bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3261: Improving targeted therapy in female patients with lung squamous cell carcinoma
Authors: Momcilovic Milica , Shackelford David 
Published: March 2024

Abstract
Non-small cell lung cancer (NSCLC) will claim the lives of ~60,000 female patients in the US in 2023. Lung squamous cell carcinoma (LUSC) is a subtype of Non-Small Cell Lung Cancer (NSCLC) that comprises ~30% of NSCLC and is characterized by high metabolic activity. Specifically, LUSC typically exhibits elevated rates of both glucose and glutamine metabolism driven by the PI3K-AKT-mTOR and KEAP1/NRF2 pathways. Further, a paucity of identifiable genetic drivers in LUSC has resulted in a lack of effective targeted therapies for patients with this devastating disease. Despite recent advances in therapy, the 5-year survival rate for patients with advanced NSCLC is 6%, underscoring the need for better treatment options. Importantly, no significant sex bias is seen in the newly diagnosed cases of lung cancer (~50%M/~50%F) (American Cancer Society, 2023), yet there are no sex-specific therapeutic approaches in clinical use. We demonstrated that the catalytic mTOR kinase inhibitor TAK228 can be utilized to effectively treat LUSC tumors via inhibition of glycolysis, an approach that is currently being evaluated on two phase I/II clinical trials (NCT02417701, NCT04250545), launched as a direct result of our pre-clinical work. However, our pre-clinical data suggests that despite the potential benefit of TAK228 inhibition in LUSC, a subset of tumors are resistant to TAK228 despite on-target activity of mTOR inhibitor, leading to the rationale of the current hypothesis, namely the possibility that sex-specific differential effects of TAK228 may exist. To evaluate this hypothesis, we have generated preliminary data demonstrating that sex is a determinant of TAK228 response in LUSCs, whereby male mice are significantly more sensitive to mTOR inhibition than females. Follow-on experiments have demonstrated that the anti-estrogen therapy (Letrozole) sensitized previously resistant female mice bearing LUSCs to TAK228, suggesting an estrogen-related link to TAK228 resistance in females. Additionally, RNASeq and biochemical analyses identified pathways that are upregulated in TAK228 resistant female mice with LUSC tumors. These results suggest that the estrogen may play a key role in the observed pattern of female resistance to mTOR inhibition. As such, the goal of the current proposal is to evaluate the catalytic mTOR kinase inhibitor TAK228, in combination with anti-estrogen therapy as a therapeutic strategy to treat LUSC in females.
Citation Format: Milica Momcilovic, David Shackelford. Improving targeted therapy in female patients with 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 3261.
Abstract 3278: Analysis of the mechanism of resistance to selpercatinib in thyroid cancer cells with RET/PTC1 fusion gene
Authors: Amitani Masatsugu , Ito Ken-ichi 
Published: March 2024

Abstract
Purpose: Precision oncology, in which molecularly targeted drugs are selected based on genetic mutations, has begun in thyroid cancer, and drugs targeting BRAF, RET, and NTRK are already in clinical use. However, as with previous therapeutic agents for malignant tumors, there have been cases of resistance to these drugs either initially or during treatment, and the mechanisms of drug resistance need to be elucidated. So far, little is known about the mechanisms of resistance to molecularly targeted drugs in thyroid cancer. To overcome resistance to the RET inhibitor, selpercatinib (SEL), and to consider next therapeutic strategies, we aimed to elucidate the mechanisms of resistance to SEL.
Method: We used papillary carcinoma cell lines TPC-1 and CUTC48, which harbor the RET/PTC1 fusion gene. We established an SEL-resistant subline (TPC-1/SELR) in TPC-1 by long-term exposure to SEL. The growth inhibitory effect of drugs was analyzed using the WST assay. The alteration of intracellular signal transduction was analyzed by western blotting.
Result: The 50% inhibitory concentration (IC50) for SEL in the parental TPC-1 was 3 nM, while growth inhibition in TPC-1/SELR did not reach 50% even at more than 100 nM of SEL. On the other hand, growth inhibition by SEL in CUTC48 did not reach 50% even at more than 100 nM of SEL. The sensitivity to SEL in CUTC48 was comparable to that in TPC-1/SELR, and CUTC48 showed an intrinsic resistance to SEL. TPC-1/SELR showed increased phosphorylation of EGFR, Erk, Akt, and mTOR compared to TPC-1. In CUTC48, phosphorylation of EGFR and Erk was not increased compared to that of TPC-1, while phosphorylation of Akt and mTOR was increased. We investigated the growth inhibitory effect of an mTOR inhibitor everolimus and found that TPC-1 (IC50: 1.3 nM), TPC-1/SELR (5 nM), and CUTC48 (9.4 nM) were all highly sensitive to everolimus.
Discussion: Our results showed that Akt and mTOR phosphorylation were elevated in the SEL-resistant TPC-1/SELR and the SEL-intrinsic resistant CUTC48 in common, suggesting the involvement of activation of the Akt-mTOR pathway in SEL resistance in thyroid cancer. The inhibition of the Akt-mTOR pathway in parallel with RET may have therapeutic potential to overcome SEL resistance in thyroid cancer.
Citation Format: Masatsugu Amitani, Ken-ichi Ito. Analysis of the mechanism of resistance to selpercatinib in thyroid cancer cells with RET/PTC1 fusion gene [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 3278.
Abstract 3434: Effect modification by levels of sex hormones in the association between adiposity and cancer incidence in the UK Biobank
Authors: Lucas LeeAnn , Lu Yujia , Giovannucci Edward L. , Song Mingyang 
Published: March 2024

Abstract
Introduction: The association between adiposity and cancer risk differs between sexes for some cancer types.
Methods: We prospectively examined adiposity in relation to cancer incidence according to sex hormones in the UK Biobank. Adiposity was assessed by body mass index (BMI) and visceral adipose tissue (VAT), the latter predicted using determinants of age, height, weight, hip circumference, waist circumference, and race. Serum sex hormone binding globulin (SHBG), testosterone, and estradiol were measured using a biochemistry assay and were classified as high or low based on median levels. Cancer incidence was ascertained using ICD-10 codes through cancer registry linkage. For cancer types showing a sex difference in the association between adiposity and cancer incidence, we assessed multiplicative and additive interaction with sex hormones in men and women separately and corrected for multiple testing using false discovery rate. We used Cox regression to calculate the multivariable hazard ratio (HR) of cancer per increase between the 90th to 10th percentile of adiposity (BMI or predicted VAT).
Results: During a median follow-up of 13.1 years, we documented 23,964 and 21,045 incident cancer cases among 217,460 men and 256,163 women, respectively. Adiposity showed a much stronger association with higher risk of colorectal, esophageal, and liver cancers in men than women. In men, BMI was more strongly associated with higher risk of colorectal cancer in low vs. high levels of SHBG (HR (95%CI) of 1.47 (1.31-1.64) vs. 1.12 (0.94-1.33) (adjusted Pinteraction = 0.027). In contrast, BMI showed a stronger association in high vs. low levels of SHBG with esophageal (HR = 2.39 vs. 1.62) and liver cancers (HR = 3.24 vs 1.96) in men (adjusted Pinteraction = 0.038 and 0.027, respectively). Among women, BMI was associated with a higher risk of esophageal cancer in those with low SHBG (HR=1.68) but not in those with high SHBG (HR=0.64) (adjusted Pinteraction = 0.025). Similar patterns were observed for predicted VAT. Men with high SHBG levels and high adiposity (BMI and predicted VAT) had 7.63 (5.08-11.46) and 8.92 (5.72 to 13.90), respectively, times higher risk of liver cancer compared to men with low SHBG levels and low adiposity. No effect modification by estradiol or testosterone was detected for any of the cancers studied.
Conclusions: The association between adiposity and colorectal, esophageal, and liver cancer differed by sex. SHBG may be an important factor underlying these differences.
Citation Format: LeeAnn Lucas, Yujia Lu, Edward L. Giovannucci, Mingyang Song. Effect modification by levels of sex hormones in the association between adiposity and cancer incidence in the UK Biobank [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 3434.
Abstract 3509: Using generative AI for filtering and comprehension of drug target discovery screen results
Authors: Rech Andrew , Goltsev Yury , Samusik Nikolay , Kaznadzey Anna 
Published: March 2024

Abstract
Recent advancements in generative AI, including models such as GPT-4 and LLAMA2, have been rapidly integrated into cancer research. Cellformatica, Inc. has developed a pipeline designed to enhance the accuracy of functional and genomic drug target discovery screens by reducing the incidence of false positives and refining the interpretation process. This pipeline is capable of conducting comprehensive investigations, including genome-wide analyses, and is accessible via web and API interfaces. At the core of the pipeline is the use of the extensive global corpus of scientific literature to assess the relevance of each gene within the context defined by the experimental design of the screen. To address the issue of AI-generated inaccuracies, often referred to as 'hallucinations,' the pipeline incorporates a custom-tuned language model (LLM) component within the generative AI framework. This fine-tuning process is specifically tailored to the gene set under investigation. The pipeline's multi-agent architecture is a distinctive feature. It scores candidates based on three orthogonally-tuned criteria: effectiveness, confidence, and novelty. In benchmarking tests, this multi-agent scoring system has outperformed GPT-4 and has proven particularly adept at identifying candidate targets that may have been overlooked in previous research. These candidates are recognized for their significant therapeutic potential and are corroborated by existing scientific findings. The versatility of the Cellformatica pipeline is demonstrated through its application in three distinct areas of cancer research. First, it has been employed to optimize chimeric antigen receptor (CAR) T-cell therapies, a form of immunotherapy for cancer treatment. Second, the pipeline has been used to elucidate the network of chemotactic molecules that orchestrate immune cell infiltration and tissue remodeling in the lungs of patients with COVID-19. Third, it has been used to spatially define signaling pathways in humanized xenograft murine tumor experiments, for which existing cross-species database knowledge is limited. These applications underscore the pipeline's potential to contribute to the understanding and treatment of complex diseases.
Citation Format: Andrew Rech, Yury Goltsev, Nikolay Samusik, Anna Kaznadzey. Using generative AI for filtering and comprehension of drug target discovery screen results [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 3509.
Abstract 3611: A patient-derived organoid platform to assess the effectiveness of γδTCR cell therapy in solid tumors
Authors: Bisso Andrea , Overmeer Rene , Baardman Sjoerd , Coomans Chris , Oyarce Cesar , Boj Sylvia F. 
Published: March 2024

Abstract
Recent advances in cancer immunotherapy have positively impacted the life expectancy of patients for an extensive range of clinical indications. With new treatment strategies and druggable targets being identified at an increasing pace, the number of patients eligible for cancer immunotherapy is expected to expand steadily. However, promising therapeutic developments face hurdles in translating preclinical findings into therapy since conventional 2D cancer models hold low clinical predictive value. HUB developed an innovative alternative, building on the discovery that adult stem cells proliferate and organise into three-dimensional organotypic structures when embedded into the extracellular matrix. Patient-derived organoids are generated from healthy and malignant tissues, and they recapitulate complex characteristics of the original parental tissue, including molecular heterogeneity and morphological and functional traits. Cell therapies have achieved positive results in treating haematological cancers. Recently, the unique tumour-targeting properties of γδ T cell receptors have been leveraged to develop safer and more effective strategies. HUB and Gadeta joined efforts to explore the therapeutic potential of GDT002 - i.e. αβ T cells engineered with a Gadeta proprietary new γδTCR - to target solid cancers. A preclinical basket trial was performed using patient-derived organoids from several tumour types (colorectal, breast, head and neck, ovarian cancers) cocultured with GDT002. The results showed broad reactivity of GDT002 against solid tumor PDOs. Interestingly, GDT002 was particularly efficient at killing ovarian cancer-derived PDOs, allowing Gadeta to move GDT002 to clinical trials for this indication confidently. This study reveals that our tumor organoid co-culture with engineered T cells platform holds significant value for the preclinical development of cellular therapies.
Citation Format: Andrea Bisso, Rene Overmeer, Sjoerd Baardman, Chris Coomans, Cesar Oyarce, Sylvia F. Boj. A patient-derived organoid platform to assess the effectiveness of γδTCR cell therapy in solid tumors [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 3611.
Abstract 362: Arsenic sulfide triggers ferroptosis in hepatocellular carcinoma cells via TRPC6/GPX4 signaling
Authors: Lu Shumin , Cai Yu , Zhu Chuanying , Feng Zhuowei , Chen Shuxian , Chen Siyu 
Published: March 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 3656: Target enrichment of methylated circulating tumor DNA for colorectal cancer detection
Authors: Huang Hsiao-Yun , Satya Ravi Vijaya , Chan Wen-Ching , Atolia Esha , Babiarz Joshua , Zimmermann Bernhard , Kawli Trupti 
Published: March 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 &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 &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 3697: Proof-of-concept study to enumerate large oncosomes using the RareCyte CTC platform
Authors: Papp Eszter , Vandesompele Jo , Vermeulen Peter B. , Dirix Luc Y. , Kockx Mark 
Published: March 2024

Abstract
Introduction: Large oncosomes (LO) are produced by tumor cells and can be detected in blood from cancer patients. The clinical utility of enumerating and characterizing LOs along with CTCs has been demonstrated, especially in settings where CTC counts are low. The RareCyte CTC platform has the potential to capture LOs along with CTCs. We performed a pilot study to evaluate the RareCyte CTC platform’s potential to analyze LOs using established preanalytical procedures.
Methods: Metastatic breast cancer patients’ (N=10) blood smears labelled with RarePlex® Enumeration panel kit were re-evaluated to identify objects with LO-like characteristics at 10x magnification, along with negative control slides (N=5). LO-like objects were annotated and re-scanned at 40x magnification using the CyteFinder® imaging instrument. After establishing the criteria for LO identification, LO enumeration was performed on a cohort of MBC patients (N=6). Sets of five blood smear slides stained with the RarePlex® Enumeration panel kit were reviewed and LO counted. Total LO counts were established by extrapolating LO counts to 7.5 mL plasma. Pearson correlation was used to determine the level of correlation between LO counts and previously obtained CTC counts.
Results: The established identification criteria enabled the consistent enumeration of LOs at 10X magnification. Total LO count was 9.6 on the negative control slides. In MBC patients the mean total LO count was 306.2 (range 3.2 - 792). There was a significant positive correlation between LO and CTC count (r=0.855, p=0.3). In samples with CTC&gt;0 (N=3), the average total LOs count was 588, about six times higher than CTC count. In CTC=0 patient samples (N=3) the mean total LO count was 24.3 (range 3.2-36).
Conclusions: We report a novel protocol to quantify large oncosomes using the RareCyte CTC platform using established preanalytical workflows. The strong CK/EpCam staining in LOs and the strong correlation of LO count with CTC count indicates their tumoral origin. Due to their higher abundance, LOs combined with CTCs offer a more sensitive tool for treatment response monitoring. Due to its broad range, LO counts in patients with CTC=0 may reveal therapy response dynamics undetectable with CTC enumeration alone. Ongoing work focuses on the parallel detection and integrated evaluation of HER2 by immunofluorescent staining of CTCs and LOs, along with digital PCR based HER2 quantification using cfDNA from matched blood plasma samples.
Citation Format: Eszter Papp, Jo Vandesompele, Peter B. Vermeulen, Luc Y. Dirix, Mark Kockx. Proof-of-concept study to enumerate large oncosomes using the RareCyte CTC platform [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 3697.