tbuckley/cabot-search huggingface dataset:
Abstract 65: Differential impacts of PD-L1 expression in tumor vs. stroma on survival in esophageal squamous cell carcinoma
Authors: Tomohiro Murakami, Satoru Furuhashi, Yuuki Sakai, Kenichi Sekimori, Ryoma Haneda, Eisuke Booka, Tomohiro Matsumoto, Hirotoshi Kikuchi, Yoshihiro Hiramatsu, Hiroya Takeuchi
Journal: Cancer Research (2024)

Abstract Background: Esophageal squamous cell carcinoma (ESCC) has high incidence and recurrence rates, particularly in advanced stages. While the combined positive score (CPS) and tumor proportional score (TPS) are standard benchmarks for PD-L1 assessment in ESCCs, they face challenges such as reliance on subjective human interpretation and the uncertain clinical significance of strong staining intensities. Our study utilizes H-scores for PD-L1 expression and separates analysis of tumor and stroma, providing additional layers of information that complement current methods and contribute to a more comprehensive understanding of the role of PD-L1 in ESCC. Methods: This retrospective single-center cohort analysis involved 194 cases of ESCC who underwent surgical resection. We performed a comprehensive evaluation of PD-L1 expression within the tumor and stroma using whole slide images (WSI). QuPath image analysis software was used to classify regions as tumor or stroma and quantify the PD-L1 expression H-score. Results: Using optimal H-score cutoffs determined from the minimum P-value method, the Kaplan-Meier survival analysis showed that higher PD-L1 expression was significantly linked with better post-operative survival across all compartments. This correlation was most pronounced in the stroma (P&amp;lt;0.001). However, in multivariate Cox regression analysis, only high tumoral PD-L1 expression emerged as an independent predictor of favorable prognosis (HR=0.47, 95% CI: 0.27-0.81, P=0.007). The non-significant contribution of stromal PD-L1 in this model could be attributed to its association with advanced pT and pN stages, and the presence of lymphatic and venous invasion (P&amp;lt;0.001, respectively). Interestingly, stromal PD-L1 expression was associated with a longer duration of cytotoxic chemotherapy (cutoff 8 months, Median H-score 98.28 vs 55.24, P=0.026), but no significant correlation was observed with the duration of immune checkpoint inhibitor treatment. Conclusions: The study underscores the complex role of PD-L1 in ESCC, with tumoral PD-L1 expression emerging as an independent prognostic factor, and stromal PD-L1 expression found to be related with tumor progression and the duration of cytotoxic chemotherapy response. Citation Format: Tomohiro Murakami, Satoru Furuhashi, Yuuki Sakai, Kenichi Sekimori, Ryoma Haneda, Eisuke Booka, Tomohiro Matsumoto, Hirotoshi Kikuchi, Yoshihiro Hiramatsu, Hiroya Takeuchi. Differential impacts of PD-L1 expression in tumor vs. stroma on survival in esophageal 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 65.
Abstract 3656: Target enrichment of methylated circulating tumor DNA for colorectal cancer detection
Authors: Hsiao-Yun Huang, Ravi Vijaya Satya, Wen-Ching Chan, Esha Atolia, Joshua Babiarz, Bernhard Zimmermann, Trupti Kawli
Journal: Cancer Research (2024)

Abstract Aberrant DNA methylation changes are one of the earliest signatures of cancer development. Methylation profiling of circulating tumor DNA (ctDNA) from plasma has emerged as a promising approach for early cancer detection (ECD). However, the set of methylation targets that can successfully distinguish cancer through liquid biopsy will vary depending on cancer type and subtype. Here, we explored a methylation target enrichment workflow and developed a methylation-based classification model to distinguish between patients with colorectal cancer (CRC) and healthy individuals. First, CRC-specific CpG targets were identified by comparing the methylation landscape of CRC and normal samples (tissue and blood) available in The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) datasets. This analysis resulted in &amp;gt;800 CRC-specific CpG targets for initial evaluation. To develop and test the classification model, CRC patients and healthy individuals with plasma samples were included. A machine learning model was used to evaluate the highest performing CpG targets that effectively discriminated between CRC patients with detected ctDNA (“CRC ctDNA-positive”) and healthy individuals. Correlation between methylation levels of the high performing CpG targets and the variant allele frequency (VAF) among CRC ctDNA-positive patients was calculated. In total, 86 patients were included in this proof of concept study (mean age, 62 ±12 years; male, 55%). 50 CRC ctDNA-positive patients (24% stage I, 40% stage II, 24% stage III, and 12% stage IV) and 36 healthy normals were included in the analysis. We investigated this cohort to identify the highest performing CpG targets among the &amp;gt;800 potential CpG targets that provided effective discrimination between CRC patients and healthy individuals. Using the highest performing CpG targets, observed methylation level was correlated with VAF of single nucleotide variants detected by ctDNA testing (R2: 0.8). In summary, we developed a cost-effective methylation target enrichment workflow and utilized machine-learning algorithms to demonstrate the potential use of ctDNA methylation markers in early detection. Additional studies are needed to confirm that these and other markers can accurately distinguish between patients with CRC and healthy individuals. Citation Format: Hsiao-Yun Huang, Ravi Vijaya Satya, Wen-Ching Chan, Esha Atolia, Joshua Babiarz, Bernhard Zimmermann, Trupti Kawli. Target enrichment of methylated circulating tumor DNA for colorectal cancer detection [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 3656.
Abstract 362: Arsenic sulfide triggers ferroptosis in hepatocellular carcinoma cells via TRPC6/GPX4 signaling
Authors: Shumin Lu, Yu Cai, Chuanying Zhu, Zhuowei Feng, Shuxian Chen, Siyu Chen
Journal: Cancer Research (2024)

Abstract Background: Ferroptosis is critically involved in the pathological process of various human diseases, including cancer. Due to this, ferroptosis-inducing drugs are gaining more attention for the clinical treatment of tumors. Methods: The cell counting kit-8 (CCK-8) assay was conducted to observe cell viability of hepatocellular carcinoma (HCC) cell lines. Ferroptosis was determined by levels of Fe2+, lipid reactive oxygen species (ROS), malondialdehyde (MDA) and transmission electron microscopy. Enzyme-linked immunosorbent assay (ELISA), western blot, quantitative polymerase chain reaction and immunofluorescence staining were utilized to evaluate glutathione peroxidase 4 (GPX4) and transient receptor potential channel 6 (TRPC6). Co-immunoprecipitation assay was conducted to determine the binding between GPX4 and TRPC6. Results: Arsenic sulfide initiated ferroptotic cell death in HCC cells, which was concomitant with ROS accumulation, lipid peroxidation, and GSH depletion. Arsenic sulfide -mediated cell death in HCC cells was blocked by ferroptosis inhibitors ferrostatin-1 (Fer-1), but not Z-VAD-FMK, necrosulfonamide, or chloroquine, suggesting that ferroptosis contributed to arsenic sulfide -induced cell death. Furthermore, TRPC6 expression was notably inhibited under arsenic sulfide intervention and the overexpression of TRPC6 rescued the effects of arsenic sulfide on cell viability and ferroptosis of HCC cells. Furthermore, GPX4 was identified to interact with TRPC6 through confocal microscopy images and co-immunoprecipitation assay. Conclusion: Our findings led us to conclude that arsenic sulfide could be considered as a prospective drug for liver cancer treatment. Citation Format: Shumin Lu, Yu Cai, Chuanying Zhu, Zhuowei Feng, Shuxian Chen, Siyu Chen. Arsenic sulfide triggers ferroptosis in hepatocellular carcinoma cells via TRPC6/GPX4 signaling [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 362.
Abstract 5021: Circulating mutated and methylated tumor DNA detection for colorectal cancer diagnosis
Authors: Pushpinder Kaur Bains, Mikhail Kulak, Zhen Cui, Alisha Babu, Stella Tran, Aiguo Zhang, Michael Sha
Journal: Cancer Research (2024)

Abstract Introduction: Detection of mutation and methylation patterns in liquid biopsies has emerged as a promising approach for screening early-stage cancers. We have developed a targeted next-generation sequencing (NGS)-based assay “OptiSeqTM Colorectal Cancer Detection Panel”, a combined platform for assessing mutation and methylation in both low-quantity (plasma cfDNA) and low-quality formalin-fixed paraffin-embedded (FFPE) tissue for colorectal cancer (CRC) detection. Methods: The OptiSeqTM Colorectal Cancer Detection Panel targets 442 SNVs and 434 CpG sites to detect circulating tumor DNA (ctDNA) in early-stage patients. With this panel, we profiled 6 early-stage and 6 metastatic CRC samples (matching cfDNA and FFPE) along with 2 primary colon specimens with adjacent normal tissue DNA. We also profiled 2 matching cfDNA and FFPE samples from precancerous adenomas (advanced adenomas (AA)) and 6 AA FFPE tissue DNA. In addition, we characterized the mutation and methylation pattern in 10 CRC fresh-frozen tissue DNA samples. For healthy individuals, we profiled 12 normal colon FFPE samples and 10 plasma cfDNA. The clinical performance for the CRC detection panel was calculated using AA, CRC, and cancer-free individuals. Results: For CRC early and metastatic matching cfDNA and FFPE samples, clinical samples testing showed that the CRC detection panel had a sensitivity of 100% (95% CI: 69.8-100.0) and specificity of 100% (95% CI: 81.5-100). For precancerous AA FFPE tissues, combined DNA mutation and methylation increased the CRC detection sensitivity to 100% (95% CI: 51.6-100.0) and specificity to 100% (95% CI: 61.8-100). More clinical samples testing is underway. Conclusion: We have developed the targeted NGS-based panel to detect clinically relevant mutation and methylation patterns and demonstrate its potential using the combined genetic and epigenetic markers making it a highly sensitive assay for early CRC diagnosis. Citation Format: Pushpinder Kaur Bains, Mikhail Kulak, Zhen Cui, Alisha Babu, Stella Tran, Aiguo Zhang, Michael Sha. Circulating mutated and methylated tumor DNA detection for colorectal cancer diagnosis [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 5021.
Abstract 412: Discovery and preclinical characterization of ISM9342A, a novel, potent, and orally bioavailable WRN inhibitor that suppresses MSI-H tumor growth
Authors: Pei Zhao, Wei Zhu, Xiaoyu Ding, Jianfei Wan, Xiaojing Chen, Man Zhang, Xiao Ding, Supriya Bavadekar, Sujata Rao, Feng Ren, Alex Zhavoronkov
Journal: Cancer Research (2024)

Abstract Loss of function mutations in DNA mismatch repair genes can result in microsatellite instabilities (MSI) and high levels of MSI (MSI-H) contributes to tumorigenesis and is frequently observed in endometrial carcinoma, gastric cancer, and colorectal cancer. Although immune checkpoint inhibitors have been approved for the treatment of MSI-H tumors, there is still a large proportion of patients with MSI-H tumors who fail to respond to these therapies. Recently, two independent genome-wide loss of function screens have identified Werner syndrome helicase (WRN) as the top dependency for MSI-H cancer cell viability. WRN plays important roles in DNA repair and in the maintenance of genome integrity. Given that WRN deficiency selectively impairs the viability of MSI-H but not microsatellite stable cancer cells, WRN is a synthetic lethal target for MSI-H tumors. ISM9342A is a novel and potent WRN inhibitor exhibiting single digit nanomolar IC50 values in both ATPase and helicase assays. ISM9342A suppressed the proliferation and increased double strand break markers in MSI-H cancer cells. Moreover, ISM9342A demonstrated promising in vivo anti-tumor efficacy in an MSI-H xenograft model along with tumor regression. ISM9342A demonstrated good drug-like properties, including excellent in vitro ADMET profiles and good in vivo exposure, including low clearance and optimal oral bioavailability across multiple preclinical species. Collectively, these findings highlight the potential of ISM9342A as a highly potent WRN inhibitor for the treatment of MSI-H tumors Citation Format: Pei Zhao, Wei Zhu, Xiaoyu Ding, Jianfei Wan, Xiaojing Chen, Man Zhang, Xiao Ding, Supriya Bavadekar, Sujata Rao, Feng Ren, Alex Zhavoronkov. Discovery and preclinical characterization of ISM9342A, a novel, potent, and orally bioavailable WRN inhibitor that suppresses MSI-H tumor growth [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 412.
Abstract 4322: Inhibition of ULK and KRASG12C control tumor growth in preclinical models of lung cancer
Authors: Phaedra Ghazi, Kayla O'Toole, Sanjana Boggaram, Michael Scherzer, Madhumita Bogdan, Bryan Smith, Dan Flynn, Conan Kinsey, Martin McMahon
Journal: Cancer Research (2024)

Abstract Approximately 30% of lung cancers are driven by mutationally activated KRAS. The recent FDA approval of sotorasib, a direct pharmacological inhibitor of KRASG12C, marks a critical milestone in the treatment of this important subset of lung cancer. However, a major obstacle in treating lung cancer is resistance to current therapeutic treatments. In response to cellular stresses such as RAS pathway-targeted therapeutics, RAS-mutated cancer cells have been demonstrated to increase autophagy, an intracellular recycling pathway. However, the mechanism(s) underlying treatment-induced autophagy is not well understood. Here, we demonstrate that KRASG12C-driven lung cancer cells increase autophagy in response to treatment with sotorasib. Currently, the only therapeutics in clinical use to inhibit autophagy are lysosomal inhibitors (hydroxy)chloroquine. High concentrations of these compounds are needed to achieve modest inhibition of autophagy, suggesting that the potency of these compounds may limit clinical responses. ULK kinases are serine/threonine kinases that are necessary for the initiation of autophagy. DCC-3116 is a potent inhibitor of the ULK1/2 protein kinases, master regulators of autophagy. Treatment with sotorasib and DCC-3116 led to superior anti-tumor effects in preclinical models of lung cancer. Additionally, about 30% of lung cancer patients with KRAS mutations also have deletions or inactivating mutations in LKB1, a protein involved in the regulation of nutrient sensing and autophagy. In other KRAS-driven cancers, the LKB1-AMPK-ULK1 signaling axis is a proposed mechanism as to how autophagic flux increases following KRAS pathway inhibition. However, our preliminary data demonstrates that LKB1 is dispensable for sotorasib-induced autophagy, suggesting the mechanism(s) of autophagy induction in KRASG12C-driven lung cancer may be different from those detected in other KRAS mutated cancers. Consequently, we have generated genetically engineered mouse models (GEMMs) of KRASG12C-driven lung cancer in which LKB1 is silenced to further investigate the role of LKB1 in the autophagy response of KRASG12C-driven lung cancers to pathway-targeted blockade of oncogenic KRAS signaling. We have treated KRASG12C-driven GEMMs with sotorasib and/or DCC-3116 to test the sensitivity of lung tumors to these treatment options. Citation Format: Phaedra Ghazi, Kayla O'Toole, Sanjana Boggaram, Michael Scherzer, Madhumita Bogdan, Bryan Smith, Dan Flynn, Conan Kinsey, Martin McMahon. Inhibition of ULK and KRASG12C control tumor growth in preclinical models of lung 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 4322.
Abstract 6417: Urinary PKM2 in muscle invasive bladder cancer
Authors: David Matye, Juliann Leak, Erika Abbott, Benjamin Woolbright, John Taylor
Journal: Cancer Research (2024)

Abstract Background &amp; Aims: Biomarkers are commonly used for both detection of cancer and monitoring response to treatment. Although several biomarkers have demonstrated promise in patients with bladder cancer (BCa), only urine cytology is widely utilized. Increased availability of effective biomarkers may improve clinical decision making and reduce the need for more invasive imaging. The M2 isoform of pyruvate kinase (PKM2) is upregulated in a number of cancers, including BCa, and promotes metabolic changes, including a shift to aerobic glycolysis. The aim of this study was to determine whether urine PKM2 levels are useful for detection and monitoring response to cisplatin-based neoadjuvant chemotherapy in patients with muscle invasive BCa. Methods: Urine samples from patients enrolled in the University of Kanas Medical Center Bladder Cancer Biorepository were analyzed for levels of PKM2. Patients were included if they had both T2 stage disease and had received cisplatin-based neoadjuvant chemotherapy and were compared to healthy controls. Patients were categorized based on their pathological response to treatment and recurrence of disease within two years of definitive surgery. Urinary PKM2 levels were measured and evaluated for their ability to predict response to treatment and two-year disease-free survival. Results: Immunohistochemistry revealed high levels of PKM2 within muscle invasive tumors compared to adjacent tissue. Patients with BCa had 150-fold increase in levels of urinary PKM2 compared to controls. However, there were no differences in urine PKM2 levels in patients with complete pathological response compared to those with no response. Urine PKM2 showed limited predictive value for disease recurrence (area under receiver operating characteristic curve = 0.65). Conclusion: Urine levels of PKM2 are significantly elevated in patients with muscle invasive BCa and may be useful for tumor detection. Urinary PKM2 is less effective at monitoring response to treatment and may instead represent a marker of urothelial susceptibility to tumor formation. Citation Format: David Matye, Juliann Leak, Erika Abbott, Benjamin Woolbright, John Taylor. Urinary PKM2 in muscle invasive bladder 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 6417.
Abstract 6953: Wnt2b deficiency exacerbates colitis and leads to increased tumorigenesis in mice
Authors: Luiz Fernando Silva Oliveira, Amy E. O'Connell
Journal: Cancer Research (2024)

Abstract Colitis-associated cancer (CAC) is considered the most severe complication of inflammatory bowel disease (IBD). It has been demonstrated that WNT2B deficiency leads to severe intestinal impairment in humans and predisposes to colitis in mice. Evaluating a human cohort from The Cancer Genome Atlas (TCGA), we observed that low expression of WNT2B is associated with poor prognosis of patients with colon cancer. However, the functional roles of WNT2B in CAC development remain unclear, and we hypothesized that WNT2B is involved in the resistance to CAC development during long-term colitis. Thus, we model CAC development using Wnt2b deficient mice subjected to mutagenesis induction with 10 mg/kg Azoxymethane (AOM) and a long-term colitis protocol with three cycles of 2.5% Dextran Sodium Sulfate in the drinking water for three days, followed by a recovery period with autoclaved water. We observed that Wnt2b KO mice had increased susceptibility to colitis and more significant body weight changes than WT mice, especially in the first and second recovery cycles of colitis recovery. The maximum weight loss and disease activity index (DAI) were significantly higher in KO than in WT mice. Interestingly, Wnt2b KO mice developed more tumors, which were more extensive than those observed in WT. Moreover, the histopathological analysis showed that Wnt2b KO had the highest score for ulceration, aberrant crypt foci, and immune cell infiltration. Our data suggest a protective role for WNT2B, conferring resistance to tumor development during colitis. Furthermore, our data provides new insights into the functional roles of Wnt ligands in colon cancer. A better understanding of the factors involved in CAC etiology is critical for improving diagnosis and developing new targeted therapies. We believe WNT2B may emerge as one of these factors and offer novel targets for improved colorectal cancer management. Citation Format: Luiz Fernando Silva Oliveira, Amy E. O'Connell. Wnt2b deficiency exacerbates colitis and leads to increased tumorigenesis in mice [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 6953.