tbuckley/cabot-search huggingface dataset:
Abstract 4356: An isoform-resolution transcriptomic atlas of colorectal cancer from long-read single-cell sequencing
Authors: Zhongxiao Li, Bin Zhang, Jia Jia Chan, Hossein Tabatabaeian, Qing Yun Tong, Xiao Hong Chew, Xiaonan Fan, Charlene Chan, Patrick Driguez, Faith Cheong, Shi Wang, Bei En Siew, Ian Jse-Wei Tan, Kai-Yin Lee, Bettina Lieske, Wai-Kit Cheong, Dennis Kappei, Ker-Kan Tan, Xin Gao, Yvonne Tay
Journal: Cancer Research (2024)

Abstract Colorectal cancer (CRC), a complex and molecularly heterogenous disease that lacks robust predictive markers and targeted therapies, is the second leading cause of cancer death worldwide. In recent years, technological advances in short-read single-cell RNA sequencing (scRNA-seq) have been instrumental in deciphering tumor cell heterogeneities. However, most studies have focused on gene-level expression quantification without considering alterations in transcript structures arising from widespread alternative end processing and/or splicing which are frequently dysregulated in cancer. Here, we combined short- and long-read scRNA-seq of CRC patient samples to build the first isoform-resolution CRC transcriptomic atlas. We identified 394 dysregulated transcript structures in tumor epithelial cells, including 299 derived from the coupling of multiple alternative splicing events. Additionally, we characterized genes and isoforms associated with different colon epithelial lineages and tumor cell subpopulations exhibiting varying levels of stemness and differentiation, as well as their distinct prognostic implications. Finally, we built an algorithm by integrating mass spectrometry data and novel peptides derived from predicted open reading frames of recurrent tumor-specific transcripts to curate a panel of recurring neoepitopes. Overall, this study unveils the transcriptomic landscape of CRC and may drive the identification of neoantigens based on full-length transcriptomic atlases to aid future development of more universal neoantigen-based cancer vaccines. Citation Format: Zhongxiao Li, Bin Zhang, Jia Jia Chan, Hossein Tabatabaeian, Qing Yun Tong, Xiao Hong Chew, Xiaonan Fan, Charlene Chan, Patrick Driguez, Faith Cheong, Shi Wang, Bei En Siew, Ian Jse-Wei Tan, Kai-Yin Lee, Bettina Lieske, Wai-Kit Cheong, Dennis Kappei, Ker-Kan Tan, Xin Gao, Yvonne Tay. An isoform-resolution transcriptomic atlas of colorectal cancer from long-read single-cell sequencing [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 4356.
Abstract 5345: Development and validation of humanized HLA mouse model platforms for preclinical evaluation of novel peptide vaccines
Authors: Zhenlan Niu, Xuan Yu, Zhiyuan Shen, Jing Guo, Qingcong Lin, Hui Xu
Journal: Cancer Research (2024)

Abstract The human leukocyte antigen (HLA) class I major histocompatibility complex (MHC) plays an integral role in immune surveillance by presenting intracellular antigen peptides on the cell surface, enabling recognition by cytotoxic T cells and subsequent elimination. Harnessing this intrinsic process for cancer immunotherapy is a promising therapeutic strategy; thus, developing preclinical models to evaluate the efficacy of novel peptide vaccines in vivo and ex vivo is critical. Previously, we developed a humanized MHC I mouse model (B-HLA-A2.1 mice), in which we successfully demonstrated efficacy of peptide vaccines as assessed by splenocyte IFN-γ production measured via ELISpot. Here, we provide evidence that B-HLA-A2.1 mice can also mount immune responses to NY-ESO-1 and WT1-Db126 peptides using the same assay. Additionally, immunization with WT1-Db126 at 7, 14, and 21 days prior to tumor inoculation with WT1-expressing MC38 colon cancer cells significantly reduced tumor volume. Additionally, we have generated two new humanized HLA models: B-HLA-A11.1 mice and B-HLA-A24.2 mice. Flow cytometric data demonstrate successful expression of the human HLAs on the cell surface of splenocytes isolated from both strains. Compared to wild-type C57BL/6 mice, analysis of leukocyte and lymphocyte subpopulations in the humanized mice indicates that the CD4/CD8 ratio is altered in favor of CD4+ T cells in both strains, similar to what was observed in B-HLA-A2.1 humanized mice. Despite these observed alterations, B-HLA-A24.2 mice were able to mount an immune response to peptide SART2 93-101, which was measured by splenocyte IFN-γ production. In summary, our data indicate that humanized HLA-A mice provide a powerful preclinical model for in vivo/ex vivo evaluation of novel peptide vaccines. Citation Format: Zhenlan Niu, Xuan Yu, Zhiyuan Shen, Jing Guo, Qingcong Lin, Hui Xu. Development and validation of humanized HLA mouse model platforms for preclinical evaluation of novel peptide vaccines [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 5345.
Abstract 2302: Innovative blood-based cell-free RNA whole transcriptome sequencing for comprehensive RNA profiling in patient plasma samples and its clinical applications
Authors: Fang Liu, Yong Huang, Min Wang, Xiangying Sun, Binggang Xiang, Shidong Jia, Pan Du, Shujun Luo
Journal: Cancer Research (2024)

Abstract Background: Plasma cell-free RNA (cfRNA) holds promise for non-invasive cancer biomarker discovery, particularly in diseases like prostate cancer where specific biomarkers (AR splicing variants and TMPRSS2:ERG fusion) are detectable at the RNA level. Despite its potential, the technical challenges posed by blood cell-originated cfRNA abundance necessitates the development of robust and reliable assays for non-invasive cancer diagnostics. This study establishes and demonstrates the clinical utility of an innovative protocol for isolating and identifying tumor-originated cfRNA in plasma samples. Methods: A novel methodology was developed for the simultaneous extraction of cfDNA and cfRNA from a single blood sample tube, enabling whole transcriptome sequencing (WTS) analysis with minimal input as low as 1ng. A proprietary method was developed to selectively deplete blood cell-originated transcripts in the library. An enrichment-based WTS assay was conducted, and a customized RNASeq analysis pipeline was employed to enable expression profiling and cancer biomarker testing from the cfRNA samples. Results: The developed extraction method yielded substantial amounts of cfDNA and cfRNA from a 4 mL blood sample. Efficient depletion of blood cell-originated transcripts, achieving over 99% removal, enhanced the detection of a broader range of gene expressions in plasma. Implementation of the cfRNA WTS assay across healthy donor and cancer samples demonstrated consistency with documented biomarker status. The assay revealed significant differential clustering between cancer samples and healthy donors, with characteristic cancer genes contributing to the distinction. Reproducibility and analytical sensitivity of the developed cfRNA WTS assay were successfully validated. Conclusions: This study introduces Predicine's proprietary cfRNA WTS assay, enabling concurrent expression profiling and RNA biomarker detection in plasma samples. Overcoming technical challenges associated with blood cell-originated cfRNA, this assay represents a significant advancement in liquid biopsy-based cancer diagnostics. Citation Format: Fang Liu, Yong Huang, Min Wang, Xiangying Sun, Binggang Xiang, Shidong Jia, Pan Du, Shujun Luo. Innovative blood-based cell-free RNA whole transcriptome sequencing for comprehensive RNA profiling in patient plasma samples and its clinical applications [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 2302.
Abstract 3769: Spatial biology <i>in situ</i> hybridization and multiplexed immunohistochemistry detection compatibility using a modified protocol
Authors: Scott T. Clarke, Mae Voeun, Leticia Montoya, Chris Vonnegut, Bhaskar Mandavilli
Journal: Cancer Research (2024)

Abstract In the field of spatial-omics imaging, combining mRNA in situ hybridization (ISH) detection with multiplexed protein immunohistochemistry detection (IHC) is desirable. We present a simplified workflow in FFPE tissue sections where ISH is detected using branched ssDNA signal amplification visible by brightfield imaging combined with multiplexed IHC using directly labeled antibodies detected by fluorescence. In multiple studies mRNA expression of PCNA (Proliferating Cell Nuclear Antigen) shows moderate to high nuclear positivity observed in most cancer cells, with gliomas and lymphomas being the few negative exceptions. In contrast, expression of PCNA in adult non-cancerous tissue has low to no expression, with tonsil and bone marrow being the exceptions. We first show the relationship between proliferation as measured by EdU detection, PCNA antibody and PCNA mRNA expression in the embryonic mouse model where PCNA expression is prevalent in developing tissue. Then we demonstrate a simplified working protocol for combining ISH and IHC in FFPE human cancer tissue sections for the co-detection of PCNA mRNA together with IHC using a panel of six protein markers relevant to the tumor microenvironment. For IHC, we directly labeled validated unconjugated antibodies with fluorophores using amine-reactive chemistry and select the degree of labeling (DOL) and titer for optimal signal/background most useful for multiplexing on FFPE tissue. We found important protocol steps to consider for compatibility between IHC and ISH detection method. Loss of IHC protein epitope due to ISH protocol use of proteases and loss of ISH signal due to presence of RNase commonly present in IHC antibody relevant reagents can prevent combining IHC with ISH. Stabilizing IHC through refixation prior to ISH workflow is also required. Modifying the protocols to avoid these incompatible treatments and using directly labeled antibodies provides useful strategies for multiplexing IHC with ISH. Citation Format: Scott T. Clarke, Mae Voeun, Leticia Montoya, Chris Vonnegut, Bhaskar Mandavilli. Spatial biology in situ hybridization and multiplexed immunohistochemistry detection compatibility using a modified protocol [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 3769.
Abstract 3947: Non-BRCA variants in hereditary breast and ovarian cancer patients in the Northern Mexico population
Authors: Carlos H. Burciaga-Flores, Diana C. Perez-Ibave, Maria L. Garza-Rodriguez, Oscar Vidal-Gutierrez, Cynthia M. Villarreal-Garza, Dione Aguilar y Mendez
Journal: Cancer Research (2024)

Abstract Background: Hereditary cancer syndromes explain 5-10% of all cancer cases. Germline pathogenic variants in BRCA1 and BRCA2 genes (BRCA) are present in 2-3% of all breast cancer (BC), and 15% of all ovarian cancer (OC) cases. BRCA1 and BRCA2 pathogenic variants (PV) represent 25-28% of BC and 40% of OC patients with a positive familial history. BRCAs are the most studied genes for the prevalence, family history, preventive surgeries, and target treatment options in both BC and OC. There are other genes, important in the diagnosis, pathogenesis, and treatment options of the patients: TP53, PALB2, CHEK2, among others. This study aims to identify the prevalence of non- BRCA genes related to the development of hereditary breast and ovarian cancer syndrome in patients of Northeast Mexico. Methods: This is a multicenter study that recruited patients from two reference oncology centers in Nuevo Leon, Mexico: the CECIL (The CUCC Early Cancer Detection Clinic) Hereditary Cancer Registry and Hereditary Cancer Program from Tec Salud. From March of 2016 to March of 2023, a total of 872 patients meeting NCCN criteria were evaluated by Medical Geneticists from both centers and were tested with NGS multigene cancer panels. Results: A total of 665 (76.26%) patients with a clinical diagnosis of HBOC (Hereditary Breast Hereditary Cancer Syndrome) were included. We found 310 (46.6%) patients had at least one variant, 180 (58%) with at least one pathogenic variant, and 130 (41%) with a VUS (a variant of uncertain significance). BRCA1 was found in 79 (43.8%) and BRCA2 in 32 (17.7%) of all PV. Non-BRCA PV were found in 69 (38.3%) patients: 4 ATM, 2 BLM, 3 BRIP1, 22 CHEK2, 4 CDKN2A, 5 MUTYH, 10 PALB2, 4 RAD51C, 2 SDHA, 2 TP53, 2 WRN, CDH1, CDK4, DICER, MSH3, NBN, PTEN, RAD50, USH2A one of each. Is remarkable that 19 of the 22 patients with CHEK2 and 5 of the 10 patients with PALB2 had the recurrent PV c.707T&amp;gt;C and c.2167_2168del, respectively. Conclusions: Non-BRCA PV in Northern Mexico corresponds to one-third of the BC and OC cases, including HRD (homologous recombination deficiency) genes. HDR patient carriers are potential targets of iPARP therapies. This project reinforces the fact that multigene panels should be employed to ensure a complete diagnosis in hereditary cancer patients. Citation Format: Carlos H. Burciaga-Flores, Diana C. Perez-Ibave, Maria L. Garza-Rodriguez, Oscar Vidal-Gutierrez, Cynthia M. Villarreal-Garza, Dione Aguilar y Mendez. Non-BRCA variants in hereditary breast and ovarian cancer patients in the Northern Mexico population [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 3947.
Abstract 6314: Potent inhibition of tumor relapse after anti-HER2 affibody tagged with cotinine (switch) plus anti-cotinine switchable CAR T cell therapy by repeated re-injection of the switch
Authors: Ki Hyun Kim, Soohwan Kim, Eun-Hoe Lee, Soo-Yoon Lim, Sung Min Kim, E-Young Kim, Hyun-Jong Lee, Seong Yeol Kim, Min Yoon, Young-Ha Lee, In-Sik Hwang, Yoon Lee, Jong-Hoon Kim, Jong-Seo Lee, Junho Chung
Journal: Cancer Research (2024)

Abstract Chimeric antigen receptor (CAR) T cells targeting CD19 or the B cell maturation antigen (BCMA) have demonstrated impressive initial clinical responses. However, on follow-up assessment, a notable fraction of the patients with significant initial clinical response eventually experienced relapse. CAR T cell therapies targeting solid tumors have shown an even lower rate of clinical response as well as shorter remission periods. A prior study has shown that re-injection of the anti-HER2 CAR T cells was effective in a rhabdomyosarcoma relapse patient (Cancer Res 79, LB147 (2019)), but the repeated production of CAR T cells is costly, thus raising questions about its feasibility in practice. Previously, we developed a cotinine-based CAR T cell system (zCART) comprised of a tumor antigen-specific affibody conjugated with cotinine and an anti-cotinine scFv CAR, and demonstrated the anti-tumor activity of an anti-HER2 zCART treatment in both in vitro and in vivo settings. In this study, we tested the efficacy of anti-HER2 zCART treatment in vivo using an intraperitoneal (IP) tumor model with a single infusion of zCART cells. The anti-HER2 switch was injected daily for 7 days. When the HER2 positive tumor relapsed, the mice were re-treated with the same dose of anti-HER2 switch treatment for an additional 7 days. We observed that re-injection of only the anti-HER2 switch and not combined with zCART cells effectively and potently inhibited relapse of HER2 positive tumors. Furthermore, the efficacy of the anti-HER2 switch re-injection treatment was maintained in one additional relapse. In summary, the zCART system has potential to treat cancer relapse following CAR T cell therapy without the need for an additional production round of CAR T cells. Citation Format: Ki Hyun Kim, Soohwan Kim, Eun-Hoe Lee, Soo-Yoon Lim, Sung Min Kim, E-Young Kim, Hyun-Jong Lee, Seong Yeol Kim, Min Yoon, Young-Ha Lee, In-Sik Hwang, Yoon Lee, Jong-Hoon Kim, Jong-Seo Lee, Junho Chung. Potent inhibition of tumor relapse after anti-HER2 affibody tagged with cotinine (switch) plus anti-cotinine switchable CAR T cell therapy by repeated re-injection of the switch [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 6314.
Abstract 3045: PPAR-α antagonist enhances immunotherapy and anti-angiogenic therapy to inhibit murine renal cancer
Authors: Michael Gillespie, Valerie Chen, Isabella Howard, Keira Smith, Dave Freund, Nathan Standifer, Dara Burdette, Thomas W. Dubensky, Sam Whiting, Dipak Panigrahy
Journal: Cancer Research (2024)

Abstract Peroxisome proliferator activated receptor alpha (PPARα) is a transcription factor and master regulator of fatty acid oxidation. PPARα ligands modulate the switch between co-activator and co-repressor transcription complexes at PPARα-controlled target genes. In addition, PPARα has been shown to transrepress NF-κB signaling and inhibit angiogenesis. Renal cell carcinoma (RCC) expresses high levels of PPAR-α and is a highly angiogenic cancer. Current frontline treatments for RCC include chemotherapy, anti-angiogenics, and immunotherapy but are limited by the immune suppressive state of the tumor microenvironment. TPST-1120 is a novel PPARα antagonist for the treatment of cancer patients that binds in the ligand binding domain, positioning the AF-2 activation helix in an inactive conformation. The inactive conformation has a lower affinity for co-activator motifs and reduces activation of PPARα regulated genes. In a CHO-based reporter cell line, TPST-1120 potently competed against the PPARα-specific agonist GW7647 (IC50 = 36 nM at 20 nM GW7647) and an endogenous PPARα agonist oleoylethanolamide (OEA; IC50 = 15 nM at 30 µM OEA). Furthermore, in an enzyme fragment complementation assay, we demonstrated that TPST-1120 inhibited agonist-induced binding of PPARα to MED1 by destabilizing the co-activator complex thereby stabilizing the inactive conformation of PPAR-α. In a murine model of renal cell adenocarcinoma (RENCA), TPST-1120 treatment for 12 days (30 mg/kg qd) reduced tumor growth by 52% as a monotherapy (p&amp;lt;0.0001). Consistent with these findings, TPST-1120 inhibited tumor angiogenesis and proliferation as quantified by Ki67 levels. Combination treatment with current frontline therapeutics resulted in synergistic tumor inhibition of 74% with anti-PD1 (200 ug Q3D for 12 days) and 81% with cabozantinib (15 mg/kg QD for 15 days) (p&amp;lt;.0001). Flow cytometry-based analysis of tumors demonstrated increased CD8+ T cell infiltration in the TME as well as decreases in M2 and elevations in M1 macrophages. Importantly, we demonstrate that TPST-1120 can reverse an immunosuppressive class of immune cells to promote anti-tumor immunity and anti-angiogenesis in kidney cancer in the absence of overt toxicity. These data support advancement of TPST-1120 into RCC. Citation Format: Michael Gillespie, Valerie Chen, Isabella Howard, Keira Smith, Dave Freund, Nathan Standifer, Dara Burdette, Thomas W. Dubensky, Sam Whiting, Dipak Panigrahy. PPAR-α antagonist enhances immunotherapy and anti-angiogenic therapy to inhibit murine renal 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 3045.
Abstract 6291: Changes in physical activity and ischemic stroke risk after cancer diagnosis: A nationwide cohort study
Authors: Dong Wook Shin, Wonyoung Jung, In Young Cho, Jinhyung Jung, Mihee Cho, Hye Yeon Koo, Be-Long Cho, Jin Ho Park, Hyuk Tae Kwon, Kyungdo Han, Yong-Moon Mark Park
Journal: Cancer Research (2024)

Abstract Background: Physical inactivity is prevalent after cancer treatment, which may pose a greater risk of ischemic stroke in cancer survivors. Objective: To investigate the association between physical activity change from pre- to post-diagnosis and ischemic stroke risk among cancer survivors. Methods: Cancer survivors without prior history of cardiovascular disease were identified. Pre- and Post-adherence to physical activity was determined within two years from cancer diagnosis. The primary outcome was incident ischemic stroke. Using the Fine-Gray model, sub-distribution hazard ratios (sHRs) and 95% confidence intervals (CIs) for ischemic stroke risk were calculated, considering death as a competing risk. Results: Among 269,943 cancer survivors (mean [SD] age 56.3 [12.1] years, 45.7% male), 10.1% remained active, 11.4% became inactive, and 16.6% became active post-diagnosis. During 1,109,566.68 person-years[YMP1] , remaining active both pre- and post-diagnosis was associated with 15% decreased risk of ischemic stroke (sHR 0.85, 95% CI 0.75-0.96), compared to those who remained inactive. Cancer survivors who became active, and inactive post-diagnosis showed a 16%, and 11% lower risk of ischemic stroke (sHR 0.84, 95% CI 0.75-0.93; sHR 0.89, 95% CI 0.79-0.99) than those who remained inactive. Conclusions: Our findings suggest that staying physically active is associated with a reduced risk of ischemic stroke among cancer survivors. Notably, these advantages are not limited to individuals who were physically active before their diagnosis, and it is not too late to start post-diagnosis. Preventive strategies against ischemic stroke in cancer survivors should emphasize the incorporation of regular physical activity at any stage of their cancer journey. Citation Format: Dong Wook Shin, Wonyoung Jung, In Young Cho, Jinhyung Jung, Mihee Cho, Hye Yeon Koo, Be-Long Cho, Jin Ho Park, Hyuk Tae Kwon, Kyungdo Han, Yong-Moon Mark Park. Changes in physical activity and ischemic stroke risk after cancer diagnosis: A nationwide cohort study [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 6291.