tbuckley/cabot-search huggingface dataset:
Abstract 6465: A population-based analysis of brain metastasis burden and management in 8705 small cell lung cancer patients
Authors: Karolina Gaebe, Anders W. Erickson, Sarah Chen, Arjun Sahgal, Benjamin H. Lok, Kelvin K. Chan, Sunit Das
Journal: Cancer Research (2024)

Abstract Introduction: Patients with small cell lung cancer (SCLC) have historically been characterized by poor overall survival (OS) and high risk for brain metastases (BM), but large-scale real-world evidence on clinical presentation and treatment in this population is lacking. Methods: The aim of this study was to describe the clinical characteristics and outcomes of patients with SCLC and BM in Ontario, Canada. This retrospective cohort study included all patients in Ontario, Canada, who were diagnosed with SCLC between April 2010 and March 2018. Data were analyzed between June 2022 and July 2023. Kaplan-Meier and multivariable Cox regression analyses were performed to compare overall survival (OS) between patient cohorts stratified by disease stage, BM diagnosis, or first-line intracranial treatment modality. Results: 8705 patients were included. Median age at diagnosis was 68 years (range 18-103). Median OS of all patients was 7.46 months (95% confidence interval, CI, 7.23-7.69). 32% (n=2686) of patients developed BM (synchronous, 43.7%; asynchronous, 56.3%) and had median OS of 9.76 months (95% CI, 9.36-10.22). 102, 1654, and 880 patients received stereotactic radiosurgery (SRS), whole brain radiation therapy (WBRT), and no treatment, respectively, for their BM in the first-line setting or after prophylactic cranial irradiation (PCI). In propensity score-matched analyses, OS was equivocal between SRS- and WBRT-treated cohorts among patients who did not receive PCI (hazard ratio, HR, 1.18, 95% CI, 0.75-1.81) and those who received PCI prior to BM development (HR, 0.77, 95% CI, 0.53-1.13). Conclusions: Survival for patients with SCLC remains poor, and many patients present with BMs. With careful selection, patients with SCLC may benefit from SRS treatment. Citation Format: Karolina Gaebe, Anders W. Erickson, Sarah Chen, Arjun Sahgal, Benjamin H. Lok, Kelvin K. Chan, Sunit Das. A population-based analysis of brain metastasis burden and management in 8705 small cell lung cancer patients [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 6465.
Abstract 552: Non-canonical disulfide isomerases are strongly selective, understudied targets for cancer therapy
Authors: Mary E. Law, Zaafir M. Dulloo, Elham Yaaghubi, Grace M. Alexandrow, Bianca Forsyth, Hanyu Su, Ronald K. Castellano, Brian K. Law
Journal: Cancer Research (2024)

Abstract A major challenge in cancer therapy is the identification of drug targets that are essential for cancer cells but not non-transformed cells. The Broad Institute’s Dependency Map (DepMap) evaluates whether knocking down or knocking out expression of specific genes is “strongly selective” against subsets of cancer cells, in contrast with genes that are “common essential.” Of the 22 human Protein Disulfide Isomerases (PDIs), only four, ERp44, TMX1, AGR2, and AGR3, were identified as strongly selective in the DepMap. Importantly, our team previously identified ERp44, AGR2, and AGR3 as targets of bicyclic thiosulfonate compounds termed Disulfide bond Disrupting Agents (DDAs). DDAs exhibit striking anti-cancer activity in xenograft tumor studies. DDA treatment of cancer cells blocks ERp44, AGR2, and AGR3 active site Cys residues, ablating their catalytic activity and binding to client proteins. Evaluation of cancer cell lines predicted to be sensitive to DDAs, based on their AGR2, AGR3, or ERp44 dependence, accurately predicts DDA sensitivity. Cell lines from a variety of tumor types exhibit AGR2, AGR3, or ERp44 dependencies. Our previous work identified HER-family members (i.e., EGFR, HER2, and HER3) and TRAIL receptors (Death Receptors 4 and 5) as important clients of DDA-sensitive PDIs in breast cancer cells, but it was unknown if these observations extend to other tumor types. Initial studies indicate that AGR2 DepMap dependencies are a strong predictor of sensitivity of cancer cells to DDAs, irrespective of their site of origin. It will be important in future studies to determine what the key client proteins for these DDA-sensitive PDIs are and whether they vary across tumor types. Citation Format: Mary E. Law, Zaafir M. Dulloo, Elham Yaaghubi, Grace M. Alexandrow, Bianca Forsyth, Hanyu Su, Ronald K. Castellano, Brian K. Law. Non-canonical disulfide isomerases are strongly selective, understudied targets for cancer therapy [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 552.
Abstract 2090: The GNAQ T96S mutation enhances the oncogenic properties of breast cancer
Authors: Ming-Hsi Wu, Hsiang-Ching Wang, Wei-Hsin Wang, Yen-Ju Lin, Wan-Ru Chen, Shih-Ta Chen, Chih-Wei Fu, Eric Chuang
Journal: Cancer Research (2024)

Abstract Breast cancer (BC) is the most commonly diagnosed cancer in the world, and metastatic breast cancer (mBC) remains responsible for the majority of breast cancer deaths. In this study, we collected 615 cases of Taiwanese BC patient's tumor samples and used whole exome sequencing (WES) to clarify the genetic mutation landscape of this population. We have compared with various BC genomic databases such as TCGA, COSMIC, and MSKCC to identify 29 novel variants in 18 genes that were predicted to have a pathogenic effect. In these pathogenic variants, we found that the GNAQ T96S mutation (threonine 96 to serine alteration of the Gαq protein) was presented in 116 out of 615 BC patients (18.9%). To examine the effect of the GNAQ T96S mutation on BC, we transfected the MCF-7 and MDA-MB-231 cell lines with the wild-type or the mutant GNAQ T96S expression vector. Transfection with the GNAQ T96S expression vector enhanced cell proliferation, colony formation, migration, and activation of the MAPK pathways compared to wild-type GNAQ expression MCF-7 cells. We also found that the tumorigenicity, and tumor growth were significantly increased in the GNAQ T96S expressed MCF-7 xenograft model, and exhibited higher rates of lung metastasis in GNAQ T96S expressed MDA-MB-231 cells. Our data suggest that the GNAQ T96S mutation may play an oncogenic role in BC by potentiating the GNAQ signaling pathway. In this study, we also found several compounds that can inhibit in vitro cell proliferation and in vivo tumor growth of GNAQ T96S expressed MCF-7 cells. These compounds showed the potential to treat the mBC patients who have GNAQ T96S mutation. Citation Format: Ming-Hsi Wu, Hsiang-Ching Wang, Wei-Hsin Wang, Yen-Ju Lin, Wan-Ru Chen, Shih-Ta Chen, Chih-Wei Fu, Eric Chuang. The GNAQ T96S mutation enhances the oncogenic properties of breast 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 2090.
Abstract 4331: Machine learning-based classification of tissue origin of cancer using methylation profiles
Authors: Marco A. De Velasco, Kazuko Sskai, Seiichiro Mitani, Yurie Kura, Shuji Minamoto, Takahiro Haeno, Hidetoshi Hayashi, Kazuto Nishio
Journal: Cancer Research (2024)

Abstract Cancer of unknown primary (CUP) is a malignancy with poor prognosis and an unknown primary site and histologically unknown metastasis. Most patients receive empiric chemotherapy including platinum-taxane therapies but experience short survival times. Patients with poor prognosis CUP could benefit from optimizing drug therapy based on primary organ estimation. We constructed and evaluated an ensemble learning model to accurately determine the primary organ using methylation profiles of tumor tissues. Methylation data from 890 samples representing 10 types of cancer from TCGA were analyzed. After data preprocessing, we extracted the top 10,000 CpGs sites based on ANOVA and Gain Ratio or 100 CpG sites from a Gradient Boosting classifier. Performance was evaluated using several machine learning models. Unsupervised analysis was carried out to determine the relationships between the CpG sites selected by Gradient Boosting. Methylation profiling by ANOVA and Gain Ratio yielded favorable performance when using various machine learning models. Using gradient boosting as a feature selector reduced the number of CpG sites by 100-fold without compromising model performance. The training and validation sets showed favorable results for the classification of primary organs with ensemble models. In validation, classification accuracy was 91.2%, 93.5%, 89.7%, and 87.7% for Extreme Gradient Boosting, CatBoost, Random Forest, and Gradient Boosting, respectively. Further profiling of the selected methylation regions was correlated with cancer types and even revealed subgroups within breast and lung cancers. Gradient Boosting as a feature selector for DNA methylation profiling was highly effective in accurately determining tissue origin. Our study has outlined an approach whereby we used an embedded machine learning algorithm to identify a select set of informative features from complex high-dimension data to train and predict cancer type. Citation Format: Marco A. De Velasco, Kazuko Sskai, Seiichiro Mitani, Yurie Kura, Shuji Minamoto, Takahiro Haeno, Hidetoshi Hayashi, Kazuto Nishio. Machine learning-based classification of tissue origin of cancer using methylation profiles [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 4331.
Abstract 2796: Colibactin mutation signatures are associated with younger age of onset in colorectal cancer
Authors: Stefanie Gerstberger, Melissa Lumish, Saskia Hartner, Farheen Shah, Seongmin Choi, Anisha Luthra, Qingwen Jiang, Hyung Jun Woo, Ahmed Mahmoud, Henry Walch, Simran Asawa, Mark Donoghue, Andrea Cercek, Rona Yaeger, Andrew McPherson, Francisco Sanchez-Vega, Karuna Ganesh
Journal: Cancer Research (2024)

Abstract Escherichia coli (E. coli) strains carrying the polyketide synthase (pks) island produce the genotoxin colibactin associated with pathogenesis of colorectal cancer (CRC). Colibactin binds directly to DNA, causing alkylating damage leading to double stranded DNA breaks. Colibactin mutagenesis results in mutations in hexameric A-T rich DNA motifs that can be identified by whole genome sequencing (WGS) as mutation signatures SBS28 and SBS88 (SBS-pks). Since WGS is not routinely used clinically, we developed an approach to specifically identify SBS-pks using a clinical targeted exon capture assay, MSK-IMPACT. In an institutional pan-cancer clinical cohort of 78,905 tumors we identified 15,967 samples with &amp;gt; 20 mutations detected by MSK-IMPACT. We identified 150/1,884 samples with microsatellite stable CRC with &amp;gt;10% mutations attributable to SBS-pks. Examining clinicopathologic and genomic features of SBS-pks+ compared to SBS-pks- CRC tumors, we found that SBS-pks+ signatures are significantly enriched in younger age of onset compared to SBS-pks- CRC patients (median age 55 vs median age 59, p= 0.0028). SBS-pks+ CRC exhibit similar driver mutations and tumor mutational burden (TMB) compared to SBS-pks- CRC but are associated with increased fraction of genome altered (FGA). To mechanistically investigate colibactin-associated damage we developed a novel long-term human colon organoid-microbe co-culture model system that takes advantage of reversal of polarity in suspension culture. WGS of human CRC organoids co-cultured for three months with pks+ and delta-pks E. coli NC101 confirmed induction of pks+ specific SBS-pks signatures, validating the model. Leveraging this model and a biobank of normal colon organoids from donors aged &amp;lt;/&amp;gt; 50 years, we are investigating the molecular mechanisms underlying the association of SBS-pks with younger age of onset CRC. Citation Format: Stefanie Gerstberger, Melissa Lumish, Saskia Hartner, Farheen Shah, Seongmin Choi, Anisha Luthra, Qingwen Jiang, Hyung Jun Woo, Ahmed Mahmoud, Henry Walch, Simran Asawa, Mark Donoghue, Andrea Cercek, Rona Yaeger, Andrew McPherson, Francisco Sanchez-Vega, Karuna Ganesh. Colibactin mutation signatures are associated with younger age of onset in colorectal 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 2796.
Abstract 472: Long non-coding RNA MIR31HG-derived circRNA enhances the oncogenicity of oral carcinoma
Authors: Chung-Hsien Chou, Hsi-Feng Tu, Kuo-Wei Chang, Shu-Chun Lin
Journal: Cancer Research (2024)

Abstract Introduction: Oral carcinoma (OC) represents a significant health challenge, with the role of non-coding RNAs, particularly microRNAs and long non-coding RNAs (LncRNAs), being well-established in its progression. However, the implications of circular RNAs (circRNAs) in this context are less well understood, presenting a notable gap in current research. Our study focuses on the MIR31HG LncRNA, identified as crucial in OC, particularly its role in producing circRNA, as evidenced by sequencing. This specific MIR31HG-derived circRNA, designated 31HGcircR, which contains a potential open reading frame (ORF), and may demonstrate phenotypic significances. Alterations to 31HGcircR, either through knockout or ORF mutation, result in remarkable phenotypic changes, highlighting its potential importance in the pathogenesis of OC. Methods: We implemented 31HGcircR overexpression in OC cell lines, utilizing the TetOff system for gene expression control. CRISPR/Cas9 was employed for gene knockout, and siRNA for gene knockdown. Gene expression was quantified using qPCR. Additionally, the BaseScope assay was used to label and detect the spatial expression of overexpressed 31HGcircR within the cells. Assays to assess cell proliferation, invasion, migration, anchorage-independent growth (AIG), and clonogenicity were conducted. Results: The findings revealed specific junctions of 31HGcircR and varied expression levels across different OC cell lines. There was a significant correlation among the expression of 31HGcircR, MIR31HG and miR-31-5p. Notably, the knockdown of 31HGcircR led to pronounced inhibition of cell growth, migration, invasion, AIG, and clonogenic activity. Conversely, overexpression of 31HGcircR or its ORFs augmented invasion and clonogenic potential in certain cell lines. The TetOff system demonstrated that minimal concentrations of Doxycycline effectively suppressed 31HGcircR expression, with reversible effects upon removal. Knocking out 31HGcircR resulted in reduced invasion and clonogenic capabilities. Conclusion: This study provides clues demonstrating the oncogenic roles of 31HGcircR in OC, which simulate the functions of MIR31HG or miR-31-5p. The changes in cell phenotypes following 31HGcircR manipulation suggest its potential as a therapeutic target or biomarker in OC. These findings offer valuable insights, contributing to the evolving understanding of circRNAs in cancer research and potential treatment avenues. Citation Format: Chung-Hsien Chou, Hsi-Feng Tu, Kuo-Wei Chang, Shu-Chun Lin. Long non-coding RNA MIR31HG-derived circRNA enhances the oncogenicity of oral 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 472.
Abstract 4636: Genome-wide drug anchor screens identify CAAP1 and AKAP17A as regulators of PRMT5 inhibitor sensitivity
Authors: Satoshi Yoda, Matthew R. Tonini, Hilary E. Nicolson, Samuel Poleretzky, Silvia Fenoglio, Steven Lombardo, Lauren Grove, Samuel R. Meier, Ashley Choi, Yi Yu, Kevin M. Cottrell, John P. Maxwell, None Teng, Jannik N. Andersen, Kimberly J. Briggs
Journal: Cancer Research (2024)

Abstract MTA-cooperative PRMT5 inhibitors are an emerging treatment option for patients with one of the 10-15% of all human cancers harboring MTAP homozygous deletion. To identify potential regulators of sensitivity to PRMT5 inhibitors, we performed genome-wide CRISPR knockout screens in the presence and absence of an MTA-cooperative PRMT5 inhibitor. Knockout of CAAP1 and AKAP17A were among the strongest sensitizing hits across multiple MTAP-deleted cancer cell lines representing different histologies. Strikingly, the CAAP1 gene co-localizes with MTAP and CDKN2A on chromosome 9p21. Co-deletion of CAAP1 is reported in 20 percent of MTAP-deleted cancers in the TCGA PanCancer Atlas. CAAP1 or AKAP17A knockout in MTAP-deleted cancer cell lines sensitized the cells to PRMT5 inhibitors including the clinical stage MTA-cooperative inhibitors, TNG908 and TNG462, and the non-MTA-cooperative inhibitor, GSK3326595. Moreover, we discovered that CAAP1 and AKAP17A protein levels are interdependent, as knockout of either gene caused decreased protein levels for the other. Consistent with this finding, CAAP1 reconstitution in CAAP1-deleted cell lines led to increased AKAP17A levels. Endogenous CAAP1 and AKAP17A protein levels are positively correlated across a panel of cancer cell lines and MTAP-deleted patient-derived xenograft models. Consistent with a previous report (Ni et al., 2023), exogenous CAAP1 and AKAP17A co-immunoprecipitation studies suggest that the proteins form a protein complex. AKAP17A and CAAP1 are not well-characterized proteins, but PRMT5 inhibitors induce global alternative splicing events (ASEs) in cancer cells, and based on preliminary studies a possible function for the CAAP1/AKAP17A complex could be to mitigate ASEs induced by PRMT5 inhibition. Collectively, these data indicate that CAAP1 and AKAP17A exist interdependently and mediate sensitivity to PRMT5 inhibitors. The colocalization and 20 percent incidence of CAAP1 deletion in the setting of MTAP deletion may suggest that such patients will have improved responses to PRMT5-targeted therapy. S. Yoda and M. R. Tonini contributed equally. Citation Format: Satoshi Yoda, Matthew R. Tonini, Hilary E. Nicolson, Samuel Poleretzky, Silvia Fenoglio, Steven Lombardo, Lauren Grove, Samuel R. Meier, Ashley Choi, Yi Yu, Kevin M. Cottrell, John P. Maxwell, Teng, Jannik N. Andersen, Kimberly J. Briggs. Genome-wide drug anchor screens identify CAAP1 and AKAP17A as regulators of PRMT5 inhibitor sensitivity [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 4636.
Abstract 5000: Low dose ionizing radiation elicits the extrusion of neutrophil extracellular traps
Authors: Alvaro Teijeira, Ana Martinez-Riaño, Beatrice Pinci, Almudena Manzanal, Paula Molero, Maria E. Rodriguez- Ruiz, Ignacio Melero
Journal: Cancer Research (2024)

Abstract The majority of cancer patients undergo radiotherapy interventions at some point in their clinical management with unintended irradiation of blood vessels. We show that very low γ-irradiation doses (0.5-1 Gy) of human and mouse neutrophils elicit neutrophil extracellular trap (NET) formation in a manner dependent on oxidative stress, NADPH oxidase activity and autocrine interleukin-8. Radiation-induced NETs interfere with NK- and T-cell cytotoxicity-repelling effector lymphocytes away from tumor cells. As a consequence, pre-injection of irradiation-induced NETs increases the number of successful metastases in mouse tumor models. Increases in circulating NETs are readily detected in series of patients following radiotherapy interventions. Our results reveal new mechanisms whose knowledge may help to improve the efficacy and safety of radiotherapy, especially when used in combination with immunotherapy approaches. Citation Format: Alvaro Teijeira, Ana Martinez-Riaño, Beatrice Pinci, Almudena Manzanal, Paula Molero, Maria E. Rodriguez- Ruiz, Ignacio Melero. Low dose ionizing radiation elicits the extrusion of neutrophil extracellular traps [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 5000.
Abstract 5009: Deciphering anticancer mechanisms of oncolytic virus-loaded stem cells
Authors: Mohamed Hammad, Arun Seth, Yate-Ching Yuan, Hoi Wa Ngai, Rachael Mooney, Jacqueline Lara, Yunyi Kang, Ivelina Minev, Duong Hoang Nguyen, Boris Minev, Antonio Santidrian, Karen Aboody
Journal: Cancer Research (2024)

Abstract Background: Oncolytic viruses (OVs) selectively trap, replicate, and eradicate tumor cells without endangering healthy cells. However, any virus that enters the body will be found and rendered inactive by our immune system. Therefore, cancer-killing viruses don't function properly when given by themselves. Loading therapeutic viruses into stem cells is a promising solution since they shield the OVs from the immune system until they reach tumor cells and eventually destroy them. Stem cells are potent immunomodulators and, apart from protecting and delivering the cancer-killing viruses may release additional cell factors that may regulate tumor microenvironment favoring the effect of the therapy. In this study, we analyze these factors secreted by clinically relevant stem cells loaded with oncolytic viruses CLD-101 (Neuronova platform) and CLD-201 (Supernova platform) Method: In our studies, we loaded neural stem cell line (NSCs) with tumor-selective oncolytic adenovirus CRAD-s-PK7 (CLD-101) and adipose-derived stem cells (AD-MSC) with tumor-selective oncolytic adenovirus vaccinia virus CAL1 (CLD-201), and studied their secretome transcriptomic and proteomic profile. Results: The transcriptomic analysis demonstrated that immunomodulatory cytokines, chemokines, and their receptors are induced after three and twenty-four hours of OV infection. The proteomic analysis of the virus-loaded stem cells revealed a notable distinction from the naive stem cells indicating a potential immunotherapeutic role of the stem cells in addition to the delivery and protection of the OVs. Conclusions: Our findings suggest that the enhanced therapeutic efficacy of stem cells loaded with OV is, at least partially because of qualitative and quantitative alterations in stem cells' secretome (including immunostimulatory cytokines and chemokines), These findings advance our knowledge of the molecular mechanisms underlying the immunostimulatory role of OV-loaded stem cells and specifically help to understand the mechanism of action of the promising clinical immunotherapies CLD-101 and CLD-201. Citation Format: Mohamed Hammad, Arun Seth, Yate-Ching Yuan, Hoi Wa Ngai, Rachael Mooney, Jacqueline Lara, Yunyi Kang, Ivelina Minev, Duong Hoang Nguyen, Boris Minev, Antonio Santidrian, Karen Aboody. Deciphering anticancer mechanisms of oncolytic virus-loaded stem cells [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 5009.