bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B103: Statins decrease mesothelial clearance, an early step in ovarian cancer metastasis
Authors: Reilly Brendan M , Martin Olivia R , Mackey Allison F , Walker Sarah R 
Published: December 2023

Abstract
Ovarian cancer has a low 5-year survival rate often associated with detection of late-stage cancer due to the difficulty of early detection. Ovarian cancer metastasis can occur via a distinct mechanism compared to other solid cancers. Ovarian cancer spheroids slough off from the primary tumor. In the ascites, these spheroids attach to and clear the protective layer of mesothelial cells that line the peritoneum. Once this mesothelial clearance occurs, the ovarian spheroids can invade the connective tissue and metastasize to further parts of the body or grow implanted in the peritoneum. Targeting mesothelial clearance may be a new mechanism to treat ovarian cancer. Previously, it was shown that the use of statins, drugs commonly used to control cholesterol, is associated with decreased ovarian cancer occurrence. In addition, statins have the potential to interfere with several signaling pathways that are known to play key roles in cancer including metastasis. The potential for statins to target metastasis could be beneficial in treating cancers like ovarian cancer that tend to be found in metastatic stages. Therefore, we hypothesized that statins would reduce mesothelial clearance by ovarian cancer spheroids. Using an in vitro mesothelial clearance assay, we have found that statins, such as simvastatin and lovastatin, decrease the mesothelial clearing abilities of ovarian cancer spheroids. To better understand the mechanism of mesothelial clearance inhibition, we analyzed several known downstream pathways. Targeting HMGCR by siRNA, the known molecular target of statins, reduced mesothelial clearance. In addition, targeting Rac1 and CDC42 using the inhibitor AZA1 has a similar inhibitory effect as simvastatin on mesothelial clearance. This suggests that inhibition of Rac1 by statins may be the mechanism that statins inhibit mesothelial clearance. To support this, siRNA knockdown of RAC1 suggests the importance of Rac1 for mesothelial clearance. Previously, we found that treatment of ovarian spheroids with geranylgeranyl-pyrophosphate partially rescued the inhibition of viability by statins. Therefore, our current working hypothesis is that statins disrupt the function of Rac1 by reducing the cellular supply of geranylgeranyl-pyrophosphate through inhibiting HMGCR and the mevalonate pathway. While we are currently further analyzing the mechanisms behind this pathway, we believe this evidence suggests an exciting new therapeutic route for treating ovarian cancer.
Citation Format: Brendan M Reilly, Olivia R Martin, Allison F Mackey, Sarah R Walker. Statins decrease mesothelial clearance, an early step in ovarian cancer 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 B103.
Abstract B104: U18666A-induced cholesterol accumulation decreases tumor-derived exosomes load and modulates malignant transformation
Authors: Beevi Syed Sultan , Verma Vinod Kumar 
Published: December 2023

Abstract
Background: Tumor-derived exosomes (TDEs) play an important role in the horizontal transfer of oncogenic information from the tumor to other sites, where they regulate pre-metastatic niche formation, organotropism, migration, invasion and survival. Cellular cholesterol homeostasis emerges as an important factor for exosomal biogenesis and cellular release. In this study, we utilized U18666A to trigger cholesterol accumulation within late endosomes of MDA-MB231 cells and evaluated the ability of exosomes derived from both U18666A-treated and untreated cells to initiate malignant transformation in recipient human epithelial kidney (HEK293) cells.
Methods: Exosomes were isolated and characterized from MDA-MB231 (untreated and U18666A-treated) and HEK293 cells. Cholesterol content of the cells and their associated exosomes were measured to confirm its accumulation following U18666A treatment. The effects of exosomes derived from untreated MDA-MB231 (UCE) and U18666A-treated MDA-MB231 (UTCE) cells on HEK293 cells were examined to determine their transforming potential.
Results: Exosomes derived from MDA-MB231 cells induced proliferation, migration, malignant transformation and epithelial-mesenchymal transition (EMT) process in non-cancerous recipients’ cells. U18666A treatment led to accumulation of cholesterol within late endosomes and significantly reversed the EMT process in MDA-MB231 cells. It also reduced TAEs load from the cancer cells and rendered them less oncogenic which was evident from their inability to induce malignant transformation in the recipient HEK293 cells.
Conclusion: Modulation of cholesterol homeostasis and disruption of cholesterol supply to aggressive cancer cells can be an attractive strategy for limiting TAEs release as well as their subsequent role in cancer progression and metastasis.
Citation Format: Syed Sultan Beevi, Vinod Kumar Verma. U18666A-induced cholesterol accumulation decreases tumor-derived exosomes load and modulates malignant transformation [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 B104.
Abstract B178: Proteomics platform identifies vulnerabilities for specific DNA damage repair drugs
Authors: Arad Gali , Hay-Koren Avital , Futorian David , Fischman Oren , Daitchman Dina , Givton Ofer , Alchanati Iris , Katzenelenbogen Yonatan , Seger Eran , Pevzner Kirill 
Published: December 2023

Abstract
While poly-ADP-ribosylation (PAR) polymerase inhibitors (PARPi) are the only DNA damage repair (DDR) agent currently approved for clinical use, there are numerous ongoing clinical and preclinical drug development efforts of many other DDR-related targets, including ATR, ATM, CHK1 and others. One of the major challenges of these efforts is the ability to identify responsive populations and assign the right population for the right drug or drug combination. Patients are routinely assigned to PARPi or to on-going DDRi clinical trials based on the presence of BRCA mutation, or BRCAness profile encompassing various homologous recombination deficiencies (HRD). However, these biomarkers only partially represent the responsive populations, resulting in low response rates as well as misidentification of potential patient populations outside the genomic label. Since DNA replication and DNA repair mechanisms are dominated by signaling events, we hypothesized that HRD extends beyond the genomic status, and is manifested also in the level of protein expression and protein modification.In the current work, we compare the differences between cell lines that are either sensitive or resistant to a variety of DDR agents and highlight potential predictive biomarkers that are independent of HRD mutation status. We combined publicly available proteomic profiles of unperturbed cell lines, with both existing and newly generated proteomic and phosphoproteomic data of multiple cell lines before and after treatment of multiple DDR drugs.Analysis of HRD mutations showed that drug sensitivity is only partially explained by mutations. In addition, we found DNA replication and spliceosome as pathways that are consistently related to response regardless of drug and mutation status. While there is a general agreement between drugs in the pathway level, we identify smaller groups of proteins that are either drug or target-specific. We present here a proteogenomic approach to tackle the challenge of predictive biomarkers to DDR drugs. While DNA repair vulnerability is essential for DDR drug response, it is often not defined by mutations alone. We provide a proteomics-based framework that would enable future patient selection in DDR clinical trials.
Citation Format: Gali Arad, Avital Hay-Koren, David Futorian, Oren Fischman, Dina Daitchman, Ofer Givton, Iris Alchanati, Yonatan Katzenelenbogen, Eran Seger, Kirill Pevzner. Proteomics platform identifies vulnerabilities for specific DNA damage repair drugs [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 B178.
Abstract C006: BID upregulation associates with sensitivity to TTK inhibitors in tumor cell lines
Authors: Bertran-Alamillo Jordi , Giménez-Capitán Ana , García-Román Silvia , Rosell Rafael , Molina-Vila Miguel A 
Published: December 2023

Abstract
Background: Drugs overriding the spindle assembly checkpoint (SAC), such as Aurora kinase B (AURKB) or dual-specificity protein kinase TTK (=Mps1) inhibitors, are in Phase I/II clinical trials. However, their clinical application has been hampered by the lack of biomarkers for patient selection. We have previously demonstrated that BID upregulation, present in 6% of human tumors, predicts sensitivity to AURKB inhibition in cell line and animal models. Here, we investigated the association of BID expression with response to TTK inhibitors (TTKi).
Methods: A panel of seven solid tumor cell lines of lung, breast, melanoma, and pancreas origin were used in the study, together with three EGFR-mut clones derived from the PC9 lung cancer cell line. All of them had been previously characterized for BID expression at the mRNA and protein levels. The effects of three TTKi (BAY1217389, CFI-402257 and BOS172722) on proliferation, cell cycle and cell death were analyzed by MTT and flow cytometry, respectively. Silencing and ectopic expression with lentiviral vectors, together with transfection with a 72-gene knock-out library, were used to investigate mechanisms of action.
Results: The concordance in response to the three TTKi among the cell lines and clones analyzed was 100%. Three of the seven tumor cell lines and 2/3 EGFR-mut clones were uniformly sensitive, showing IC50s &lt;100 nM for CFI-402257 and BOS172722 and &lt;10 nM for BAY1217389. BID expression was significantly associated with response to TTKi (p&lt;0.05). All cells sensitive to TTKi had high BID mRNA and protein levels; while the cells with low BID were resistant. Flow cytometry showed G2/M arrest after TTKi in all lines and clones, followed by cell death only in those with high BID. Silencing using shRNA viral particles significantly reduced sensitivity to the three TTKi in the two sensitive cell lines and clones tested. Conversely, ectopic expression of BID in two resistant cell lines increased sensitivity to BAY1217389 and BOS172722. Finally, among a library of 72 genes, only knock-out of BID and the genes coding for the components of the PIDDosome (PIDD, CRADD and CASP2) triggered resistance to TTKi.
Conclusions: BID upregulation associates with sensitivity to TTKi through a mechanism involving the PIDDosome. Our results warrant clinical exploration of TTKi in BID overexpressing tumors.
Citation Format: Jordi Bertran-Alamillo, Ana Giménez-Capitán, Silvia García-Román, Rafael Rosell, Miguel A Molina-Vila. BID upregulation associates with sensitivity to TTK inhibitors in tumor cell lines [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 C006.
Abstract C007: Improved T-cell and B-cell receptor repertoire profiling and immunophenotyping for biomarker discovery
Authors: Chenchik Alex , Makhanov Mikhail , Liu Tianbing , Hu Dongfang , Ghias Khadija , Kobzik Lester 
Published: December 2023

Abstract
T-cell receptor (TCR) and B-cell receptor (BCR) repertoire profiling, also referred to as adaptive immune receptor repertoire (AIRR) profiling, holds great potential for the understanding of disease mechanisms and for the development of new treatments in infectious disease, autoimmunity, and immuno-oncology. This potential could be greatly improved by combining information about receptor clonotypes with immunophenotypes of T- and B- cells. A new technology we developed that combines profiling of all human TCR and BCR variable regions with phenotypic characterization of immune cells using the same workflow could be particularly useful. The TCR and BCR immunophenotyping method proposed involves RT-PCR amplification and sequencing of the CDR3 regions of the TCR and BCR genes, and subsequently determining the expression levels of the most informative T- and B-cell phenotyping genes. Preliminary results show that this method allows for comprehensive profiling of all seven TCR and BCR chains from a single sample, in a highly reproducible manner, directly from micro-samples including cancer tissue, whole blood, sorted cells and more. Bioinformatic analysis of the next-generation sequencing (NGS) data from the TCR and BCR clonotypes profile combined with RNA expression profiling of the same samples results in a richer data set that includes the identification of major immune cell subtypes and their activation status. Data from human cancer tissues and whole blood samples will be presented.
Citation Format: Alex Chenchik, Mikhail Makhanov, Tianbing Liu, Dongfang Hu, Khadija Ghias, Lester Kobzik. Improved T-cell and B-cell receptor repertoire profiling and immunophenotyping for biomarker discovery [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 C007.
Abstract C015: FGFR1 and RB1 genetic alteration impair clinical benefit of CDK4/6 inhibitors plus endocrine therapy in HR+/HER2- advanced breast cancer
Authors: Zhong Jianxin , Shao Bin , Jiang Hanfang , Li Huiping 
Published: December 2023

Abstract
Background: One of the great challenges for HR+/HER2- advanced breast cancer (ABC) is to determine who respond poorly to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). Chemotherapy is still used in HR+/HER2- patients. We aimed to explore cfDNA biomarkers for CDK4/6i plus endocrine therapy (ET), and compare its efficacy with chemotherapy in subgroups stratified by clinical and cfDNA characteristics.
Method: Patients diagnosed with HR+/HER2- advanced breast cancer underwent first-line CDK4/6i plus ET or chemotherapy in Peking University Cancer Hospital from January 2018 to June 2022 were enrolled in this study. Baseline blood samples of patients were collected before first-line treatment for cfDNA sequencing.
Results: Among all the 125 patients included in this study, the median PFS (mPFS) of CDK4/6i plus ET group (n=51) was significantly longer than patients treated with chemotherapy(n=74) (22.0 vs. 16.0 months, P = 0.025). In multivariate analysis, RB1 loss (Hazard ratio [HR] = 6.4, adjusted P = 0.031), FGFR1 gain (HR: 4.9, adjusted P = 0.030) were associated with shorter PFS of patients treated with CDK4/6i plus ET. A better efficacy of CDK4/6i plus ET was observed in patients with visceral metastasis, higher Ki-67 (≥20%) and smaller SLD (&lt; 35mm) than chemotherapy. In subgroup analysis, interaction effects were found between RB1 loss (P interaction = 0.028), FGFR1 gain (P interaction = 0.004) and first-line treatment.
Conclusion: This study revealed that FGFR1 gain and RB1 loss are independent prognostic factors for PFS of CDK4/6i plus ET, and chemotherapy was not superior to CDK4/6i plus ET in the absence of FGFR1 gain and RB1 loss, which might improve selection of patients for CDK4/6 inhibitors.
Citation Format: Jianxin Zhong, Bin Shao, Hanfang Jiang, Huiping Li. FGFR1 and RB1 genetic alteration impair clinical benefit of CDK4/6 inhibitors plus endocrine therapy in HR+/HER2- advanced breast 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 C015.
Abstract C017: Exploiting tumor RNA-sequencing data for prediction of immune checkpoint inhibition response
Authors: Mestdagh Pieter 
Published: December 2023

Abstract
Immune checkpoint inhibitors (ICI) have become the standard of care as a first- or second-line systemic treatment for patients with various cancer types. Unfortunately, many patients do not respond to this treatment and the occurrence of immune-related adverse events varies widely. There is an urgent need for robust predictive biomarkers for ICI response to select patients with likely clinical benefit from this costly treatment. Several biomarkers, aimed at predicting response to ICI, have been proposed, including PD-L1 expression, tumor mutation burden (TMB), infiltration of cytotoxic T-cells in the tumor, Microsatellite Instability (MSI) and expression of various immune gene signatures. However, these individual biomarkers have suboptimal performance and multiple complementary omics technologies are required to properly quantify them. Integration of these multi-omic biomarkers has proven valuable in increasing the accuracy and robustness of ICI response prediction. We have developed a computational pipeline that determines the expressed mutation burden (eTMB), MSI status, fraction of infiltrating immune cells and various immune gene expression signatures directly from the RNA-sequencing profile of the tumor. Each biomarker is quantified using a dedicated algorithm that applies machine learning (eTMB and MSI) or computational deconvolution (infiltrating immune cells) and integrates external data sources to maximize performance. Algorithm performance has been validated on large cohorts of tumor RNA-sequencing data with matching gold standard quantification of said biomarkers. Moreover, integrating these biomarkers improves prediction of response to checkpoint inhibition therapy. Taken together, our approach enables the quantification of various ICI response biomarkers from a single omics layer (RNA-seq) and can contribute to ICI response prediction.
Citation Format: Pieter Mestdagh. Exploiting tumor RNA-sequencing data for prediction of immune checkpoint inhibition response [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 C017.
Abstract C041: Drug repurposing to target TGF-β in chemoresistant high-grade serous ovarian cancer
Authors: Wong-Brown Michelle WY , Johnson Zlata , Salem Saad , Matthews Bayley G , Ford Caroline E , Marsh Deborah J , Bowden Nikola A 
Published: December 2023

Abstract
High-grade serous ovarian cancer (HGSOC) has low 5-year survival rate of 48%, due to chemotherapy resistance. Effective new therapies are required to improve the survival rate of HGSOC. TGF-β is a family of proteins associated with epithelial-mesenchymal transition and have been implicated in ovarian cancer progression and chemoresistance. Drugs that target TGF-β may have potential to be used to treat chemoresistant HGSOC and control tumour growth and progression. Drug repurposing is a strategy to identify new uses for approved drugs outside of their original indication, and ensure timely access to efficacious and cost-effective therapy for chemoresistant HGSOC. The aims of the study is to determine the effect of the repurposed drug teniposide on HGSOC cell growth, death, and apoptosis. A ligand-based screening was performed by Cresset Discovery for approved drugs that bind to the TGF-β receptor complex and ligand. Teniposide was shortlisted according to its dosing, lipid solubility, pharmacokinetics, and side effects. MTT assays were performed on eight molecularly-characterised HGSOC cell lines to obtain the IC50 of teniposide. The effect of the IC50 dose of teniposide on HGSOC cell growth, death, and apoptosis were monitored on the IncuCyte live-cell imager. Western blotting was performed to determine the expression of TGF-β signalling pathway proteins after treatment with teniposide. The average IC50 of teniposide in HGSOC cell lines is 10µM, within the range of the maximum plasma concentration (61µM). HGSOC cell lines treated with 10µM teniposide showed decreased cell growth, and increased cell death and apoptosis, similar to HGSOC cell lines treated with clinically-relevant dose of carboplatin (30µM). HGSOC cell lines treated with 10µM teniposide showed significantly higher cell death and apoptosis compared to treatment with 30µM carboplatin. Our preliminary results show that teniposide significantly reduced proliferation of HGSOC and has potential to be repurposed for treatment of chemoresistant HGSOC.
Citation Format: Michelle WY Wong-Brown, Zlata Johnson, Saad Salem, Bayley G Matthews, Caroline E Ford, Deborah J Marsh, Nikola A Bowden. Drug repurposing to target TGF-β in chemoresistant high-grade serous ovarian 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 C041.
Abstract C050: Comprehensive analysis of causes for unsuccessful genomic profiling in a Phase 1 setting
Authors: Iden Cecilie , Belcaid Laila , Jacobsen Ida , Hoejgaard Martin , Spanggaard Iben , Mau-Soerensen Morten , Lassen Ulrik , Yde Christina Westmose , Rohrberg Kristoffer Staal 
Published: December 2023

Abstract
Purpose: Genomic profiling (GP) has revolutionized personalized cancer therapy, enabling tailored treatment strategies based on individual tumor characteristics. However, despite its widespread use, there are instances where GP fails. Understanding the causes of such failures is important for improving the success rate of GP. Here, we present a comprehensive analysis of unsuccessful GP within a phase 1 clinical setting.
Materials and Methods: A prospective, single-center, single-arm open label study (NCT02290522) was conducted, enrolling patients with advanced cancer referred to a phase I unit. Fresh tumor tissue was obtained by core needle biopsy for whole genome- or whole exome sequencing and RNA sequencing. In cases where fresh tumor tissue was unavailable, archival, formalin-fixed, paraffin-embedded tumor tissue or circulating tumor DNA extracted from plasma were obtained.
Results: Between March 2013 and December 2021, a total of 2151 patients with advanced cancers and exhausted or almost exhausted treatments options were enrolled in the study. GP was unsuccessful in 281 patients (13%). The reasons for failure were; abstaining from biopsy due to performance decline from the time of consent (115/281= 41%), inadequate tissue quality due to normal tissue or necrosis (52/281= 19%), absence of lesions for tissue biopsy at the time of biopsy (41/281= 15%), patient withdrawal of consent (23/281= 8%), pre-analytical factors preventing tissue or liquid biopsy analysis (14/281= 5%), unsuccessful analyses (13/281= 4%), other treatment initiated at time of planned biopsy (10/281= 4%), unknown reasons (9/281= 3%) or biopsy contraindicated (4/281= 1%).
Conclusion: The main cause of unsuccessful GP in this study was pre-analytical factors, primarily linked to performance status decline. Performing the biopsy and GP in earlier treatment lines, may reduce failure rates. Furthermore, considering the risk of rapid performance status decline, prior to biopsy referral, along with reduced lag time from obtaining consent to biopsy, may enhance GP success rates.
Citation Format: Cecilie Iden, Laila Belcaid, Ida Jacobsen, Martin Hoejgaard, Iben Spanggaard, Morten Mau-Soerensen, Ulrik Lassen, Christina Westmose Yde, Kristoffer Staal Rohrberg. Comprehensive analysis of causes for unsuccessful genomic profiling in a Phase 1 setting [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 C050.