tbuckley/cabot-search huggingface dataset:
Abstract 6412: Inactivation of CDK12 remodels the transcription machinery and promotes epigenetic plasticity
Authors: Jing Liang, Aishwarya Gondane, Harri M. Itkonen
Journal: Cancer Research (2025)

Abstract Background: Prostate cancer (PC) is the most common cancer in men, and inactivation of cyclin-dependent kinase 12 (CDK12) characterizes a subset of PCs but it is not understood how cells adapt to decline in the activity of this major transcription elongation kinase. CDK12 phosphorylates RNA polymerase II (RNA Pol II) to promote transcription elongation and cancer cells in general have high levels of transcription. It is therefore unexpected that the loss of CDK12 activity would confer a proliferative advantage. Methods and Results: We used PC patient data to probe if inactivation of the CDK12-gene is associated with any particular feature. Curiously, we discovered that truncating mutations in the CDK12-gene are associated with a loss of DNA methylation in PC patient samples (the TCGA-dataset). Encouraged by this discovery, we then identified patient samples from breast and ovarian cancers with alterations in the CDK12-locus. Strikingly, we found that compromised CDK12 activity is associated with decrease in DNA methylation also in these tumors. Epigenetic plasticity is emerging as one of the hallmark features of cancer progression. To establish if the loss of CDK12 activity leads to decrease in DNA methylation, we profiled DNA methylation in vitro. Indeed, our validation experiments revealed that the decrease in CDK12 activity leads to loss of DNA methylation. DNA methylation usually closes the chromatin for transcription factors and RNA Pol II, and thereby regulates gene expression. We reasoned that these effects necessitate remodeling of the RNA Pol II-interactome. Therefore, we immunoprecipitated RNA Pol II after treatment with the CDK12 inhibitor and established the RNA Pol II-interactome using mass spectrometry in PC cell line. We showed that one protein is recruited to the polymerase rapidly when CDK12 activity is lost. We hypothesize that proteins recruited to RNA Pol II in this situation represent synthetic lethal partners with CDK12 inactivation. Currently, we are using proliferation assays to probe if the loss of CDK12 activity is synthetically lethal with the inhibition of the proteins recruited to RNA Pol II in prostate, breast and ovarian cancer cells. Conclusion: In brief, we show that defects in transcription elongation promote epigenetic plasticity and rewire the transcription machinery, which may open actionable therapeutic vulnerabilities. Citation Format: Jing Liang, Aishwarya Gondane, Harri M. Itkonen. Inactivation of CDK12 remodels the transcription machinery and promotes epigenetic plasticity [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 6412.
Abstract 4200: Elevated dNTP pools impair homologous recombination-mediated repair, promoting apoptosis in therapy-resistant glioblastoma
Authors: Dominique Monroe, Mercy Kehinde-Ige, Apeksha Anand, Arilyn Williams, Edidiong Usoro, Matthew Kededa, Aman Kalsi, Christian Fahmy, Ramsha Khanam, Huidong Shi, Waaqo Daddacha
Journal: Cancer Research (2025)

Abstract Glioblastoma (GBM) is a deadly brain tumor that often develops resistance to DSB-inducing therapeutics due to dysregulated DNA repair. Ionizing radiation (IR) targets these cancer cells by causing DNA double-stranded breaks (DSBs). However, GBM often has overactive genes involved in the error-free DSB-repair process known as Homologous Recombination (HR). This results in therapy resistance and poor patient outcomes. Here, we provide an alternative approach to target DSB-resistant GBM by modulating the dNTP pool instead of solely targeting DNA-repair proteins. Through a comet assay, we found that increasing the dNTP pool prior to IR resulted in impaired DSB-repair. Immunofluorescence analysis of key HR proteins revealed significant disruptions in end resection, a necessary phase of HR. Our RNA-seq results show that increasing the dNTP pool prior to IR treatment caused significant changes in gene expression when compared to IR or dN treatment alone. Pathways most affected include apoptosis and cell cycle arrest. Flow cytometry analysis confirmed the significant increase in apoptosis in irradiated cancer cells with elevated dNTP pools. Not only do these data suggest that HR efficiency is reduced due to end resection impairment, but they also show that as a result, cell viability is destabilized due to prolonged DNA damage, resulting in apoptosis. The identification of this impairment may be essential in finding novel therapeutic approaches to sensitize therapy-resistant GBM. Citation Format: Dominique Monroe, Mercy Kehinde-Ige, Apeksha Anand, Arilyn Williams, Edidiong Usoro, Matthew Kededa, Aman Kalsi, Christian Fahmy, Ramsha Khanam, Huidong Shi, Waaqo Daddacha. Elevated dNTP pools impair homologous recombination-mediated repair, promoting apoptosis in therapy-resistant glioblastoma [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 4200.
Abstract 5638: Preclinical and clinical studies of PEP07, a novel brain penetrating Chk1 inhibitor, on solid tumor treatments
Authors: Chieh-Fang Cheng, Hui-Ling Chen, Feng_Yu Lee, Cheng-Hao Liu, Chien-Feng Li, Hong-Ren Wang
Journal: Cancer Research (2025)

Abstract PEP07 is a potent and selective brain penetrating oral Chk1 inhibitor. Chk1 is involved in the DNA damage response and cell cycle regulation and helps maintain the integrity of the genome during cell division, especially in response to DNA damage or replication stress. PEP07 showed strong activity in repressing cancer cell growth in vitro and in vivo in different solid cancer models. Over 100 cell lines showed IC50&amp;lt;0.5μM toward PEP07 in vitro, and PEP07 achieved over 90% tumor growth inhibition (TGI) in multiple in vivo models either by monotherapy or combined with standard of care (SoC) treatments. With the property of blood-brain barrier (BBB) penetration, PEP07 was able to inhibit brain cancer in orthotopic models when combined with SoC treatments. In addition, in vitro cell proliferation and transcriptome data were used to train artificial neuron network (ANN) models to identify cancer cells that are sensitive to PEP07. Patient-derived tumor cells (PDCs) were used to validate the prediction of sensitive cells by ANN models. PEP07 is currently being evaluated in clinical studies for both hematologic and solid cancers. PEP07-102 (NCT05983523), a Phase 1, open-label, multi-center PK/PD and dose-escalation study employs an accelerated titration design combined with a traditional 3+3 approach assessing PEP07 as monotherapy in patients with advanced or metastatic solid tumors. Citation Format: Chieh-Fang Cheng, Hui-Ling Chen, Feng_Yu Lee, Cheng-Hao Liu, Chien-Feng Li, Hong-Ren Wang. Preclinical and clinical studies of PEP07, a novel brain penetrating Chk1 inhibitor, on solid tumor treatments [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 5638.
Abstract 6878: Ag5: a novel quantum cluster therapy targeting mitochondria and antioxidant systems in glioblastoma
Authors: Jayesh Telang, Marleen Derweduwe, Vanesa Porto, Blanca Dominguez, Ross Breckenridge, Martin Treder, Fernando Dominguez, Annelies Claeys, Isabel Aguirre Alcolea, Frederik De Smet
Journal: Cancer Research (2025)

Abstract Despite extensive efforts from drug developers, physicians, and patients, the prognosis for glioblastoma (GBM) remains one of the poorest in adult oncology. Current oncology drug development often revisits established technologies, with few truly novel treatments emerging to tackle challenging diseases like GBM. ARJUNA Therapeutics is breaking new ground with quantum cluster technology, creating a unique family of small molecules. The first of these, Ag5, consists of five silver atoms (a quantum cluster) with demonstrated drug-like qualities, including the ability to cross the blood-brain barrier. Ag5 penetrates cells and specifically catalyzes the irreversible inactivation of both glutathione and thioredoxin antioxidant systems in cancer cells, rapidly depleting mitochondrial glutathione and inducing cell death with minimal off-target effects at therapeutic doses. In collaboration with ARJUNA, the Laboratory for Precision Cancer Medicine at KU Leuven, Belgium, screened 20 patient-derived glioma stem cell lines from adult GBM tumors. Ag5 demonstrated cell-killing effectiveness at submicromolar concentrations in approximately 50% of these models, showing activity in both newly diagnosed and recurrent tumor models, as well as in cells from both the core and infiltrating regions. Importantly, tumor cell lines taken from individual patients at various disease stages retained their Ag5 sensitivity, even as they acquired resistance to radiotherapy and/or TMZ. Biomarkers defining sensitivity and resistance to Ag5 in patient-derived GBM lines have been identified, supported by promising preclinical in vivo data. Ag5 has the potential to benefit a significant proportion of GBM patients. A clinical phase 0 neuro-oncology trial at University Hospitals Leuven, Belgium, is planned to test both the biomarker and therapeutic hypothesis for Ag5 in adult GBM patients. Citation Format: Jayesh Telang, Marleen Derweduwe, Vanesa Porto, Blanca Dominguez, Ross Breckenridge, Martin Treder, Fernando Dominguez, Annelies Claeys, Isabel Aguirre Alcolea, Frederik De Smet. Ag5: a novel quantum cluster therapy targeting mitochondria and antioxidant systems in glioblastoma [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 6878.
Abstract 4866: Attenuating CD8 T cell exhaustion and enhancing anti-tumor responses with microRNA-29a
Authors: Xuebing Leng, Lance Buchness, Christine Rafie, Natasha Khatwani, Miguel Gallardo, Svetlana Ristin, Luisa Cimmino, Aristeidis Telonis, Erietta Stelekati
Journal: Cancer Research (2025)

Abstract CD8 T cells are important players of adaptive immunity, mediating protection against viral infections and cancer. CD8 T cell differentiation into memory T cells depends on effective clearance of the initial pathogen. Thus, chronically persisting pathogens or tumors result in a distinct T cell differentiation state, termed “exhaustion”. Exhausted T cells (TEX) are not able to generate optimal immune responses and provide immunological protection. Improving the function of exhausted T cells (TEX) by antagonizing surface inhibitory receptors, such as PD-1, is a potent immunotherapeutic strategy. However, a large number of patients do not benefit from immunotherapy or do not exhibit long-term protection, creating a need for improved immunotherapeutic strategies. Failure to respond to immunotherapy is attributed to the epigenetic stability of TEX and inability of immunotherapy to reverse TEX differentiation. Transcriptional and epigenetic analyses of TEX have identified cellular and molecular pathways associated with exhaustion. Most, if not all, of these exhaustion-associated pathways are regulated by microRNAs (miRs); therefore, miRs represent novel ideal targets for immunotherapy. We recently demonstrated that miR-29a redirects TEX differentiation into functional stem-like differentiation; therefore, presents an attractive target for novel immunotherapeutic strategies. Using ectopic overexpression of miR-29a as well as miR-29a deficient T cells, we demonstrate that miR-29a attenuates exhaustion and enhances the durability of protective T cell responses. Mechanistically, miR-29a directly targeted the 3’UTR of key transcriptional and epigenetic modulators, including Tet-2, Dusp2, Bach2, and Nfat. Importantly, miR-29a regulated CD8 T cell responses to TCR stimulation. Thus, miR-29a was found to regulate T cell differentiation by protecting CD8 T cells from deleterious overstimulation and, therefore, promoting functional anti-tumor responses. Thus, we propose that miR-29a is a novel regulator of TEX differentiation that can promote durable protective T cell responses and improve immunotherapy. Citation Format: Xuebing Leng, Lance Buchness, Christine Rafie, Natasha Khatwani, Miguel Gallardo, Svetlana Ristin, Luisa Cimmino, Aristeidis Telonis, Erietta Stelekati. Attenuating CD8 T cell exhaustion and enhancing anti-tumor responses with microRNA-29a [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 4866.
Abstract 4022: Leveraging multidisciplinary partnerships to overcome barriers to advance racial equity in healthcare
Authors: Regina M. Sharma, Frankie M. Palazzolo, Shelley G. Skinner, Klementina Sula, Evelyn M. Jiagge
Journal: Cancer Research (2025)

Background: Racial disparities in funding continue to be one of the most significant barriers to Black women research scientists progressing; impacting career trajectories and access to research grants. Because of this, there is a dire need to build connections and overcome barriers for funding opportunities for research in underrepresented communities. A multidisciplinary team of fund development professionals, research scientists, and pharmaceutical professionals came together with one intended goal; transition barriers into opportunities by navigating the complexities of a large healthcare organization and successfully build a leadership-driven model that demonstrates when people come together across a variety of entities and disciplines results will follow. Method: Navigated the complexities of a large healthcare organization Successfully built a leadership-driven model to produce results Engaged stakeholders by overcoming obstacles by leveraging educational opportunities to help the community and prospective donors understand the complexities of inequity in healthcare. Created an elevator pitch that we could utilize in various public spaces - meetings, conferences, the community Translated the work into ideas non-scientists could understand Made connections across US and global Biotech, Pharma, and Precision Medicine organizations Results: Over four years we have raised over 3.5 million dollars to support basic, translational, and qualitative research in Detroit and globally. With funding we received at Henry Ford Health, through our partnership, we generated needed preliminary data on the unique aggressive biology of African breast cancers, that was used for a successful NIH grant application. Through our initiative Precision Medicine for Aggressive Breast Cancer PMABC, we have supported research in Ghana, Tanzania, Rwanda, Uganda, Botswana, Nigeria, and South Africa. We have supported researchers in these countries with the training and education needed for cancer research in the country and have helped raise seed funding for local cancer research. We have ongoing community-based research in Detroit and SE Michigan to address barriers to Black/African Americans participating in cancer clinical trials. Conclusion: In this session, we will review a framework that will highlight how to organize stakeholders, develop a plan of engagement, and leverage the necessary resources to execute a leadership-driven model. Citation Format: Regina M. Sharma, Frankie M. Palazzolo, Shelley G. Skinner, Klementina Sula, Evelyn M. Jiagge. Leveraging multidisciplinary partnerships to overcome barriers to advance racial equity in healthcare [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 4022.
Abstract 1717: Establishment and characterization of enzalutamide resistant prostate CDX models
Authors: Haiting Dai, Jie Yang, Xiu Fan, Wen-Jen Yu
Journal: Cancer Research (2025)

Abstract Prostate cancer (PCa) is common and mostly androgen dependent cancer occurred in men and ranked fifth of the causes of death over the world, reduction the serum level of androgen become the priority therapy method for treating PCa patients. Although the first generation of anti-androgen receptor (AR) new drugs such as flutamide, nilutamide, and bicalutamide were launched few years ago and lighted new hopes for treatment of androgen dependent PCa, drug resistance was developed quickly and push the second generation of anti-AR drugs such as enzalutamide, apalutamide, and darolutamide to the market by their high specific binding to AR and better drug efficacy. Despite new anti-AR drugs exerted better efficacy, drug resistance still hampered the treatment of PCa patients, new challenge was burst for anti-PCa drugs through AR pathway. In this study, we developed an enzalutamide resistant C4-2B cell line in vitro by escalated the enzalutamide concentration gradually. The phenotype and genotype of C4-2B cell line were checked while enzalutamide concentration was increased. After 6 months of induction and identification, C4-2B enzalutamide resistant cell line was established and showed 140 times of drug-resistant index compare to that of parental cell. The in vivo drug-resistant efficacy was also confirmed in C4-2B enzalutamide resistant (C4-2B Enz-R) CDX models using 30 mpk enzalutamide through PO administration for 28 days (TGI=8.37%, T/C=93.22%) compared to the enzalutamide efficacies on LNCAP and 22RV1 CDX models. Western blot for androgen receptor expression level in tumor tissues and ELISA assay for prostate specific androgen (PSA) level in serum are highly correlated to the tumor volume of C4-2B Enz-R CDX models. The well characterized novel C4-2B Enz-R cell line and CDX model were appropriate for new drug discovery of anti-PCa drugs through AR pathway in vitro and in vivo. Citation Format: Haiting Dai, Jie Yang, Xiu Fan, Wen-Jen Yu. Establishment and characterization of enzalutamide resistant prostate CDX models [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 1717.
Abstract 6887: Targeting JMJD6: A Novel Approach in Cancer Therapy?
Authors: Mathilde Calmels, Dorian Brager, Christophe Marcireau
Journal: Cancer Research (2025)

Abstract The Jumonji Domain Containing 6 protein (JMJD6) is part of the Jumonji C domain-containing protein family and functions as an arginine demethylase and lysine hydroxylase. JMJD6 facilitates demethylation of arginine and hydroxylation of lysine in both histone and non-histone proteins. Its activity on histones is primarily mediated by the JMJC domain, which is involved in demethylating H3R2me2 and H4R3me2. These demethylation events at histone H3 arginine 2 (H3R2me2) and histone H4 arginine 3 (H4R3me2) are crucial for regulating chromatin accessibility and gene transcription. JMJD6 also targets non-histone proteins such as TRAF6, STAT1, RNA helicase A, ERa, HSP70, EIF3B, EIF3C, etc. Additionally, more than 150 sites of JMJD6-catalyzed lysine hydroxylation on 48 protein substrates have been identified. JMJD6 plays an important role in transcriptional regulation, RNA splicing, inflammation, and immune responses. It downregulates pathways and activities like p53, TGF-β signaling, and Myc-induced apoptosis, while upregulating processes such as CDKs, WNT, MAPK, and autophagy pathways. Abnormal JMJD6 expression is linked to various diseases, including cancer. Elevated JMJD6 expression has been reported in many tumor types, including breast invasive carcinoma (BRCA), lung adenocarcinoma (LUAD), liver hepatocellular carcinoma (LIHC), colon adenocarcinoma (COAD) and rectum adenocarcinoma (READ). High JMJD6 levels are also associated with poor prognosis, making it an attractive target for cancer therapy. In this study, we confirmed the critical role of JMJD6 in a NSCLC cell line and a liver cancer cell line. Using CRISPR/Cas9, we replaced the endogenous JMJD6 promoter with a doxycycline-regulated promoter, creating conditional JMJD6 cells. We will examine the effects of JMJD6 depletion in these cells and assess the complementation results with various JMJD6 alleles. Citation Format: Mathilde Calmels, Dorian Brager, Christophe Marcireau. Targeting JMJD6: A Novel Approach in Cancer Therapy [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 6887.
Abstract 4887: TIM-3 signaling modulates brain tumor growth in an orthotopic mouse model
Authors: Su Bin Won, Hyung-Seok Kim, Dae Yeon Kim, Ki Sun Kim, Su Jeong Gu, Chanju Lee, Hee Jung Yoon, Eun Jung Park
Journal: Cancer Research (2025)

T-cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3) is a transmembrane protein originally identified as a T helper type 1 (Th1)-specific protein. While there is growing interest in the roles of diseases, including tumors, the properties of TIM-3 in brain tumors remain unexplored. In this study, we investigated the functional properties of TIM-3 in the brain tumor microenvironment using TIM-3 mutant mice with intracellular signaling defects (Tim-3mut). To determine whether defects in TIM-3 signaling could affect brain tumor, we examined tumor growth using an intracranial mouse brain tumor model with glioma. EGFP-GL26 glioma cells were injected into the right hemisphere of mice with Tim-3mut mice and WT mice, and tumor growth was monitored using MRI. Interestingly, TIM-3 singling defects lead to reduced glioma growth and improved survival in the orthotopic mouse glioma model. Next, we performed experiments to investigate how TIM-3 signaling defects influence brain tumor growth and identified alterations in several signaling molecules, including CBP35, a lectin family member in Tim-3mut mice with GL26 tumor cells. Collectively, Our findings suggest that modulating TIM-3 signaling affects the brain tumor microenvironment, thereby influencing tumor growth and survival. Citation Format: Su Bin Won, Hyung-Seok Kim, Dae Yeon Kim, Ki Sun Kim, Su Jeong Gu, Chanju Lee, Hee Jung Yoon, Eun Jung Park. TIM-3 signaling modulates brain tumor growth in an orthotopic mouse model [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 4887.