bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 7192: Teriflunomide overcomes gemcitabine resistance by inhibiting the GSK3β/mTOR pathway in pancreatic cancer
Authors: Xu Caiming , Li Yuan , Sui Silei , Chen Meiling , Melstorm Laleh , Han Haiyong , Rosen Steven T. , Goel Ajay 
Published: March 2024

Abstract
Background: Pancreatic cancer (PC) is a lethal malignancy that is partly attributable to the acquisition of chemoresistance to conventional chemotherapies. Hence, developing strategies to overcome such chemoresistance is essential. Teriflunomide, an active metabolite of leflunomide, has been widely utilized in managing autoimmune disorders, and emerging evidence suggests that it can augment the efficacy of chemotherapy in cancer. We investigated the therapeutic effect of teriflunomide in overcoming resistance to Gemcitabine-based therapy in PC.
Methods: We performed docking and genomewide transcriptomic profiling analyses to identify therapeutic targets of Teriflunomide associated with Gemcitabine resistance (Gem-R) in PC. Subsequently, we analyzed the TCGA dataset to determine the prognostic significance of candidate genes in PC patients. A series of experiments were performed in PC cells, and the key findings were validated in patient-derived 3D organoids and a Gem-R Mia-PaCa2 xenograft model.
Results: Docking and transcriptomic profiling studies identified GSK3β, MAPK8, and MAPK9 as potential targets of Teriflunomide, which were significantly upregulated in Gem-R cell lines (P &lt; 0.05). GSK3β was independently associated with poor overall and disease-free survival in PC patients. Combined Teriflunomide and Gemcitabine treatment exhibited superior synergistic anti-tumor potential, as evidenced by reducing PC cell proliferation, clonogenicity, invasion, and migration. The combined treatment with Teriflunomide and Gemcitabine primarily inhibited GSK3β phosphorylation, resulting in the silencing of the downstream AKT/mTOR pathway. Lentiviral-based silencing of GSK3β inhibited the AKT/mTOR pathway and reduced the IC50s of Gemcitabine in PC cells. Furthermore, co-administrating both drugs to Gem-R Mia-PaCa-2 xenograft mice significantly reduced tumor growth rates and volumes. These findings were recapitulated in patient-derived 3D-organoids, where the combined treatment resulted in fewer and smaller organoids vs. each drug individually (P &lt; 0.05).
Conclusions: We provide novel evidence that Teriflunomide helps overcome resistance to Gemcitabine by inhibiting the GSK3β/AKT/mTOR pathway, which could improve treatment outcomes in PC.
Citation Format: Caiming Xu, Yuan Li, Silei Sui, Meiling Chen, Laleh Melstorm, Haiyong Han, Steven T. Rosen, Ajay Goel. Teriflunomide overcomes gemcitabine resistance by inhibiting the GSK3β/mTOR pathway in pancreatic 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 7192.
Abstract 7204: Therapeutic potential of targeting autophagy to overcome chemoresistance in glioblastoma
Authors: Kiang Karrie Mei Yee , Leung Gilberto Ka Kit 
Published: March 2024

Abstract
Glioblastoma (GBM) is the most malignant subtype of brain tumor in adults, characterized by relentless recurrence and an overall survival of approximately 18 months. Temozolomide (TMZ) has been the basis for current standard of care and represents the control-arm in GBM trials. Despite the use of TMZ having shown promising results in improving patient survival, drug resistance and tumor relapse is almost inevitable. Current literature has provided strong evidence on autophagy modulation as an adjuvant therapy to cytotoxic treatments. By using in vitro and in vivo GBM models, combination regimen with TMZ and an autophagy activator significantly enhanced the cytotoxic effect in tumors that were resistant to chemotherapy. Combined treatment readily induced a mortal autophagy flux in chemo-resistant GBM cells resulted from its high intrinsic autophagy. Our findings suggest that treatment resistant tumors are more sensitive to autophagy activation when compared to treatment-naive tumors. As they often exhibit higher basal level of autophagy after long-term chemotherapy, a mortal autophagy flux can be readily achieved. In conclusion, combination therapy of a cytotoxic drug with autophagy modulator is emerging as a novel therapeutic strategy in the adjuvant setting for cancer patients.
Citation Format: Karrie Mei Yee Kiang, Gilberto Ka Kit Leung. Therapeutic potential of targeting autophagy to overcome chemoresistance in glioblastoma [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 7204.
Abstract 7208: Targeting histone demethylase KDM6B to overcome cisplatin resistance in testicular germ cell tumors
Authors: Singh Ratnakar , Shokry Doha , Boyd Raya I. , Rennels Brayden C. , Powell Christine , Kahn Mehwish , Freemantle Sarah J. , Spinella Michael J. 
Published: March 2024

Abstract
Testicular germ cell tumors (TGCTs) represent the most common carcinoma of young men and are believed to arise from the transformation of primordial germ cells (PGCs). TGCTs are highly curable with platinum-based chemotherapeutics. However, resistance to cisplatin does occur, leading to therapeutic failure with very limited further therapy options. Previously we demonstrated polycomb and histone H3K27me3 methylation is repressed in cisplatin resistance TGCT cells. In TGCT patients the expression of H3K27 histone methylase EZH2 and H3K27 histone demethylase KDM6B is significantly associated with recurrence free survival. Induction of H3K27 methylation using demethylase inhibitor JSK-J4 or knockdown of KDM6B resulted in restored cisplatin sensitivity in cisplatin resistant TGCT cells. Furthermore, Inhibition of H3K27 demethylase by GSK-J4 or genetic knockdown of KDM6B sensitized TGCTs to cisplatin in vivo suggesting potential clinical utility of targeting H3K27me3 in refractory TGCTs. To explore underlying mechanisms H3K27me3 ChIP-seq was performed that demonstrated genome-wide loss of H3K27me3 in cisplatin resistant cells. Integrative analysis of H3K27me3 ChIP-Seq and transcriptomics is ongoing. Together findings suggests that repression of H3K27 methylation may be a viable approach to overcome treatment failure in cisplatin resistant TGCTs.
Citation Format: Ratnakar Singh, Doha Shokry, Raya I. Boyd, Brayden C. Rennels, Christine Powell, Mehwish Kahn, Sarah J. Freemantle, Michael J. Spinella. Targeting histone demethylase KDM6B to overcome cisplatin resistance in testicular germ cell 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 7208.
Abstract 7240: Intratumor delivery of plasmid DNA encoding immune stimulating agents induces both local and systemic responses
Authors: Heller Richard , Heller Loree C. , Shi Guilan , Synowiec Jody , Singh Julie , Otten Alex , Jaroszeski Mark J. 
Published: March 2024

Abstract
Immune checkpoint inhibitors (ICIs) have significant clinical benefits, but are limited by both primary and acquired resistance. The absence of T cells within the tumor microenvironment (TME) is a significant hurdle, reducing the efficacy of ICIs against solid tumors. Multiple studies have been initiated to modify the TME to enhance the effectiveness of ICIs. We previously demonstrated that the intratumor delivery of a plasmid encoding interleukin-12 (pIL-12) using gene electrotransfer (GET) resulted in a significant increase in T effector cells and a reduction in T regulatory cells and myeloid derived suppressor cells within the TME, inducing a robust immune response. Combining pIL-12 GET with ICIs resulted in local and systemic responses in both preclinical and clinical studies. While encouraging results were obtained, improvements were possible. For example, the established GET technology requires high applied voltage for plasmid delivery. In addition, satisfactory delivery cannot be immediately detected. Our current research has focused on developing the next generation GET technology to overcome these issues. This new system includes a pulse generator, a heat source and a tissue impedance measuring device. An array that incorporates independently addressable electrodes was also developed. A moderate elevation of the tissue temperature coupled with the electrode array enabled a 75% reduction in the applied voltage. We tested the approach in the B16.F10 mouse melanoma model. Delivery of pIL-12 with the new system resulted in 100% long-term complete regression and 100% protection from challenge. In addition, monitoring impedance within each independent section of the electrode array revealed different pulse numbers were needed to achieve delivery in each section. We next evaluated a combination therapy, pIL-12 plasmid combined with a plasmid encoding a PD1 peptide, delivered with the next-gen device. In a multi-tumor model, the plasmids were delivered to the subcutaneous tumor; tumors generated with an intraperitoneal injection were untreated. This new therapy induced complete regression of the subcutaneous tumor and blockage of peritoneal tumor growth as assessed via in vivo imaging. Peritoneal tumor growth was not affected by single plasmid delivery or when both plasmids were delivered with the established GET technology. Work is ongoing to translate this approach to clinical evaluation.
Citation Format: Richard Heller, Loree C. Heller, Guilan Shi, Jody Synowiec, Julie Singh, Alex Otten, Mark J. Jaroszeski. Intratumor delivery of plasmid DNA encoding immune stimulating agents induces both local and systemic responses [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 7240.
Abstract 7275: GS-P-328, a brain-penetrant small molecule p53 Y220C reactivator for tumors harboring p53 Y220C mutation
Authors: Liu Meng , Geng Kaijun , Lu Biao , Xia Yuanfeng , Yang Fanglong 
Published: March 2024

Abstract
As a tumor suppressor, p53 can prevent tumor development through multiple pathways. However, mutation of TP53 and the resultant inactivation of p53 allow evasion of tumor cell death and rapid tumor progression. The oncogenic Y220C mutation is the ninth most frequent p53 missense mutation in cancer. Y220C mutation creates a narrow, hydrophobic pocket on the surface of the p53 DBD that reduces its thermal stability. As a result, the Y220C mutation causes a rapidly unfold of the p53 protein under physiological conditions, abrogates p53 signaling and drives tumorigenesis. There are approximately 100,000 new Y220C mutation cancer cases per year worldwide with limited treatment choices. The initial clinical evaluation of PC14586 that can restore missense-mutant p53 protein has seen efficacy in patients harboring p53 Y220C mutation even though there is still room for improvement. Here we report a brain-penetrable, highly potent p53 Y220C reactivator which has great in vitro activity as well as induce tumor shrinkage in multiple tumor models at a much lower systematic exposure comparing to PC14586. In vitro, GS-P-328 could bind to p53 Y220C protein with a single nM potency and potently induce cell death in a wide range of p53 Y220C tumor cells while have no anti-proliferative effects with p53 WT cells. GS-P-328 is also active in patient-derived cell (PDC) models in various tumor background including SCLC, gastric, ovarian and colon. In vivo, GS-P-328, at approximately 1/3 of systematic exposure comparing to a leading clinical reactivator, causes tumor shrinkage in multiple CDX models. GS-P-328 could induce MDM2/p21 upregulation in cell systems. In vivo, GS-P-328 could induce 2 fold and more increase in MDM2/p21 protein levels in tumor tissues at approximately 1/3 of plasma concentrations comparing to PC14586. More importantly, in a NUGC3-luc intracranial model, GS-P-328 could strongly inhibit growth of cancer cells in the mouse brain. GS-P-328 has a favorable ADME profile in rodents, dogs and NHPs, as well as a much better safety profile. GS-P-328 is now under IND-enabling study and P1 study is planned in early 2025.
Citation Format: Meng Liu, Kaijun Geng, Biao Lu, Yuanfeng Xia, Fanglong Yang. GS-P-328, a brain-penetrant small molecule p53 Y220C reactivator for tumors harboring p53 Y220C mutation [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 7275.
Abstract 7311: Lipid soluble vitamin B1 derivatives, benfotiamine and fursultiamine, prevent breast cancer cells growth
Authors: O'Neill Caroline Ciaciuch , Langmead Aveline P. , Ramana Kota V. 
Published: March 2024

Abstract
Breast cancer is the leading cause of cancer death in women in the US and the second leading cancer after skin cancer in women worldwide. According to the CDC, women from 45-84 years of age are most at risk, with approximately 30% of deaths in this group being from cancer. Increased free radical formation, and oxidative and inflammatory responses have been shown to be major contributing factors for the progression of breast cancer. Several antioxidants and vitamins have been tested for their efficacy in preventing breast cancer. However, the role of vitamin B1 derivatives in the prevention of breast cancer is not known. Therefore, we hypothesize that with potent anti-oxidative and anti-inflammatory actions, lipid-soluble derivatives of vitamin B1 (thiamine), such as benfotiamine and fursultiamine, could prevent breast cancer growth and spread. We have treated human breast cancer cells such as MCF-7 and T-4D1 and mouse breast cancer cells 4T1 with vitamin B1 derivatives and examined the cancer cells growth. Our results indicate that treatment of various breast cancer cells with benfotiamine and fursultiamine prevents the proliferation of cancer cells in a dose-dependent manner. Further, both benfotiamine and fursultiamine by regulating the activation of caspase-3 and cleavage of PARP protein could prevent breast cancer cells growth. Benfotiamine and fursultiamine also regulates generation of reactive oxygen species in breast cancer cells. Further, vitamin B1 derivatives regulate the expression of various anti-apoptotic, pro-apoptotic, survival and inflammatory factors in both human and mouse breast cancer cells. We next planned to examine the effect of vitamin B1 derivatives on breast cancer growth in vivo using athymic nude mouse models. In conclusion, our in vitro results suggest that vitamin B1 derivatives, benfotiamine and fursultiamine, by promoting the apoptotic pathways prevent breast cancer cells growth and could be further developed as chemopreventive drugs.
Citation Format: Caroline Ciaciuch O'Neill, Aveline P. Langmead, Kota V. Ramana. Lipid soluble vitamin B1 derivatives, benfotiamine and fursultiamine, prevent breast cancer cells 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 7311.
Abstract 7412: METI: Deep profiling of tumor ecosystems by integrating cell morphology and spatial transcriptomics
Authors: Jiang Jiahui , Liu Yunhe , Qin Jiangjiang , Wu Jingjing , Chen Jianfeng , Pizzi Melissa , Segura Rossana , Yamashita Kohei , Xu Zhiyuan , Pei Guangsheng , Cho Kyung Serk , Chu Yanshuo , Sinjab Ansam , Peng Fuduan , Han Guangchun , Wang Ruiping , Yan Xinmiao , Dai Enyu , Li Mingyao , Futreal Andrew , Maitra Anirban , Lazar Alexander , Cheng Xiangdong , Kadara Humam , Ajani Jaffer , Jazaeri Amir , Hu Jian , Wang Linghua , Gao Jianjun 
Published: March 2024

Abstract
The recent progression in spatial transcriptomics (ST) offers invaluable perspectives on the structure and dynamics of cells within the tumor microenvironment (TME). Though several analytical tools exist for tasks like spatial clustering and spatially variable gene identification, most of them are general methods lacking consideration of histological features in spatial data analysis. This oversight compromises their performance and interpretability when studying the TME. Here, we introduce a computational framework, the Morphology-Enhanced Spatial Transcriptome Analysis Integrator (METI). METI provides a comprehensive framework for spatially mapping both cancer cells and various TME cells, robust stratification of cell type and transcriptional states, and cell co-localization analysis. By integrating spatial transcriptomics with cell morphology and curated gene signatures, METI deepens our insight into the molecular landscape and cellular interactions within tissues, paving the way for intricate studies of the TME and its consequential impacts. The performance of METI has been assessed using ST data derived from a range of tumor tissues, encompassing gastric, lung, and bladder cancers, and premalignant tissues. Throughout these varied tissues and conditions, METI consistently exhibited robust performance.
Citation Format: Jiahui Jiang, Yunhe Liu, Jiangjiang Qin, Jingjing Wu, Jianfeng Chen, Melissa Pizzi, Rossana Segura, Kohei Yamashita, Zhiyuan Xu, Guangsheng Pei, Kyung Serk Cho, Yanshuo Chu, Ansam Sinjab, Fuduan Peng, Guangchun Han, Ruiping Wang, Xinmiao Yan, Enyu Dai, Mingyao Li, Andrew Futreal, Anirban Maitra, Alexander Lazar, Xiangdong Cheng, Humam Kadara, Jaffer Ajani, Amir Jazaeri, Jian Hu, Linghua Wang, Jianjun Gao. METI: Deep profiling of tumor ecosystems by integrating cell morphology and spatial transcriptomics [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 7412.
Abstract 7422: Enabling biomarkers of chromosomal instability for tumor only targeted gene panel sequencing
Authors: Gómez-Sánchez David , Thompson Joe Sneath , Hernando Barbara , García-López Diego , de Galard Hector , Roy Abhipsa , Cullen Amy , Madrid Laura , Teles José , Piskorz Ania , Yip Jason , Cádiz Alice , Escobar-Rey Maria , Moreno-Vellisca Roberto , Carrizo Nuria , Álvarez Eva , Quintela-Fandino Miguel , Barbacid Mariano , Ramos-Paradas Javier , Coya Juan Manuel , Ferrer Irene , Zugazagoitia Jon , Paz-Ares Luis , Macintyre Geoff 
Published: March 2024

Abstract
Capture-based targeted sequencing is routinely used for small variant detection in cancer clinical care. Alongside targeted DNA, off-target DNA is also sequenced. These off-target reads are distributed across the genome, allowing for a whole genome copy number profile to be derived without the need for a SNP backbone. Here we present CopyRight, a method that generates robust genome-wide copy number profiles, which can be used for downstream chromosomal instability (CIN) quantification, overcoming various sources of technical noise with a novel approach that only requires a single tumor sample.
We analyzed a variety of capture-based NGS protocols using our novel computational method, including the TruSight Oncology 500 (TSO500) panel, and compared them to the current gold standard for genome-wide copy number profiling from FFPE tissues: shallow whole genome sequencing (sWGS). Comparable results were obtained from targeted sequencing depending on sample purity, preservation method, and read depth. Additionally, benchmarks of CopyRight against other computational algorithms show an improvement in performance without the need for a matched normal tissue, the usual drawback for other methods in the cancer field.
CIN signatures are a new set of emerging biomarkers that reflect the diversity of defective pathways that have operated in a tumor, which require robust genome-wide copy number profiles. These CIN signatures can be used to predict response to cytotoxic agents and targeted therapies and could ultimately help guide therapy selection in patients. As most clinical sequencing workflows rely on targeted sequencing, CopyRight can be included in current clinical assays, enabling CIN biomarker quantification with no extra technical or experimental requirements.
Citation Format: David Gómez-Sánchez, Joe Sneath Thompson, Barbara Hernando, Diego García-López, Hector de Galard, Abhipsa Roy, Amy Cullen, Laura Madrid, José Teles, Ania Piskorz, Jason Yip, Alice Cádiz, Maria Escobar-Rey, Roberto Moreno-Vellisca, Nuria Carrizo, Eva Álvarez, Miguel Quintela-Fandino, Mariano Barbacid, Javier Ramos-Paradas, Juan Manuel Coya, Irene Ferrer, Jon Zugazagoitia, Luis Paz-Ares, Geoff Macintyre. Enabling biomarkers of chromosomal instability for tumor only targeted gene panel 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 7422.
Abstract 7487: Construction of a reliable CTC detection method and validity evaluation of CTC markers in colorectal cancer
Authors: Takahashi Yusuke , Ijiri Yuichi , Fujino Shiki , Elnaz Nakhaei , Kishimoto Ayuko , Shirai Kentaro , Iwanaga Shigeki , Yanagida Masatoshi , Bhagat Ali Asgar , Miyoshi Norikatsu 
Published: March 2024

Abstract
Even in modern times when medical technology has advanced, cancer remains a life-threatening disease, and recurrence and metastasis are major issues in cancer treatment. The characteristics of cancer cells change with progression and treatment. Therefore, timely evaluation on their characteristics and decision on the treatment strategy are required. Circulating tumor cells (CTCs) are released into blood vessels in solid tumors and promote metastasis by circulating in the blood. CTCs are thus attractive targets for liquid biopsy and can provide useful information for selection of appropriate treatment. To obtain reliable results from CTC testing, it is important to prove that the detected cells are derived from cancerous tissue. In molecular tests targeting CTCs, it is still unclear whether the detected cells are derived from cancer tissue displaying genetic mutations. Aiming to establish reliable CTC testing, we have developed a simple method using molecular imaging flow cytometry to detect APC gene mutation together with Cytokeratin and Vimentin, which are epithelial-mesenchymal transition markers. Since, abnormalities in the APC gene are detected in 60-70% of colorectal cancer patients, detecting such mutations provides strong evidence that the detected cells are derived from cancerous tissue. Here, we show that upon evaluation of analytical performance of our method using cells isolated from cancerous tissue, our method showed high concordance rate against APC gene mutation. A clinical proof-of-concept using 5 mL of whole blood from colorectal cancer patients revealed that counts of cells with APC mutation in blood and cells with Cytokeratin and/or Vimentin expression in blood are highly correlated. Our results demonstrated a pathological stage-dependent increase in the count and frequency of Cytokeratin and/or Vimentin positive CTCs. We believe that our study not only establishes a practical approach for identifying CTCs in cancer patients but also provides potential implications in clinical practice, prognostic evaluation, and selection of treatment strategies.
Citation Format: Yusuke Takahashi, Yuichi Ijiri, Shiki Fujino, Nakhaei Elnaz, Ayuko Kishimoto, Kentaro Shirai, Shigeki Iwanaga, Masatoshi Yanagida, Ali Asgar Bhagat, Norikatsu Miyoshi. Construction of a reliable CTC detection method and validity evaluation of CTC markers in colorectal 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 7487.