tbuckley/cabot-search huggingface dataset:
Abstract 5715: Enhancing PARP inhibitor efficacy with CDK12/7/9 degradation in prostate cancer
Authors: Fu Gui, Baishan Jiang, Jie Jiang, Marian Kalocsay, Anne Fassl, Steven P. Balk, Adam S. Kibel, Li Jia
Journal: Cancer Research (2025)

Abstract Current treatments for advanced prostate cancer (PCa) mainly target the androgen receptor (AR) signaling pathway. However, the development of castration-resistant prostate cancer (CRPC) and resistance to AR signaling inhibitors remains a significant clinical challenge.In recent years, the FDA has approved four PARP inhibitors (PARPis) - olaparib, rucaparib, talazoparib, and niraparib - either as monotherapy or in combination with AR signaling inhibitors for CRPC patients carrying deleterious germline or somatic BRCA1/2 mutations or other homologous recombination repair (HRR) gene mutations. CDK12, a kinase associated with the phosphorylation of the carboxy-terminal domain of RNA polymerase II, is crucial for the transcriptional processivity of long mRNA transcripts, including key HRR genes such as BRCA1 and BRCA2. CDK12 alterations, primarily biallelic truncating mutations, have been identified in 5-7% of PCa cases. In this study, we demonstrate that acute CDK12 loss results in BRCA1/2 downregulation and sensitizes CRPC cells to PARP inhibition. However, this sensitization is absent in CRPC adapted to chronic CDK12 loss, where BRCA1/2 expression is restored. Furthermore, degradation of CDK12/7/9 enhances the synthetic lethality of PARP inhibition through acute induction of a "BRCAness" state and AR signaling suppression in PCa. We developed BSJ-5-63, a CDK12/7/9 proteolysis-targeting chimera (PROTAC) degrader, which effectively degrades CDK12 to induce an acute "BRCAness" state, sensitizing cancer cells to PARP inhibitors regardless of their HRR status. In addition, BSJ-5-63 degrades CDK7/9, attenuating AR signaling and further promoting the synthetic lethality of PARP inhibition.Acute CDK12/7/9 degradation by BSJ-5-63 exhibits potent anti-tumor effects in both in vitro and in vivo CRPC models. This study introduces BSJ-5-63 as a promising therapeutic agent that targets both DNA repair and AR signaling pathways, offering potential benefits for a broad patient population. Citation Format: Fu Gui, Baishan Jiang, Jie Jiang, Marian Kalocsay, Anne Fassl, Steven P. Balk, Adam S. Kibel, Li Jia. Enhancing PARP inhibitor efficacy with CDK12/7/9 degradation in prostate cancer [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 5715.
Abstract 6040: Exploring the impact of analytical factors on B-cell receptor profiling with high-throughput sequencing technologies
Authors: Xiashiyao Zhang, Rittika Mallik, Miguel Pacheco, Shaveta Goyal, Mark Izraelson, Li Song, Henk-Jan van den Ham, Jun Wan, Wenming Xiao, None BCR-SEQC consortium
Journal: Cancer Research (2025)

Abstract This abstract reflects the views of the authors and should not be construed to represent FDA’s views or policies. High-throughput sequencing of B-cell receptor (BCR) gene rearrangements, along with downstream analysis, provides researchers with the tools to define the B-cell clonal landscape and identify biomarkers for minimal residual disease (MRD). Despite significant advancements in the field over the past decade, comprehensive comparisons on different analytical methods, sequencing technologies, and bioinformatics tools remain largely unexplored. To bridge this gap, the FDA-led B-cell Receptor Sequencing Quality Control (BCR-SEQC) consortium developed protocols for generating reference materials derived from nine well-characterized B-cell lines and peripheral blood mononuclear cells (PBMCs) from healthy donors. This study aimed to evaluate the impact of key analytical factors—including input material quality and quantity, sequencing depth, sequencing technologies, and bioinformatics workflows—on BCR sequencing (BCR-seq) performance. The study employed multiple commercial BCR-seq products to prepare libraries with varying input amounts (25ng, 100ng, and 500ng) of reference materials. These libraries were sequenced using three different platforms: Illumina NextSeq 2000, ElementBio Aviti, and MGI DNBSEQ. Subsequently, four bioinformatics workflows (MiXCR, Immcantation, TRUST4, and IGX-Profile) were applied to assemble BCR sequences and determine clonotypes. This research provided the first comprehensive analysis of how variables in wet-lab and computational workflows influence sequencing-based BCR profiling, specifically in terms of linearity, accuracy, and sensitivity. Additionally, the study developed quality control (QC) metrics to ensure the robustness of assays and analytical workflows. Ultimately, this work highlights current capabilities and limitations in BCR-seq technology, identifies critical technical challenges, and establishes actionable best practices for reconstructing BCR repertoires from high-throughput sequencing data. Citation Format: Xiashiyao Zhang, Rittika Mallik, Miguel Pacheco, Shaveta Goyal, Mark Izraelson, Li Song, Henk-Jan van den Ham, Jun Wan, Wenming Xiao, BCR-SEQC consortium. Exploring the impact of analytical factors on B-cell receptor profiling with high-throughput sequencing technologies [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 6040.
Abstract 5707: Augmentation of statin-induced ATF4 stress response enhances the cancer cell-killing effect of statin
Authors: Thi Thinh Nguyen, Gia-Buu Tran, Jane Ding, Han-fei Ding
Journal: Cancer Research (2025)

Abstract Statins are a class of drugs widely used to reduce cholesterol levels and have been rediscovered as promising anti-cancer drugs. Statins inhibit HMG-CoA reductase (HMGCR), a rate-limiting enzyme in cholesterol synthesis. We found that statin treatment of neuroblastoma cells triggered stress responses characterized by upregulation of the master stress regulator ATF4. The primary function of ATF4 is to initiate a gene expression program to mitigate stress and promote cell survival. However, ATF4 can also induce cell death under severe or prolonged stress conditions. Our study revealed that combinations of simvastatin with compounds that amplify ATF4 stress signaling synergistically inhibited the growth and survival of neuroblastoma cells. These compounds include the endoplasmic reticulum (ER) stress sensor ATF6 activator, AA147, and the two ATF4 activators, Sal003 and Nelfinavir. The combination of simvastatin with AA147, Sal003 or Nelfinavir significantly increased ER stress marker, XBP1s, and strongly stimulated ATF4-ATF3-CHOP signaling, leading to apoptosis as evidenced by cleavage of caspase 3 and PARP. Moreover, knocking down ATF4 was able to inhibit apoptosis and partially protect neuroblastoma cells from the effects of these drug combinations. These results suggest a strategy to enhance the anti-tumor effect of statins by amplifying ATF4 stress signaling to trigger apoptosis. Citation Format: Thi Thinh Nguyen, Gia-Buu Tran, Jane Ding, Han-fei Ding. Augmentation of statin-induced ATF4 stress response enhances the cancer cell-killing effect of statin [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 5707.
Abstract 5814: Immune-related adverse effects in patients with autoimmune disorders treated with immune checkpoint inhibitors
Authors: Aseel Saadeh, Pragosh Saini, Favour Nelson, Sumera Khan, Christian Adonizio, Ahmad Hanif
Journal: Cancer Research (2025)

Abstract Background: Immune checkpoint inhibitors (ICI) have tremendously improved outcomes for various cancers but can be associated with immune-related adverse effects (IrAE), which can affect multiple organ systems. For patients with pre-existing autoimmune diseases (AD), there is an added risk of exacerbating autoimmunity, either through a flare of prior IrAEs or the development of de novo IrAEs during ICI therapy. Clinical trials leading up to FDA approval of ICIs excluded patients with pre-existing AD, resulting in a lack of data on the specific risks faced by this patient population. Our study aims to assess whether patients with pre-existing AD are more likely to develop IrAEs when treated with ICIs, and if so, whether these IrAEs are more severe. Methodology: We conducted a retrospective chart review of all patients diagnosed with AD and received ICIs for treatment of a solid tumor malignancy within the Geisinger Health System from January 1, 2017, to December 31, 2023. We analyzed the occurrence, subtype, and severity (grade) of IrAEs based on the Common Terminology Criteria for Adverse Events (CTCAE). Additionally, we assessed steroid use, treatment discontinuation, and hospitalization rates. Results: A total of 250 patient charts were identified using the cancer registry, 105 of them were excluded due to the absence of a pre-existing AD. Of the 145 patients with a pre-existing AD, 59 (40.7%) developed an IrAE, and 21 (14.5%) developed a severe (grade 3/4) IrAE. Additionally, 44 (30.3%) patients required steroids for the treatment of IrAE, and 12 (8.3%) were hospitalized due to an IrAE. The most prevalent IrAEs were colitis, rash, hypothyroidism, transaminitis, and pneumonitis, which occurred in 52 (35%) cases; of these, 13 (8.9%) were severe (grade ¾). Discussion: When comparing our results to those of previous studies, we found that the rates and severity of IrAEs were higher in patients with pre-existing AD compared to historical data on patients without AD. A meta-analysis by de Velasco et al. of 21 studies reported an IrAE incidence of 28% for all grades and 5% for grades 3 and 4. Similarly, Silverstein et al. analyzed 3,137 patients treated with ICIs and found that 3.8% were hospitalized due to IrAEs. These significant differences underscore the need for multidisciplinary collaboration and heightened monitoring for IrAEs in patients with AD. Citation Format: Aseel Saadeh, Pragosh Saini, Favour Nelson, Sumera Khan, Christian Adonizio, Ahmad Hanif. Immune-related adverse effects in patients with autoimmune disorders treated with immune checkpoint inhibitors [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 5814.
Abstract 6566: FTIR microscope imaging and neural network analysis reveal consistent spectral markers of cancer-associated fibroblasts in cells, plasma sEVs, and tissues
Authors: Abhay Mishra, Akhilesh Mishra, Saroj Kumar
Journal: Cancer Research (2025)

Background: Cancer-associated fibroblasts (CAFs) are pivotal contributors to tumor progression, influencing tumor biology through interactions within the tumor microenvironment. Distinguishing CAFs from normal fibroblasts is essential for understanding their molecular mechanisms and identifying relevant biomarkers. This study utilized Fourier-transform infrared (FTIR) microscope imaging spectra and neural networks (NNs) to classify CAFs and normal fibroblasts and explored the consistency of identified spectral markers across blood plasma small extracellular vesicles (sEVs) and tissue samples. Methods: FTIR spectra from CAFs and normal fibroblasts were preprocessed using normalization and baseline correction. A feed-forward NN model was developed, employing regularization techniques to reduce overfitting. Model performance was evaluated using 10-fold cross-validation, with metrics including accuracy, area under the curve (AUC), sensitivity, and specificity. NN-based sensitivity analysis identified key infrared (IR) spectral regions for classification. Comparative FTIR analysis of blood plasma sEVs and tissue samples was conducted to assess the reproducibility of identified spectral markers. Results: The NN model demonstrated high classification performance, achieving 92% accuracy, an AUC of 0.89, and robust sensitivity and specificity metrics. Sensitivity analysis highlighted significant IR spectral regions, including Amide I and Amide II (proteins): Indicative of changes in protein structure and extracellular matrix remodeling. Lipid Regions: Reflecting altered lipid metabolism, critical for membrane dynamics and signaling in CAFs. Nucleic Acid-Associated Regions: Suggesting transcriptional and epigenetic modifications linked to fibroblast activation. Notably, similar spectral markers were observed in FTIR analysis of blood plasma sEVs and tissue samples, revealing a consistent pattern associated with CAFs. This suggests systemic changes in the tumor microenvironment that are detectable across different biological matrices. Conclusion: This study highlights the potential of NN-based FTIR spectral analysis as a robust and versatile tool for identifying biomarkers of CAFs. The reproducibility of key spectral markers in blood plasma sEVs and tissue samples underscores the translational potential of this approach for cancer diagnostics and therapeutic targeting of the tumor microenvironment. Citation Format: Abhay Mishra, Akhilesh Mishra, Saroj Kumar. FTIR microscope imaging and neural network analysis reveal consistent spectral markers of cancer-associated fibroblasts in cells, plasma sEVs, and tissues [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 6566.
Abstract 6225: Association of UV radiation exposure with risk of malignant melanoma and melanoma in situ in the NIH-AARP Diet and Health Study
Authors: Samer Wahood, Yufei Li, Matthew Kaczynski, John Monroe, Fatima N. Mirza, Linda M. Liao, Rashmi Sinha, Martin A. Weinstock, Abrar A. Qureshi, Eunyoung Cho
Journal: Cancer Research (2025)

Abstract While ultraviolet radiation (UVR) exposure is a risk factor for skin cancer, there is little evidence from prospective studies exploring the association with both malignant melanoma (MM) and melanoma in situ (MIS).1, 2 Within the NIH-AARP Diet and Health Study involving 491, 367 participants ages 50-71 when the study began in 1995, we investigated the relationship between July erythemal UVR levels and the incidence of MM and MIS prospectively. July erythemal UVR is the average noon-time ground-level erythemal dose measured in July.3 UVR levels were linked to participants’ residences at baseline and categorized into quartiles. Participants were predominantly non-Hispanic white with a median age of 62 years. After adjusting for demographic and lifestyle factors, we utilized multivariable-adjusted Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Over 6, 611, 941 person-years, with a median follow-up time of 15.5 years, 5, 034 MM and 3, 284 MIS cases were documented. We found a significant trend between higher erythemal UVR levels and increased risk of both MM and MIS. The highest quartile of UVR exposure (&amp;gt;236 J/m^2), compared with the lowest quartile (≤180 J/m^2), was significantly associated with a greater risk of MM; the HR was 1.32 (95% CI:1.22-1.44) for MM and 1.37 (95% CI:1.25-1.51) for MIS (P-trend &amp;lt;0.001 for both). The study underscores the need for heightened awareness and preventative measures for MM and MIS, especially in regions with higher UVR levels. Further research is needed to explore this association across different body sites. References 1. Lin SW, Wheeler DC, Park Y, et al. Prospective study of ultraviolet radiation exposure and risk of cancer in the United States. Int J Cancer. 2012;131(6):E1015-E1023. doi:10.1002/ijc.27619 2. Li Y, Liao LM, Sinha R, et al. Fish intake and risk of melanoma in the NIH-AARP diet and health study. Cancer Causes Control. 2022;33(7):921-928. doi:10.1007/s10552-022-01588-53. Ozone and Air Quality. NASA. Accessed September 5, 2023. https://ozoneaq.gsfc.nasa.gov/data/toms/# Citation Format: Samer Wahood, Yufei Li, Matthew Kaczynski, John Monroe, Fatima N. Mirza, Linda M. Liao, Rashmi Sinha, Martin A. Weinstock, Abrar A. Qureshi, Eunyoung Cho. Association of UV radiation exposure with risk of malignant melanoma and melanoma in situ in the NIH-AARP Diet and Health Study [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 6225.
Abstract 6567: Metabolic reprogramming of pentose phosphate pathway mediated by small extracellular vesicles facilitates tumor metastasis and drug resistance in HCC
Authors: Xiaoxin Zhang, Zhixian Chen, Jiaqi Lai, Judy Wai Ping Yam
Journal: Cancer Research (2025)

Abstract Emerging evidence have proved that the interplay between tumor and its microenvironment facilitate tumor metastasis, including the hepatocellular carcinoma (HCC). Therefore, identifying novel target for HCC metastasis and is essential to improve the survival. In recent years, extracellular vesicles (EV) mediated metabolic regulation has been a growing interest in cancer metabolism. For instance, the ectosomal pyruvate kinase M2 isoform (PKM2) was found to facilitate glycolysis reprogramming in monocyte-to-macrophage differentiation and tumor microenvironment remodeling. Compared to directly receiving metabolite or substance from the EV, we proposed that the tumor cells are more likely to obtain proteomics alteration to exert long-term metabolic reprogramming. EVs were extracted from the metastatic and non-metastatic HCC cells. The DEPs were identified by LC-MS/MS. Meanwhile, the metabolomic screening will also be conducted to clarify the differences of metabolite which the HCC cells produced after the treatment of sEVs which derived from metastatic and non-metastatic HCC cell. The expression of G6PD was knockdown by shRNA. The plate cloning and transwell assays were conducted to evaluate the effect of G6PD on the metastasis. Besides, parallel validation of G6PD inhibitors was performed. The expression of gene was validated by real-time PCR. The MTT assay was conducted to test IC50 of sorafenib resistance HCC cells. Western blot was performed to measure expression of different proteins. Our study found that key enzyme involved in pentose phosphate pathway (PPP) was extremely enriched in metastatic HCC derived small extracellular vesicles (sEVs). Inhibition the enzymic activity of sEVs-derived G6PD significantly reduce the invasion and metastasis of HCC tumor cells. Besides, the sEV-G6PD was associated with activation of cancer-associated fibroblast. Moreover, sEV derived PPP enzymes enhanced sorafenib resistance. In conclusion, PPP enzymes derived from sEV in metastatic HCC cells promotes tumor metastasis and sorafenib resistance. Citation Format: Xiaoxin Zhang, Zhixian Chen, Jiaqi Lai, Judy Wai Ping Yam. Metabolic reprogramming of pentose phosphate pathway mediated by small extracellular vesicles facilitates tumor metastasis and drug resistance in HCC [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 6567.
Abstract 6219: Population-based analysis of rurality and its impact on survival in gastric adenocarcinoma
Authors: Nicole M. Hwang, Matthew Dixon
Journal: Cancer Research (2025)

Abstract Background: Despite growing efforts to understand the impact of rurality on cancer survival outcomes, significant gaps remain on how it influences prognosis within specific cancer types. In this study, we examine how residential location (rural vs urban) affects survival outcomes for patients diagnosed with gastric adenocarcinoma. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified 56, 371 patients with gastric adenocarcinoma between 2007 and 2020, who were 18 years or older at diagnosis and had complete data for all analyzed variables. Demographics of patients living in rural vs urban areas were compared using Wilcoxon rank sum or chi-squared testing for categorical or continuous variables, respectively. The impact of area of residence on cancer-specific survival (CSS) was assessed through Kaplan-Meier and Cox proportional hazards analysis. A multivariable Weibull regression survival model was used to control for potential confounding covariates. Results: Most patients lived in urban areas (88.9% vs 11.1%). There were no significant differences in age and stage at diagnosis between rural and urban populations. Rural patients tended to be male (p &amp;lt; 0.001) and non-Hispanic White (p &amp;lt; 0.001) with lower median household income (p &amp;lt; 0.001). Patients residing in rural areas had significantly worse CSS [hazard ratio (HR) = 1.158; 95% CI: 1.122-1.195; p &amp;lt; 0.0001]. When stratified by race, the prognostic impact of rurality was absent in Non-Hispanic Black patients (p = 0.62). When adjusting for age, sex, race, stage, and income, rurality remained an independent predictor of survival [HR = 1.064; 95% CI: 1.026-1.103; p = 0.0007]. Conclusion: Rurality is associated with worse prognosis in patients with gastric adenocarcinoma. Further research is needed to understand the mechanisms of how area of residence contributes to outcome disparities to identify targeted interventions. Citation Format: Nicole M. Hwang, Matthew Dixon. Population-based analysis of rurality and its impact on survival in gastric adenocarcinoma [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 6219.