutant KRAS-driven lung cancer
Authors: Maroli Sree Lakshmi Velandi , Reggiardo Roman E , Khojah Reem , Kim Daniel H 
Published: December 2023

Abstract
RAS genes are the most frequently mutated oncogenes in cancer, yet the effects of oncogenic RAS signaling on the noncoding transcriptome remain unclear. We analyzed the transcriptomes of human airway and bronchial epithelial cells transformed with mutant KRAS to define the landscape of KRAS-regulated noncoding RNAs. We find that oncogenic KRAS signaling upregulates noncoding transcripts throughout the genome, many of which arise from transposable elements (TEs). These TE RNAs exhibit differential expression and are regulated by KRAB zinc-finger (KZNF) genes, which are broadly downregulated in mutant KRAS cells and lung adenocarcinomas in vivo. Using both affinity- and nanofiltration-based EV isolation approaches, we show that specific TE RNAs, lncRNAs, and mRNAs, some of which are prognostic for lung adenocarcinoma (LUAD) patient survival, are preferentially released in extracellular vesicles (EVs). Moreover, we find that inhibition of oncogenic KRAS signaling broadly reprograms the noncoding transcriptome, as evidenced by a substantial increase in TE RNA secretion. Mutant KRAS inhibition also increases the abundance of secreted lncRNAs and retained intron-containing transcripts, while decreasing the mRNA content of EVs. Notably, oncogenic KRAS signaling is required for the secretion of mRNAs from a set of 20 genes that are significantly associated with unfavorable clinical outcomes in LUAD. Our results indicate that mutant KRAS remodels the repetitive noncoding transcriptome, demonstrating the broad scope of intracellular and extracellular RNAs regulated by this oncogenic signaling pathway. Our study also suggests that both coding and noncoding RNAs that are secreted in EVs may serve as mutant KRAS-specific signatures for diagnosing lung cancer via minimally invasive RNA liquid biopsy technology, which we are currently developing as a companion diagnostic for mutant KRAS-targeting therapies.
Citation Format: Sree Lakshmi Velandi Maroli, Roman E Reggiardo, Reem Khojah, Daniel H Kim. Extracellular RNA signatures of mutant KRAS-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 LB_B21.