bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5559: The anti-tumor efficacy and immune effects of combining of ceralasertib, an oral ATR kinase inhibitor, with imipridones, in prostate cancer treatment in vitro and in vivo
Authors: Xia Yutong Linda , Zhang Leiqing , Ghandali Maryam , Schwermann Maximilian P. , El-Deiry Wafik 
Published: March 2024

Abstract
Prostate cancer is the most common cancer and the second leading cause of cancer death among men in the United States. There is an estimated 10% to 50% of cases progress to metastatic castration resistant prostate cancer (mCRPC) state within 3 years of diagnosis. mCPRC remains lethal despite therapeutic advances. There is approximately 20% of mCRPC patients present somatic DNA damage repair (DDR) gene mutations. Ceralasertib, formerly known as AZD6738, is a potent and selective orally bioavailable inhibitor of the ataxia tenlangiectasia and Rad3-related (ATR) kinase, which is involved in DNA repair in response to DNA damage and replication stress. Preclinical studies have demonstrated ATRi sensitizing alterations in DNA damage response (DDR) genes. Ceralasertib’s antitumor activity as a monotherapy in treating prostate cancer is moderate. Thus, we combined ceralasertib with imipridones (ONC201 and ONC206), which target mitochondrial caseinolytic protease P (ClpP) and the integrated stress response, resulting in enhanced antitumor efficacy in vitro. Prior data have demonstrated sensitivity of 4 prostate cancer lines to ceralasertib and imipridones monotherapies, synergistic activities with the combination treatments, and immune enhancement effects with the combination treatments when co-cultured with NK92MI cell line. We proceeded to a short term in-vivo study validating the combination treatment efficacy. Preliminary results include cytokine profiling using the Luminex 200 technology to understand treatment induced changes in the tumor microenvironment (TME) from both in vitro and in vivo studies. Our results guide novel clinical trials for effective clinical responses in mCPRC patients.
Citation Format: Yutong Linda Xia, Leiqing Zhang, Maryam Ghandali, Maximilian P. Schwermann, Wafik El-Deiry. The anti-tumor efficacy and immune effects of combining of ceralasertib, an oral ATR kinase inhibitor, with imipridones, in prostate cancer treatment in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5559.
Abstract 557: Clofarabine inhibits U87MG glioblastoma cell line proliferation through CD99 signaling pathway
Authors: de Souza Camila Cristina , Soares Roseli da Silva , Lerario Antonio Marcondes , Marie Suely Kazue , Oba-Shinjo Sueli Mieko 
Published: March 2024

Abstract
The present work aimed to test the efficacy of clofarabine in glioblastoma (GBM) cells that express high levels of CD99. GBMs are the most malignant with the poorest prognosis among tumors of the central nervous system. Patients have a median survival of 12 to 15 months despite surgical, radio, and chemotherapy. CD99 is a cell surface receptor overexpressed in several types of tumors, including GBMs, justifying the interest of studies in CD99 as a possible therapeutic target. Our group has previously demonstrated that knockout of CD99 in the U87MG GBM cell line promoted a decrease in cell adhesion, migration, and invasion. Clofarabine is a third-line drug used in the treatment of refractory/relapsed childhood acute lymphoblastic leukemia. It is a purine analog that is transported into intracellular space, phosphorylated, and incorporated into DNA chain, inhibiting DNA synthesis and ultimately inducing cell death by apoptosis. The clofarabine effect has also been demonstrated in cells from solid tumors, such as breast, gastric, and bladder. Clofarabine action on the proliferation of Ewing sarcoma cells in vitro and in vivo was proved to be by direct binding to CD99 and independent of the drug internalization. In addition, clofarabine also had an effect on cells from other tumor types that express CD99. The present work demonstrated the significant action of clofarabine on the high CD99-expressing U87MG cells by inhibiting cell proliferation, adhesion, and migration, and by inducing cell cycle arrest and apoptosis. U87MG cells knocked out for CD99 expression were more resistant to clofarabine action on proliferation. RNAseq analysis of U87MG cells treated with clofarabine and compared to control showed downregulated genes involved in cell cycle regulation and mitosis, while upregulated genes were enriched in extracellular proteins, cell adhesion, locomotion, p53 signaling pathway, and apoptosis. Our data indicates clofarabine as a potential CD99 inhibitor to treat GBM patients.
Citation Format: Camila Cristina de Souza, Roseli da Silva Soares, Antonio Marcondes Lerario, Suely Kazue Marie, Sueli Mieko Oba-Shinjo. Clofarabine inhibits U87MG glioblastoma cell line proliferation through CD99 signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 557.
Abstract 558: Stearoyl-CoA desaturase is a synthetic lethal target in SMAD4-deficient cancers
Authors: Lu Alvin , Fenoglio Silvia , Wu Hsin-Jung , Zhang Minjie , Tsai Alice , Ferdinez Maria L. , Grove Lauren , Liu Shangtao , Wu Edward , Choi Ashley , Throner Scott , Meier Samuel , Yu Yi , Zhang Wenhai , Maxwell John , Andersen Jannik N. , Teng Teng , Haines Brian B. , Chen Yingnan P. 
Published: March 2024

Abstract
Mothers against decapentaplegic homolog 4, or SMAD4, is a member of the SMAD family of transcription factors that mediate TGF-β signal transduction. SMAD4 loss of function mutation or deletion is found in about 30% of PDAC and 15% of COAD and EAC patients, and it is associated with their poor prognosis. Over the past two decades, its tumor suppressor role has been elucidated, and the loss of SMAD4 is sufficient to promote tumorigenesis in multiple GEM models. To identify novel therapeutic vulnerabilities for SMAD4-deficient cancers, a CRISPR dropout screening approach was employed in SMAD4 isogenic PDAC models. We identified stearoyl-CoA desaturase, SCD, as a synthetic lethal target in SMAD4-deficient context. SCD is critical for de novo lipid biogenesis and catalyzes the rate-limiting step in the production of monounsaturated fatty acid. Genetic and pharmacologic studies in vitro confirmed this synthetic lethal relationship. Additionally, drug-anchored CRISPR dropout screening and RNA expression profiling demonstrated that accumulation of saturated fatty acid in response to SCD inhibition drives cytotoxicity in SMAD4-deficient cells. Mouse studies with CRISPR-based knockout of SCD and a well-characterized SCD inhibitor (A939572) demonstrated anti-tumor efficacy in SMAD4-mutant xenograft models. However, compared to genetic KO of SCD the pharmacological inhibitor was less effective at inhibiting tumor proliferation in vivo. Together, these data identify SCD as a selective vulnerability in SMAD4-mutant cancers.
Citation Format: Alvin Lu, Silvia Fenoglio, Hsin-Jung Wu, Minjie Zhang, Alice Tsai, Maria L. Ferdinez, Lauren Grove, Shangtao Liu, Edward Wu, Ashley Choi, Scott Throner, Samuel Meier, Yi Yu, Wenhai Zhang, John Maxwell, Jannik N. Andersen, Teng Teng, Brian B. Haines, Yingnan P. Chen. Stearoyl-CoA desaturase is a synthetic lethal target in SMAD4-deficient cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 558.
Abstract 5596: Exploring BRCA1-Y1853ter and potential therapeutic targets in BRCA1-BRCT mutated cancers
Authors: Chen Jingjing 
Published: March 2024

Abstract
The breast cancer gene BRCA1 plays a pivotal role as a tumor suppressor gene. Despite the use of poly (ADP-ribose) polymerase inhibitors (PARPi) in treating BRCA1 mutation carriers, the lack of response or the development of acquired drug resistance underscores the pressing need for new therapeutic targets. One intriguing BRCA1 mutation, BRCA1-Y1853ter, characterized by a minimal truncation, has been identified in multiple individuals with Hereditary Breast and Ovarian Cancer (HBOC) syndrome. We have developed a Halo Tag and adenovirus-based system where wild-type BRCA1 (WT BRCA1) and mutant BRCA1 protein complexes can be studied in multiple cell types. Here, we used this system to affinity purify BRCA1 wild-type and mutant complexes, followed by label-free quantitative proteomics to investigate the dynamic interactome variations between WT BRCA1 and BRCA1 mutant. Contrary to the assumed loss of function, our preliminary findings suggest a potential gain of function, as a significant number of candidate proteins exhibit enhanced binding affinity with the mutant BRCA1. We are currently exploring whether these distinct binding characteristics are shared among various BRCA1-BRCT mutants, which may hint at a common tumorigenesis mechanism. Our overarching hypothesis is that identifying a specific binding partner, shared among various BRCA-BRCT mutants, could unveil a novel therapeutic target with broader applicability in treating BRCA1-related malignancies.
Citation Format: Jingjing Chen. Exploring BRCA1-Y1853ter and potential therapeutic targets in BRCA1-BRCT mutated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5596.
Abstract 5640: Unlocking the therapeutic potential of SF3B1 inhibitors for bladder cancer treatment
Authors: Columbres Rod Carlo , Chakraborty Arup , Apolo Andrea , Banday Rouf 
Published: March 2024

Abstract
RNA splicing dysregulation is a hallmark of cancer, occurring in multiple solid and hematological malignancies. Splicing factor 3 subunit B1 (SF3B1), a key component of the U2 small nuclear ribonucleoprotein (snRNP) complex that regulates RNA splicing, is frequently altered in a variety of cancer types, including non-muscle-invasive and muscle-invasive bladder cancer, where the E902K mutation is common. In this study, we investigated the therapeutic potential of the SF3B1 inhibitor, pladienolide B, in bladder cancer using in vitro models. We used a recombinant plasmid containing the SF3B1E902K mutation and established an UMUC3E902K mutant urothelial cell line. Both UMUC3WT and UMUC3E902K cells were treated with pladienolide B alone or in combination with cisplatin to evaluate differences in cell viability. Flow cytometry using annexin V staining and propidium iodide exclusion was utilized to assess the cell death mechanism. RNAseq was performed after RNA extraction from UMUC3WT, UMUC3E902K, RT4, and HT1376 bladder cancer cell lines were treated with pladienolide alone or combined with cisplatin. We determined that the IC50 for pladienolide B is 5nM for UMUC3 cells observed 72 hours post-treatment. Treatment with pladienolide B halted the cell cycle and caused cell death by apoptosis for both UMUC3WT and UMUC3E902K cell lines. We also observed that UMUC3E902K cells were significantly more sensitive to pladienolide B compared to UMUC3WT cells (p≤0.05). Furthermore, there was a synergistic effect observed after co-treatment with low-dose pladienolide B (2 nM) and cisplatin (3 µM) for both UMUC3WT and UMUC3E902K cell lines, with UMUC3E902K cells showing greater sensitivity to combination treatment. Our results provide insights into the potential use of splicing inhibitors, alone or in combination with chemotherapy, for treating bladder cancer, specifically for tumors that bear driver mutations in splicing factors. Currently, we are evaluating the mechanism by which SF3B1 mutations make cells sensitive to pladienolide B in vitro and in vivo, with the goal of identifying specific mRNA splicing vulnerabilities that can be targeted by anti-sense or splice-switching oligonucleotides to achieve anti-tumor outcomes. Additional differential splicing patterns and preliminary in vivo results will be presented.
Citation Format: Rod Carlo Columbres, Arup Chakraborty, Andrea Apolo, Rouf Banday. Unlocking the therapeutic potential of SF3B1 inhibitors for bladder cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5640.
Abstract 5680: Circular MALAT1 - the new kid on the block in breast-to-brain metastatic cancer
Authors: Szczepaniak Adrian , Bronisz Agnieszka , Godlewski Jakub 
Published: March 2024

Abstract
Introduction: Breast-to-brain metastatic (BTB met) cancer constitutes a great challenge for modern medicine and science. As the research on protein-coding genes brought only incremental progress in developing anticancer therapy, much attention is devoted to understanding the role of non-coding RNAs, including a relatively recently discovered group - of circular RNAs. This project aimed to determine the relationship between BTB met cancer cells and cells derived from a deadly brain tumor - glioblastoma stem-like cells (GSCs), considering the circular RNA signatures and selecting a reliable candidate for mechanistic study - a circular form of non-coding oncogene MALAT1 (circMALAT1).
Methods: The circular RNA expression profile in patient-derived BTB met cancer cells (n=4), GSCs (n=8), and neural progenitor cells (NPC) as a non-malignant control (n=3) was evaluated by the microarray approach. Expression of circMALAT1 was also validated in non-malignant breast epithelial cells by digital PCR and data mining in the GEO database. CircMALAT1 knockdown by antisense oligonucleotides was followed by functional analysis.
Results: 12,660 circular RNAs were detected using the Arraystar platform, and upon applying the cutoff of FC ≥2 and p-value &lt;0.05, 547 circular RNAs were selected as significantly deregulated in all cancer groups compared to NPC. CircMALAT1 was elevated in BTB met compared to NPC and normal breast epithelial cells. Knockdown of circMALAT1 affected cancer cell viability and proliferation while promoting p21 expression, thus decelerating the cell cycle manifested by a reduction in 3D spheroids volume.
Conclusions: The analysis of the circular RNA landscape showed for the first time some striking similarities between BTB mets and GSCs despite different tissue-of-origin. Of note, the circRNAome of BTB mets clustered especially closely with mesenchymal GSC - the most aggressive and therapy-resistant subtype of GSCs. These results also demonstrated the role of circMALAT1 in shaping the oncogenic traits of these cells. Therefore, circular RNAs can serve as valuable biomarkers and promising novel mechanistic candidates whose modulation may become a paradigm-shifting therapeutic approach.
Citation Format: Adrian Szczepaniak, Agnieszka Bronisz, Jakub Godlewski. Circular MALAT1 - the new kid on the block in breast-to-brain metastatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5680.
Abstract 5709: PF-07104091, a first-in-class CDK2-selective inhibitor for the treatment of HR+/HER2- breast cancer and CCNE1high ovarian cancer
Authors: Shen Chen , Qiu Ming , Huser Nanni , Pascual Bernadette , Zhang Qin , VanArsdale Todd , Murtaza Anwar , Almaden Jonathan , Kim berly , Anders Lars , Eisele Koleen 
Published: March 2024

Abstract
The selective inhibition of Cyclin\CDK complexes controlling cell cycle progression has been established as cancer therapy by selective CDK4/6 inhibitors in HR+/HER2- breast cancer. Expanding control of the cell cycle through selective inhibition of CDK2 offers novel therapeutic opportunities in cancer, including targeting CCNE1 amplified tumors and countering resistance to CDK4\6 inhibitors in ER+ breast cancer. PF-07104091 is a first-in-class CDK2-selective inhibitor under clinical investigation in patients with HR+/HER2- breast cancer and ovarian cancer. Preclinical studies using PF-07104091 establish the therapeutic impact of CDK2 inhibition in both diseases and highlight distinct mechanistic roles for CDK2 in control of cancer cell proliferation. In models of CCNE1 amplified ovarian cancer, CDK2 plays the dominant role in control of RB1 phosphorylation and the G1 checkpoint. CDK2 inhibition with PF-07104091 induces G1 growth arrest and controls tumor xenograft growth as single agent therapy. In ER+ breast models CDK2 plays a supportive role in the control of RB1 phosphorylation cooperating with CDK4\6. Whole genome CRISPR KO and CRISPR activation screens in conjunction with CDK4\6 inhibition establish CDK2 KO as a primary sensitizer to CDK4\6 inhibition, and support Cyclin E\CDK2 complexes as the driver of resistance to CDK4\6 inhibitors in ER+ breast models. PF-07104091 combined with CDK4\6 inhibitor Palbociclib or CDK4-selective inhibitor PF-0060 synergistically controls proliferation of ER+ BC cells in vitro and induces tumor regression in ER+ BC xenograft models, including PDX models with acquired resistance to CDK4\6 inhibitors and endocrine therapy.
Citation Format: Chen Shen, Ming Qiu, Nanni Huser, Bernadette Pascual, Qin Zhang, Todd VanArsdale, Anwar Murtaza, Jonathan Almaden, berly Kim, Lars Anders, Koleen Eisele. PF-07104091, a first-in-class CDK2-selective inhibitor for the treatment of HR+/HER2- breast cancer and CCNE1high ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5709.
Abstract 5712: Functional dissection of CDK7 in transcription using a highly selective CDK7 inhibitor Q901
Authors: Jung Hyerim , Um Dahun , Lee Yoonji , Yu Donghoon , Lee Dayoung , Ahn Jiye , Kim Jeongjun , Lee Seung-Joo , Kim Jaeseung , Nam Kiyean , Kim Tae-Kyung 
Published: March 2024

Abstract
CDK7 is a well-known regulator of both the cell cycle and transcription and plays a crucial role in cell cycle progression by catalyzing T-loop phosphorylation of other CDKs. CDK7 is also an integral subunit of the general transcription factor, TFIIH and regulates transcription through phosphorylation of RNA Polymerase II (Pol II) at CTD Ser5 and CDK9. We used Q901, a highly selective CDK7 inhibitor to further investigate the molecular function of CDK7 in the transcriptional process. Q901 is currently being evaluated in a phase 1 clinical study for selected advanced solid tumors. Compared to previously reported CDK7 inhibitors, Q901 has increased specificity and efficacy, but the impact on transcription have not been studied in detail. In our study, we combined RNA Pol II (pan, Ser5P, Ser2P) ChIP-seq and PRO-seq techniques in the MCF7 breast cancer cell line. The findings demonstrated that the Q901 effectively altered transcription and the RNA Pol II profile in a subset of genes, leading to a significant reduction in Ser5 phosphorylation levels in RNA Pol II. The downregulated genes were associated with critical pathways including downstream of oncogenic genes (MYC and E2F), DNA damage repair, cell cycle checkpoint, and gene expression. To verify whether these genes were the direct targets of CDK7, we performed CDK7 ChIP-seq analysis. CDK7 binding exclusively to the genes that were downregulated by Q901, without any detectable binding to upregulated genes. Despite the universal role of general transcription machinery in transcription, the data demonstrated that the highly selective inhibition of CDK7 in transcription of various oncogenic pathways underlies the potent in vitro and in vivo anti-cancer efficacy of this specific CDK7 inhibitor.
Citation Format: Hyerim Jung, Dahun Um, Yoonji Lee, Donghoon Yu, Dayoung Lee, Jiye Ahn, Jeongjun Kim, Seung-Joo Lee, Jaeseung Kim, Kiyean Nam, Tae-Kyung Kim. Functional dissection of CDK7 in transcription using a highly selective CDK7 inhibitor Q901 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5712.
Abstract 5736: Sonochemical preparation of SP94 peptide-decorated pH-responsive biodegradable biopolyester nanoparticles for targeted therapy in hepatocellular carcinoma
Authors: Wu Mingfang , Wang Qi , Gong Zhengran , Liu Zixuan , Zheng Haodong , Chen Xinjie , Zhong Chen 
Published: March 2024

Abstract
Stimulation in response to nanoparticles responding to endogenous stimuli in the tumor microenvironment has been extensively studied for the release of chemotherapeutic drug. Therefore, we aimed to develop a biocompatible delivery of taxol (TAX) delivery vector system for the treatment of hepatocellular carcinoma (HCC). A basic backbone, TAX loaded poly (3-hydroxybutyrate-co-3-hydroxyvalerate) PHBV nanoparticle (PHBV-TAX-NPs), were designed and prepared via sonochemical method. The pH-responsive shell of PHBV-TAX-NPs was formed by oxidative self-polymerization of dopamine (PDA) in an alkaline environment. The HCC-targeted peptide SP94 binds to PDA-coated nanoparticles (NPs) through the Michael reaction. Moreover, the nanoparticle surface-grafted SP94 peptide serve as a specific ligand for targeting HCC. The chemical structures and properties of these nanoparticles were characterized by transmission electron microscope, dynamic light scattering-autosizer, differential scanning calorimetry, fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy and thermogravimetry. As expected, excellent targeting of these SP94-PDA-PHBV-TAX-NPs was demonstrated by cellular uptake and cytotoxicity experiments in HCC cells. Compared with that of free TAX, the SP94-PDA-PHBV-TAX-NPs showed more superior antitumor efficacy in the xenograft mouse model. Notably, the SP94-PDA-PHBV-TAX-NPs were except for their potent anticancer activity, it was less toxic in vitro and in vivo compared to TAX in mice. These studies suggest the potential beneficial use of SP94-PDA-PHBV-TAX-NPs in future HCC-targeted therapy with drug-loaded nanocarriers.
Citation Format: Mingfang Wu, Qi Wang, Zhengran Gong, Zixuan Liu, Haodong Zheng, Xinjie Chen, Chen Zhong. Sonochemical preparation of SP94 peptide-decorated pH-responsive biodegradable biopolyester nanoparticles for targeted therapy in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5736.