tbuckley/cabot-search huggingface dataset:
Abstract 2440: Cancer driver mutations as quantitative biomarkers of cancer risk interspecies analyses using CarcSeq
Authors: Kelly L. Harris, Binsheng Gong, Barbara Parsons, Jennifer Faske, Joshua Xu
Journal: Cancer Research (2024)

Abstract Unmet needs in cancer risk assessment include the ability to predict rodent life-time tumor responses from short-term exposures and a scientific basis for rodent to human extrapolation. As an approach to address these needs, the use of hotspot cancer driver mutations (CDMs) as biomarkers of cancer risk was integrated with an error-corrected, next generation sequencing (NGS) approach. We have developed and investigated the sensitivity of a high-throughput NGS method capable of detecting a panel of the most prevalent point mutations observed in human oncogenes and tumor suppressor genes. This method, CarcSeq, involves performing multiple, high-fidelity PCR reactions to amplify the most prevalent mutations reported to occur in human tumors, tagging the amplicons with 9 bp unique identifier sequences at each end, constructing libraries using Illumina ChIP Seq kits, sequencing the libraries on an Illumina NextSeq500 platform and generating single-strand consensus sequences (SSCS), bioinformatically, as a means of error-correction. We validated CarcSeq mutant fraction measurements through observations related to known cancer driver tissue-specificities and mutation spectra for normal human breast and lung, ductal carcinoma, and lung adenocarcinoma samples. Performance of a reconstruction experiment established CarcSeq has a sensitivity of 104. The approach has now been adapted to analyze analogous conserved codons in rat and mouse. For each of the three species, the developed panel includes 13-15 amplicons encompassing known cancer driver genes (e.g., KRAS, PIK3CA, and TP53) encompasses the equivalent of 30 known human hotspot codons and has a combined target sequence length of ~1 kb. Amplicons were generated from DNA isolated from 16-week-old, untreated rodent tissue samples with known differences in spontaneous tumor incidence: female Wistar, Sprague Dawley, and F344 rat mammary samples and male and female B6C3F1 and CD-1 mouse lung samples. The rodent panel was optimized to generate ~100,000 SSCS/amplicon. CDMs were observed at conserved codons in young, untreated rodents, and results are consistent with what was expected based on strain differences in spontaneous tumorigenesis. Citation Format: Kelly L. Harris, Binsheng Gong, Barbara Parsons, Jennifer Faske, Joshua Xu. Cancer driver mutations as quantitative biomarkers of cancer risk interspecies analyses using CarcSeq [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 2440.
Abstract 484: Enhancing therapeutic responses in NSCLC using iron-oxide nanoparticles combined with pharmacological ascorbate
Authors: Mekhla Singhania, Miachael S. Petronek, Casey F. Pulliam, Kranti A. Mapuskar, Amira Zaher, Douglas R. Spitz
Journal: Cancer Research (2024)

Abstract High dose Vitamin C (pharmacological ascorbate; P-AscH‒ &amp;gt; 20 mM plasma levels) given intravenously (I.V.), has made a remarkable re-emergence as an adjuvant to combined modality approaches in cancer therapy. P-AscH‒ can be readily oxidized in the presence of redox active metals (i.e., P-AscH‒ serves as an iron reducing agent), which can result in increased fluxes of H2O2. This chemical phenomenon allows for the tumor-selective enhancement of chemo-radiation in NSCLC. We hypothesized that enhancing labile Fe2+ in cancer cells using iron-oxide nanoparticles (ferumoxytol, FMX) can increase the effectiveness of P-AscH‒ in enhancing cancer cell sensitivity to chemo-radiation in NSCLC by increasing H2O2 production. To test this hypothesis, we performed clonogenic cell survival assays in-vitro. To test the role of H2O2 in the combined effect of P-AscH‒ and FMX, we developed lentiviral-based doxycycline-inducible overexpression models for catalase, and to determine the changes in Fe, we used fluorescent probes that specifically detect changes in labile Fe2+. Results from these experiments showed FMX enhanced clonogenic cell killing in NSCLC. Furthermore, catalase overexpression inhibited this effect, suggesting that enhanced H2O2 production plays a central role in the additive effect of P-AscH- and FMX. Finally, staining the cells with the fluorescent iron probes showed that FMX enhanced labile Fe2+ in cells treated with P-AscH‒. These studies continue to support the hypothesis that H2O2 plays a significant role in P-AscH‒ toxicity in cancer cells that can be exacerbated using iron oxide nanoparticles. Future studies will test these findings in-vivo using preclinical xenograft models. (supported by P01 CA217797, P30 CA086862, T32 CA078586, and P01 CA244091). Citation Format: Mekhla Singhania, Miachael S. Petronek, Casey F. Pulliam, Kranti A. Mapuskar, Amira Zaher, Douglas R. Spitz. Enhancing therapeutic responses in NSCLC using iron-oxide nanoparticles combined with pharmacological ascorbate [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 484.
Abstract 5927: ACBP/DBI inhibition suppresses NASH-induced hepatocarcinogenesis
Authors: Sijing Li, Omar Motiño, Flavia Lambertucci, Maria Chiara Maiuri, Isabelle Martins, Guido Kroemer
Journal: Cancer Research (2024)

Abstract Background: Non-alcoholic fatty liver disease (NAFLD) or its severe form non-alcoholic steatohepatitis (NASH) is becoming an ever more prevalent risk factor of hepatocellular carcinoma (HCC). Currently, there are no approved drugs for the treatment of NASH. Extracellular ACBP/DBI (Acyl coenzyme A binding protein, also called diazepam-binding inhibitor) acts as an autophagy checkpoint and neutralization of ACBP/DBI prevents NASH. Therefore, we investigated the functional roles, mechanisms, and clinical relevance of ACBP/DBI in HCC. Methods: ACBP/DBI was blocked by four strategies: an inducible Acbp/Dbi knockout (Acbp-/-, control: Acbp+/+), a constitutive Gabrg2F77I mutation that prevents binding of ACBP/DBI to the receptor (control: WT), induction of ACBP/DBI-specific autoantibodies (induced by KLH-DBI, control: KLH), and monoclonal anti-DBI antibody (control: isotype). Three different types of HCC mouse models, including toxins/diet-based NASH-induced models (western diet plus CCl4), hydrodynamic transfection of oncogenes (Myc+Ctnnb1), and orthotopic transplantation (Hep55.1C) were used in combination with the aforementioned ACBP/DBI inhibition strategies to determine the association of ACBP/DBI and HCC. Results: ACBP/DBI inhibition attenuates tumorigenesis in mice with NASH, blunts oncogene induced HCC, and reduces the growth of orthotopically transplanted cancers. Mechanistically, ACBP/DBI inhibition retards cell cycle, suppresses cell proliferation, and favors ferroptosis, as determined by RNA-seq data and mass spectrometric metabolomics. CCK-8 proliferation, colony formation, and cell cycle assays performed on Huh-7, HepG2 and Hep55.1C cells demonstrated that ACBP/DBI knockdown reduced cell proliferation and induced G0/G1 arrest. IHC detection of Ki67 and PCNA in liver sections revealed antiproliferative effects of ACBP/DBI inhibition. qRT-PCR demonstrated the ACBP/DBI inhibition-induced upregulation of cell cycle inhibitor genes and downregulation of genes invoded in G0/G1 phase in liver tissues. qRT-PCR and immunoblot confirmed the upregulation of pro-ferroptotic and the downregulation of anti-ferroptotic genes and proteins in liver tissues upon ACBP/DBI inhibition. Primary HCC cell lines from Acbp+/+ and Acbp-/- mice further confirmed the pro-ferroptotic effects of ACBP/DBI inhibition obtained in liver tissues. Acbp-/- cell lines were more sensitivity to RSL3-induced ferroptosis. Conclusion: ACBP/DBI inhibition constitutes a potential strategy for treating NASH and NASH-induced HCC. Citation Format: Sijing Li, Omar Motiño, Flavia Lambertucci, Maria Chiara Maiuri, Isabelle Martins, Guido Kroemer. ACBP/DBI inhibition suppresses NASH-induced hepatocarcinogenesis [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 5927.
Abstract 4040: Hypoxia-induced HIF-1α/USP3 pathway promoting immune escape in lung squamous cell carcinoma
Authors: Xiuwen Zhang, Hua Huang, Chen Ding, Chen Chen, Yongwen Li, Hongyu Liu, Chen Jun
Journal: Cancer Research (2024)

Abstract Background: Immune escape poses a significant mechanism for tumor progress as well as enormous challenge for the treatment of lung squamous cell carcinoma (LUSC). The close association between hypoxic environments and tumor immune escape, with PD-L1 serving as a key marker, has garnered considerable attention. This study aims to delve into the molecular mechanisms underlying the regulation of PD-L1 deubiquitination by the hypoxia-induced HIF-1α/USP3 pathway, shedding light on the immune escape mechanisms in LUSC. Methods: NSCLC cells were cultured under hypoxia condition and the expression of USP3, HIF-1α and PD-L1 were measured by Western blot. Chromatin Immunoprecipitation (ChIP) and Co-immunoprecipitation (CO-IP) were employed to elucidate the direct regulatory mechanisms of the HIF-1α/USP3 pathway in PD-L1 deubiquitination. In vitro T cell-mediated killing assays was used to investigate the functional roles of USP3 in antitumor immunity in NSCLC. Results: We demonstrated that hypoxia score was increased in LUSC and negatively correlated with CD8+ T cell infiltration. Hypoxia as a major factor triggering LUSC cell immunosuppression and against T cell surveillance via stabilization of PD-L1. Mechanistically, USP3, induced by HIF-1α, is required for hypoxia-mediated PD-L1 stabilization in LUSC cells. USP3 inhibits the ubiquitination and degradation of PD-L1. The combination of USP3 inhibitors with PD-1/PD-L1 monoclonal antibodies significantly enhances the anti-LUSC effect, possibly through promoting the infiltration of CD8+ T and NK cells. Conclusion: This research unveils a novel mechanism by which hypoxia, through the HIF-1α/USP3 pathway, regulates PD-L1 deubiquitination, thereby promoting immune escape in LUSC. Furthermore, our study provides a new strategy involving USP3 inhibitors in combination with PD-1/PD-L1 monoclonal antibodies, offering novel insights for molecular targeted therapy and reversal of drug resistance in LUSC. Citation Format: Xiuwen Zhang, Hua Huang, Chen Ding, Chen Chen, Yongwen Li, Hongyu Liu, Chen Jun. Hypoxia-induced HIF-1α/USP3 pathway promoting immune escape in lung squamous cell 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 4040.
Abstract 2606: Targeting mesothelin on tumor cells with a novel, completely human fusion construct delivering the serine protease granzyme B
Authors: Khalid A. Mohamedali, Lawrence H. Cheung, Mihai G. Iurascu, Louis R. DePalatis, Claire Thuning-Roberson, Michael G. Rosenblum
Journal: Cancer Research (2024)

Abstract Mesothelin is a cell-surface antigen identified as an excellent cancer-associated target upregulated on numerous tumors, including pancreatic and ovarian cancers, as well as mesotheliomas and lung cancers. Granzyme B is a highly cytotoxic serine protease nominally delivered by immune effector cells to target cells, resulting in induction of cell death pathways that are both caspase-dependent and -independent. We developed a fusion protein (GrB-Fc-SD1) composed of GrB and containing SD1, a novel human single-domain antibody that uniquely targets Region III of the mesothelin glycoprotein. The SD1 and GrB domains are tethered by a human IgG heavy chain fragment which enables dimerization. The fusion protein was transiently expressed in HEK-293E cells in serum-free conditions with a final yield of 5 mg/L. Western blot analysis confirmed the expression of this construct as a homodimer. The GrB enzymatic activity in GrB-Fc-SD1 was similar to that of commercially available human granzyme B. ELISA studies confirmed the specific recognition of the SD1 antibody to mesothelin extra-cellular domain. Biacore analysis confirmed binding of GrB-Fc-SD1 with a dissociation constant between 10−7 and 10−8 M. In vitro cytotoxicity against a limited panel of lung, pancreatic and ovarian cancer cell lines expressing surface mesothelin indicate cytotoxicity in the nanomolar range, while cytotoxicity against mesothelin-negative cells was at micromolar levels. Ex vivo serum stability studies showed excellent stability of GrB-Fc-SD1 at both 4°C and -20°C over ninety days and a half-life of approximately three days at elevated temperatures (37°C). In vivo efficacy studies against Capan-2 xenografts in nude mice using both weekly x 5 and QOD x 5 doses of GrB-Fc-SD1 (130 mg/mg total dose, delivered IP) indicated highly significant efficacy in both dose regimens, with p &amp;lt; 0.001 compared to vehicle-treated mice. Mouse body weights were not impacted at the efficacy doses used in this study, indicating that this dose was non-toxic. Histopathology studies revealed a significant decrease in the percentage of Ki-67+ nuclei in treated tumors compared to controls. These data warrant continued investigation of the protein as a therapeutic candidate. Research supported by H2Biologics. Research conducted, in part, by the Clayton Foundation for Research. Citation Format: Khalid A. Mohamedali, Lawrence H. Cheung, Mihai G. Iurascu, Louis R. DePalatis, Claire Thuning-Roberson, Michael G. Rosenblum. Targeting mesothelin on tumor cells with a novel, completely human fusion construct delivering the serine protease granzyme B [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 2606.
Abstract 3497: Glioma Immune Microenvironment Composition Calculator (GIMiCC): A method of estimating the proportions of eighteen key cell types from human brain tissue assayed using Illumina DNA methylation microarray technology
Authors: Steven C. Pike, John K. Wiencke, Ze Zhang, Annette M. Molinaro, Devin C. Koestler, Brock C. Christensen, Karl T. Kelsey, Lucas A. Salas
Journal: Cancer Research (2024)

Abstract Precise detection of both tumor subclass and immune composition is critical in the pursuit of personalized immunotherapeutic treatment strategies for glioma. DNA methylation (DNAm) biomarkers are promising on both fronts. DNAm-based biomarkers for molecular classification have been developed and integrated into World Health Organization (WHO) diagnostic criteria. However, prediction of the tumor microenvironment is not as well defined. To fill this gap, we present GIMiCC, an approach for cellular deconvolution of DNAm microarray data for four WHO 2021 tumor subclasses: glioblastoma, oligodendroglioma, grade 2/3 astrocytoma and grade 4 astrocytoma. Using data from 17 isolated cell types, we describe the derivation of the deconvolution libraries and test the method on independent datasets from the Cancer Genome Atlas (TCGA) and the DKFZ molecular neuropathology classifier (PMID: 29539639). We utilize GIMiCC to illustrate that DNAm-based glioma classification is unlikely to be biased by compositional variation. In addition, we utilize GIMiCC to identify composition independent DNAm alterations that are associated with high immune infiltration. Our future work aims to optimize GIMiCC and advance the clinical evaluation of glioma with this new tool. Citation Format: Steven C. Pike, John K. Wiencke, Ze Zhang, Annette M. Molinaro, Devin C. Koestler, Brock C. Christensen, Karl T. Kelsey, Lucas A. Salas. Glioma Immune Microenvironment Composition Calculator (GIMiCC): A method of estimating the proportions of eighteen key cell types from human brain tissue assayed using Illumina DNA methylation microarray technology [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 3497.
Abstract 4509: Discovery of potent and highly efficacious STAT3 PROTAC degraders capable of achieving long-lasting tumor regression
Authors: Ranjan K. Acharyya, Longchuan Bai, Haibin Zhao, Dimin Wu, Metwally Hoda, McEachern Donna, Wen Bo, Duxin Sun, Shaomeng Wang
Journal: Cancer Research (2024)

Abstract STAT3 (signal transducer and activator of transcription 3) is a transcription factor and a promising therapeutic targets for cancer and other human diseases. We have previously reported the discovery of SD-36 and SD-91 as potent, selective and highly efficacious STAT3 degraders. In the present study, we report the discovery of highly potent, selective and efficacious new STAT3 degraders. These STAT3 degraders were designed using our high-affinity STAT3 ligands and high-affinity VHL-1 ligands, with UM-STAT3-3100 being the best. In direct comparison, UM-STAT3-3100 is &amp;gt;10-times more potent than SD-36 and SD-91 in inducing STAT3 degradation in cells and are highly selective over other STAT members in vitro and in vivo. A single intravenous administration of UM-STAT3-3100 resulted in complete and long-lasting depletion of STAT3 protein for &amp;gt;48 hrs in tumor and native tissues. Weekly administration of UM-STAT3-3100 at 10 mg/kg achieved complete and long-lasting tumor regression in animal models of human cancer without any signs of toxicity. UM-STAT3-3100 is a promising compound for extensive evaluation for the treatment of human cancers and other human diseases in which STAT3 plays a key role. Citation Format: Ranjan K. Acharyya, Longchuan Bai, Haibin Zhao, Dimin Wu, Metwally Hoda, McEachern Donna, Wen Bo, Duxin Sun, Shaomeng Wang. Discovery of potent and highly efficacious STAT3 PROTAC degraders capable of achieving long-lasting tumor regression [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 4509.
Abstract 4854: Breast cancer incidence trends in Ukraine 2010-2019: Rising incidence at young ages
Authors: Nataliia Verovkina, Olena Sumkina, Liubov Syvak, Wafik El-Diery
Journal: Cancer Research (2024)

Abstract Background. BC commonly affects women of older age, however, in developing countries around 20-25% cases of BC presented in young woman. Age-specific clinical characteristics or outcomes data for young women are lacking. Most of the standard treatments used in this subpopulation currently are derived from older patients. Early onset BC is often defined aggressive in nature. Several research have attributed this to a hidden unique biology. However, findings remain controversial. Purpose: The aim of this study is to describe recent trends for BC incidence in Ukraine since 2010 by age groups and interpret them to seek clue for improvement. Methods: We analyzed records from the NCR on 143420 BC cases (C50, International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10)) diagnosed in 2010-2019 in female Ukrainian population. The data were submitted on the beginning of 2022. We calculated annual age-standardized incidence rates (ASRWs) for three age groups. The estimated annual percent change (EAPC) of the rates was calculated using the generalized linear regression. The difference of the rates with its statistical significance was determined with the standardized rate ratio. Results: During 2010-2019, the proportion of BC in all cancers detected at the age of 20-44 increased from 21.7% to 25.9%, while the frequency of BC detection at the age of 45+ did not change and ranged 19.3-20.2%. During the study period, the BC incidence rate has increased significantly (≤0.01): the ASRW of females aged 0-85+ grew with EAPC=0.6% amounting to 42.4-45.7 per 100,000 population, the incidence rate of women aged 45+ grew with EAPC=0.3% ranging from 130.0 to 139.6 per 100,000 population, while the incidence rate of women aged 20-44 grew with EAPC=1.8% amounting to 22.8-27.8 per 100,000 population. In age group 20-44 years, EAPC of BC incidence (1.8%) significantly exceeds the EAPC of the incidence for all cancers combined (0.2%). The dynamics of stage distribution showed increasing proportion of BC cases detected in women aged 20-44 in stage 1 (by 4.1% from 2010 to 2019) and its decreasing for BC cases detected in stage 2 by 4.5%; the proportion of cases diagnosed in stage 4 decreased by 0.5% along with increase in number of cases with undefined stage by 0.6%. Conclusions: The obtained results indicate trends for increasing the incidence of Early Onset BC in Ukraine and justify need for the further research elucidating prognosis and validating novel biomarkers for customizing therapy for this patient group . Citation Format: Nataliia Verovkina, Olena Sumkina, Liubov Syvak, Wafik El-Diery. Breast cancer incidence trends in Ukraine 2010-2019: Rising incidence at young ages [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 4854.
Abstract 4483: New drug development opportunities for PARP1
Authors: Pablo Iglesias, David Moreiras, Laura Porres-Ventin, Lara Gonzalez-Rendo, Jose A. Zumalave, Victor M. Arce, Jose A. Costoya
Journal: Cancer Research (2024)

Abstract Personalized therapies allow, not only the increase of its therapeutic efficiency, but also the reduction of the secondary effects associated to the treatment of cancer. Data obtained in our group suggest that PARP1 could play a key role in the cell cycle regulation through its interaction with E2F1 transcription factor. Considering that most oncogenic processes is associated with cell cycle deregulation, the disruption of this interaction would provide a new therapeutic target of great interest and wide spectrum of indications. Therefore, our goal was to find molecules that interfere its role in cell-cycle regulation without affecting its function on DNA repair. The identification of novel compounds disrupting the PARP1/E2F1 interaction was carried out by combining in silico and in vitro screening, using a rational drug design. The virtual screen was performed using a molecular library of several million compounds at the selected target site, using AtomNet® (Atomwise), the first deep learning neural network for structure-based drug design and discovery. Since there is no complete structural information of the PARP-1/E2F1 protein-protein interaction, a homologous structure of BRCT domain of BRCA1 complex with the phospho-peptide (PDBID: 1T2V) was utilized to identify the potential binding interface of BRCT domain of PARP-1 (PDBID: 2COK) and the E2F1 protein. Top scoring compounds were clustered and filtered to arrive at a final subset of 83 compounds, library that were incorporated to our in vitro screening, which included both transcriptional (E2F1 activity) and survival studies. Twelve compounds were finally selected, based upon their higher capacity of inhibiting E2F1 activity.This work was supported by Agencia Estatal de Investigación (AEl/10.13039/501100011033), Xunta de Galicia (GPC GI-1862, ED431B 2020/26; ED431G 2019/02) and European Regional Development Fund-ERDF. AIMS Awards Program - Project A19-513, Atomwise Inc. Citation Format: Pablo Iglesias, David Moreiras, Laura Porres-Ventin, Lara Gonzalez-Rendo, Jose A. Zumalave, Victor M. Arce, Jose A. Costoya. New drug development opportunities for PARP1 [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 4483.