tbuckley/cabot-search huggingface dataset:
Abstract 2076: Spatiotemporal mapping of colitis-associated colorectal cancer evolution
Authors: Yoonho Lee, Yongjae Kim, Minseok Lee, Do Kyung Yoon, Jiwon Baek, Sung Wook Hwang, Jong Lyul Lee, Sang Hyoung Park, Dong-Hoon Yang, Jihun Kim, Suk-Kyun Yang, Buhm Han, Kyuyoung Song, Yong Sik Yoon, Byong Duk Ye, Ho-Su Lee
Journal: Cancer Research (2025)

Abstract Colitis-associated colorectal cancer (CAC) is a severe complication of inflammatory bowel disease, particularly ulcerative colitis. Despite its clinical significance, the spatiotemporal dynamics of neoplastic progression in CAC remain poorly understood. This study aimed to elucidate the evolutionary trajectory of CAC using spatial transcriptomics. We employed spatial transcriptomics to analyze four tissue samples from three patients with ulcerative colitis at various stages of neoplastic progression. Whole-slide spatial transcriptomics RNA sequencing was performed, enabling simultaneous analysis of gene expression and tissue architecture. Integrated spatial transcriptomic data revealed recurring epithelial programs along the progression of copy number variation (CNV). Our analysis using CNV score and hematoxylin and eosin staining image revealed progressive changes in gene expression patterns as tissue transitioned from non-tumor to pre-tumor and finally to tumor states. This progression was quantified using beta coefficient values, allowing us to track gradual alterations in gene expression across the disease continuum. We identified a core set of 412 genes that exhibited consistent changes in at least three of the analyzed samples. Among these, 349 genes showed a progressive decrease in expression, while 63 genes, including CLDN1, E2F1, and RECQL4, demonstrated a gradual increase in expression as the tissue advanced towards a tumorous state. These upregulated genes pointed to potential oncogenic drivers or compensatory mechanisms activated during tumor development. Pathway analysis revealed that downregulated genes were enriched in processes such as KRAS signaling, hypoxia, and inflammatory response, while upregulated genes were enriched in the MYC targets pathway. This study provides high-resolution mapping of evolutionary trajectory of CRC, revealing key molecular events and spatial features associated with neoplastic progression. Our findings enhance the understanding of CAC pathogenesis and highlight potential targets for early intervention and personalized treatment strategies, contributing significantly to the field and potentially informing future therapeutic approaches. Citation Format: Yoonho Lee, Yongjae Kim, Minseok Lee, Do Kyung Yoon, Jiwon Baek, Sung Wook Hwang, Jong Lyul Lee, Sang Hyoung Park, Dong-Hoon Yang, Jihun Kim, Suk-Kyun Yang, Buhm Han, Kyuyoung Song, Yong Sik Yoon, Byong Duk Ye, Ho-Su Lee. Spatiotemporal mapping of colitis-associated colorectal cancer evolution. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2076.
Abstract 2372: Circulating pre-diagnosis immune markers and breast cancer risk: findings from the Cancer Prevention Study-3
Authors: Shamim Shahi, James Hodge, Mia Gaudet, Alpa V. Patel, Laure Dossus, Sabina Rinaldi, Lauren Teras
Journal: Cancer Research (2025)

Abstract Background: Breast cancer is recognized as potentially immunogenic with early evidence suggesting patients may benefit from immunotherapy. Cytokines including tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), and those from the interleukin (IL) family (IL-6, IL-8, and IL-10) play a critical role in immune system regulation. However, the association of pre-diagnostic cytokines levels with breast cancer risk remains unclear with few studies reporting inconsistent findings. Objective: The goal of this study was to examine associations between circulating cytokines (IL-6, IL-8, and IL-10, TNF-α and IFN-γ) and subsequent breast cancer risk. Methods: For this study, we utilized data from the Cancer Prevention Study 3 (CPS-3), a prospective cohort study initiated by the American Cancer Society (ACS), which fully enrolled 198, 632 women aged 30-65 years from 2006-2013, across 35 states, Washington D.C., and Puerto Rico. A nested case-control design was used for this study. The analytic sample included 606 primary invasive breast cancer cases, matched to 606 controls based on age at study enrollment, race, blood draw date, and menopausal status. Blood collected at CPS-3 enrollment was used to quantify five immune markers of inflammation and immune regulation: IL-6, IL-8, IL-10, IFN-γ, and TNF-α using the V-PLEX multiplex immunoassay at the International Agency for Research on Cancer (IARC). Each immune marker was analyzed both as a continuous and a categorical (quartiles) variable. Conditional logistic regression was used to estimate odds ratios for the association between each immune marker and overall breast cancer risk. Results: The median age at diagnosis was 54 years (interquartile range (IQR): 48, 59). Cases and controls were fairly comparable across key demographic, clinical and behavioral variables. For every one-unit increase in log-transformed IFN-γ, the odds of breast cancer decreased by 16% (OR=0.84, 95% CI: 0.72-0.99). All other immune markers were not significantly associated with overall breast cancer risk. Conclusion: With the exception of IFN-γ, the findings do not provide evidence that these selected immune markers are associated with breast cancer risk. Given the heterogenous nature of breast cancer, future studies should consider breast cancer molecular and histologic subtypes and potential modifications by other clinical and tumor characteristics. Citation Format: Shamim Shahi, James Hodge, Mia Gaudet, Alpa V. Patel, Laure Dossus, Sabina Rinaldi, Lauren Teras. Circulating pre-diagnosis immune markers and breast cancer risk: findings from the Cancer Prevention Study-3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2372.
Abstract 2818: Targeting PIKfyve sensitizes gastroenteropancreatic neuroendocrine tumor to mTOR inhibition by disrupting ferritinophagy and lipid homeostasis
Authors: Yizhi Cao, Yitong Yin, Caleb Cheng, Shannon VanAkon, Sarah Nicole Yee, Jacinda Jiali Liu, Yang Zheng, Andrej Coleski, Radha Paturu, Somnath Mahapatra, Fan Yang, Rupam Bhattacharyya, Rahul Mannan, Yuanyuan Qiao, Arul Chinnaiyan
Journal: Cancer Research (2025)

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have shown a significant global increase over the past decade. The mTOR signaling pathway is a positive regulator of cell cycle progression, with its activation playing a key role in the pathogenesis of NETs. Since 2011, the FDA-approved mTOR inhibitor everolimus has been used as an anti-tumor agent for treating progressive NETs, and its clinical efficacy is limited due to rapid disease relapse and progression. In this study, we investigated the role of autophagy, specifically ferritinophagy, in mediating resistance to mTOR inhibition in GEP-NETs. Enhanced ferritinophagy followed by mTOR inhibition increases intracellular iron availability, supporting tumor cell energy production and survival. Genetic or pharmacological inhibition of PIKfyve, a lipid kinase integral to lysosomal functioning, disrupted ferritinophagy, reducing the intracellular iron pool elevated by mTOR inhibition. Interestingly, mTOR inhibition also restored cholesterol and fatty acid biosynthesis resulting from PIKfyve inhibition. Notably, dual inhibition of mTOR and PIKfyve exhibited a strong synergistic antitumor effect in vitro and significantly prolonged survival in an orthotopic GEP-NET preclinical model. Together, our findings highlight the therapeutic potential of combining mTOR and PIKfyve inhibitors in the treatment of GEP-NETs. Citation Format: Yizhi Cao, Yitong Yin, Caleb Cheng, Shannon VanAkon, Sarah Nicole Yee, Jacinda Jiali Liu, Yang Zheng, Andrej Coleski, Radha Paturu, Somnath Mahapatra, Fan Yang, Rupam Bhattacharyya, Rahul Mannan, Yuanyuan Qiao, Arul Chinnaiyan. Targeting PIKfyve sensitizes gastroenteropancreatic neuroendocrine tumor to mTOR inhibition by disrupting ferritinophagy and lipid homeostasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2818.
Abstract 2152: NT-I7 increases lymphocytes and enhances chemotherapy and immunotherapy efficacy in HNSCC
Authors: Zhibin Cui, Jacqueline L. Yee, Hua Li, Yan Zeng, Liam Woerner, Alexandra A. Wolfarth, Sara Ferrando-Martinez, Hyunseok Kang, Jennifer R. Grandis, Matthew H. Spitzer, Daniel E. Johnson
Journal: Cancer Research (2025)

Background: Lymphopenia is associated with poor outcomes and is exacerbated by conventional chemoradiation therapies in head and neck squamous cell carcinoma (HNSCC). NT-I7 (rhIL-7-hyFc, efineptakin alfa; NeoImmuneTech, Inc.), a long-acting human IL-7, has the potential to restore lymphocyte populations, modulate immune responses, and enhance anti-tumor activity. This study investigated NT-I7’s effects on lymphocyte populations and its synergy with cisplatin and immune checkpoint inhibitors (ICIs) in syngeneic, immunocompetent HNSCC mouse models. Methods: The impact of NT-I7 was studied in two syngeneic tumor models, MOC1 and MOC22. Flow cytometry and Cytometry by Time of Flight (CyTOF) analyses were used to evaluate NT-I7 effects on peripheral and intratumoral immune cells. Anti-tumor efficacy was assessed following NT-I7 treatment alone, in combination with cisplatin, or with anti-PD-1 therapy. Results: Mice bearing syngeneic MOC1 and MOC22 tumors exhibited significant lymphopenia, characterized by reductions in CD4+ and CD8+ T-cells, Tregs, NK cells, and NKT cells, resembling clinical observations in HNSCC patients. NT-I7 treatment significantly increased lymphocyte levels in both spleen and tumor, with notable induction of CD8+ T-cells and NKT cells, peaking at day 7 and day 4 post-treatment, respectively, and minimal impact on intratumoral Treg levels. NT-I7 modestly inhibited MOC1 tumor growth and potently suppressed MOC22 tumor growth. Combining NT-I7 with cisplatin significantly enhanced anti-tumor activity in MOC1 tumors, accompanied by increased numbers of peripheral and intratumoral CD4+, CD8+, and NKT cells. Furthermore, NT-I7 augmented the efficacy of anti-PD-1 therapy in MOC1 tumors, resulting in greater tumor growth inhibition compared to either treatment alone. CyTOF analysis revealed preferential expansion of CD8+ Tpex cells, a key subset of tumor-specific cells that expand in response to ICIs, highlighting NT-I7’s role in overcoming lymphopenia and potentiating anti-tumor immunity. Conclusions: NT-I7 effectively increases lymphocyte populations in HNSCC preclinical models that demonstrate tumor-associated lymphopenia, and enhances the efficacy of cisplatin and anti-PD-1 in HNSCC preclinical tumor models. Citation Format: Zhibin Cui, Jacqueline L. Yee, Hua Li, Yan Zeng, Liam Woerner, Alexandra A. Wolfarth, Sara Ferrando-Martinez, Hyunseok Kang, Jennifer R. Grandis, Matthew H. Spitzer, Daniel E. Johnson. NT-I7 increases lymphocytes and enhances chemotherapy and immunotherapy efficacy in HNSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2152.
Abstract 662: Clinical and biomarker analyses of SHR-1701 combined with famitinib in patients with previously treated advanced biliary tract cancer or pancreatic ductal adenocarcinoma: A phase II trial
Authors: Lixia Yi, Zhiqiang Meng, Jing Xie
Journal: Cancer Research (2025)

Abstract Background: Advanced biliary tract cancer (BTC) and pancreatic ductal adenocarcinoma (PDAC) are aggressive malignancies with poor prognoses and limited treatment options. This first-in-class phase II study evaluated the efficacy and safety of SHR-1701, a bifunctional fusion protein targeting PD-L1 and TGF-β, combined with famitinib, a multi-targeted receptor tyrosine kinase inhibitor, in patients with advanced BTC or PDAC who failed previous standard treatment. Methods: In this open-label, single-arm trial (ChiCTR2000037927), patients with advanced BTC or PDAC who had failed at least one line of prior therapy received SHR-1701 (30 mg/kg IV Q3W) plus famitinib (20 mg PO daily). The primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Exploratory biomarker analyses were performed using RNA sequencing, multiplex immunohistochemistry, and machine learning. Results: Among 51 patients (BTC, n=25; PDAC, n=20), the BTC cohort showed an ORR of 28% (including 2 complete responses [CRs]) and a DCR of 80%, with a median PFS of 5.1 months and a median OS of 16.0 months. In the PDAC cohort, the ORR was 15% (2 CRs), with a DCR of 60%, and the median PFS and OS were 2.1 and 5.3 months, respectively. Grade 3/4 treatment-related adverse events occurred in 29.4% of patients, with no grade 5 events reported. Primary tumor resection history, peripheral blood immunophenotype changes, and distinct immune-metabolic profiles were associated with treatment benefits, with the TGF-β trap function of SHR-1701 potentially sequestering TGFB1 that was elevated in responders. An immune/metabolism (I/M) score integrating six genes was developed as a predictive biomarker for immunotherapy response in multiple cohorts, allowing to identify patients most likely to benefit from this therapy regimen. Conclusions: SHR-1701 plus famitinib showed promising efficacy and manageable toxicity in advanced BTC and PDAC, providing proof-of-concept for targeting PD-L1, TGF-β, and angiogenesis pathways simultaneously. The I/M score may help select patients most likely to benefit from this regimen. Citation Format: Lixia Yi, Zhiqiang Meng, Jing Xie. Clinical and biomarker analyses of SHR-1701 combined with famitinib in patients with previously treated advanced biliary tract cancer or pancreatic ductal adenocarcinoma: A phase II trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 662.
Abstract 1652: Preclinical characterization of ICT-011, a first-in-class, highly selective, potent and orally bioavailable MET degrader for the treatment of NSCLC harboring MET amplification
Authors: Jong Seok Kang, Yo Han Hong, Yong Hwan Kim, Hyeji Lee, Ji-Seong Yoon, Kyusic Jang, Bo Kyoung Kim, Young-Jun Shin, Moon Hwan Kim, Hye-Dong Yoo
Journal: Cancer Research (2025)

Abstract Background: The MET (also known as c-MET) tyrosine kinase receptor plays important roles in cancer cell growth, survival, migration, and invasion/metastasis. More importantly, MET alterations, including MET gene exon 14 skipping mutation, amplification and protein overexpression are recognized as oncogenic drivers for non-small cell lung cancer (NSCLC). MET amplification is the most common acquired resistance mechanism to EGFR tyrosine kinase inhibitor (TKI) treatment in EGFR-mutated NSCLC. Although MET TKIs are approved for the treatment of NSCLC patients with MET exon 14 skipping mutation, there are currently no effective treatments for those with MET amplification and overexpression. We discovered and evaluated ICT-011, which is a potent, selective, oral degrader of MET for treatment of NSCLC with MET amplification. Results: ICT-011 potently induced the degradation of MET protein in vitro in CRBN and ubiquitin-proteosome-dependent manners and demonstrated its selectivity for MET degradation when evaluated with proteome profiling analyses. In addition, in vitro cell-based analyses exhibited that ICT-011 induced protein proximity between MET and CRBN proteins. ICT-011 showed strong anti-proliferative activity against cancer cells with MET alterations, including MET amplification, but not normal cells. ICT-011 potently suppressed MET downstream signals and sustained the prolonged degradation of MET for 48 hours post-washout. ICT-011 had favorable PK profile suitable for oral administration in mouse, rat, and dog. ICT-011 exhibited rapid and robust anti-tumor activity, which was sustained after discontinuing its treatment in MET-amplified EBC-1 NSCLC xenograft models. ICT-011 also demonstrated superior anti-tumor activities compared with MET TKI, Tepotinib, and showed durable anti-tumor activities after discontinuing its treatment in patient-derived xenograft models of MET-amplified and EGFR-mutant (exon19 del) NSCLC. Conclusions: These results demonstrate that ICT-011 is a first-in-class, highly selective, potent and orally bioavailable MET degrader for the treatment of NSCLC harboring MET amplification. Citation Format: Jong Seok Kang, Yo Han Hong, Yong Hwan Kim, Hyeji Lee, Ji-Seong Yoon, Kyusic Jang, Bo Kyoung Kim, Young-Jun Shin, Moon Hwan Kim, Hye-Dong Yoo. Preclinical characterization of ICT-011, a first-in-class, highly selective, potent and orally bioavailable MET degrader for the treatment of NSCLC harboring MET amplification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1652.
Abstract 1421: RNA-seq for somatic tumor detection reveals synergy between whole transcriptome and targeted RNA library preparation methods
Authors: Chelsea Pinegar, Chen Song, Gautam Naishadham, Jian Sun, Bradley W. Langhorst, Keerthana Krishnan
Journal: Cancer Research (2025)

Abstract The interplay between variations in transcriptome profiles and disease progression is an important area of study emerging in cancer diagnostics. Whole-genome or targeted sequencing are conventional methods for somatic tumor assessment, but RNA sequencing has emerged as a powerful tool that can provide additional information on translation events in tumorigenesis. Transcriptome dynamics reflect cell state and can reveal key features in the evolution of disease. RNA sequencing (RNA-seq) has transformed cancer research by providing a more comprehensive view of the tumor especially in comparison to adjacent tissue allowing for advances in characterization and therapeutic options. Using streamlined RNA library preparation workflows in combination with a target enrichment approach can provide quick and cost-effective surveillance of samples, with the addition of sensitivity achieved with targeted sequencing. In this study, we compare bulk RNA-seq datasets with and without target enrichment and assess the power of each data type. They can be used in combination with other DNA based screening methods for biomarker detection in somatic tumors. RNA extracted from paired tumor and normal tissue samples were collected and prepared for Illumina sequencing using the NEBNext UltraExpress RNA Library Prep Kit. Target enrichment panels from Twist Bioscience were utilized to enrich specific transcripts and fusion-gene targets using the same Illumina libraries. Comparison of the whole transcriptome RNA-seq data with the target enrichment dataset for the same libraries reveals the strengths of each approach. The non-enriched RNA-seq library dataset provides a view of transcript levels, and can also be used to call SNVs and short structural variants, as well as splice variants and fusion genes. Target-enriched RNA-seq datasets provide more consistent depth and enhance sensitivity for low-level allele variants in targeted regions. The combination of both methods highlights the synergy between datasets in revealing well-known pathogenic mutations and gene fusions as well as rare or novel events. These sequencing methods, in combination with well validated bioinformatic pipelines, have the power to reveal genetic variations that may otherwise be omitted in more conventional detection methods. Citation Format: Chelsea Pinegar, Chen Song, Gautam Naishadham, Jian Sun, Bradley W. Langhorst, Keerthana Krishnan. RNA-seq for somatic tumor detection reveals synergy between whole transcriptome and targeted RNA library preparation methods [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1421.
Abstract 2158: Developing therapeutic strategy to address chemoresistance in cervical cancer using 3D <i>ex vivo</i> sensitivity testing drug
Authors: Lesetja Raymond Motadi
Journal: Cancer Research (2025)

Abstract Cervical cancer (CC) is ranked the fourth most common cause of cancer related deaths amongst women. The situation is particularly dire in low to lower middle-income countries. It continues to affect these countries due to poor vaccine coverage and screening. Cervical cancer is mostly detected in the advanced stages leading to poor outcomes. Many different chemotherapy drugs are used to treat recurrent CC, including cisplatin, ifostamide, carboplatin and gemcitabine. These drugs may be used alone or in combination. However, in a country like South Africa limited in resources this has become a challenge. In this study we aimed to develop a new therapuetic strategy that include repurposing current HPV vaccine through immune targeting strategy. The 3D ex vivo cancer cells were used and cells were targeted with neutralizing antibodies from HPV targed with cannabidiol. Following treatement, Cell viability, qPCR, Annexin V, immunocytochemistry and DNA fragmantation was performed. The IC50 was observed to be at 26ug/ml. The DNA fragmentation showed positive apoptosis induction while genes like p53, bax and bak1 were all increased. immunocheckpoint were all down in all treatments. The staining for protein showed increase in proteins associated with apoptosis. The results suggest apoptosis induced mechanism. Citation Format: Lesetja Raymond Motadi. Developing therapeutic strategy to address chemoresistance in cervical cancer using 3D ex vivo sensitivity testing drug. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2158.