tbuckley/cabot-search huggingface dataset:
Abstract 2750: Alternative enhancer usage of <i>PER2</i> locus regulating 3D genome architecture in epithelial-mesenchymal states
Authors: Yi-Chia Chiu, Qing You Pang, Tuan Zea Tan, Wendy W. Hwang-Verslues, Ruby Y. J. Huang
Journal: Cancer Research (2025)

Abstract The regulation of epithelial (E) and mesenchymal (M) states requires orchestrated adaptation at the epigenomic level. The 3D genome hierarchical orders, together with chromatin accessibility, histone modifications, and local DNA looping, establish the architectural backbone of the genome in response to functional ques for EM plasticity during cancer progression. Here, we delved into alternative enhancer usage and the accompanied changes in 3D genome architecture which could govern the interconversion between these two states. Using ovarian cancer (OC) cells as a model, distinct enhancer usage at the circadian gene Period 2 (PER2) loci was identified in OC cells of epithelial-like Epi-A (PEO1 and OVCA429) and mesenchymal-like Mes (SKOVE3 and HeyA8) subtypes. Intron 6-14 of PER2 consisted of multiple enhancers in PEO1 and OVCA429 suggesting an open chromatin state compared to a relatively closed chromatin in SKOV3 and HeyA8 marked by latent/inactive regions. OC tumors of epithelial-like Epi-A subtype with high PER2 expression were also correlated with better overall survival, suggesting the clinical relevance of this region. CRISPR/Cas9-mediated deletion of 3 enhancers, namely A, B, and C regions, was performed to generate clones in OVCA429. Deletion of specific enhancer B and C regions of PER2 resulted in a spindly mesenchymal morphology, compared to the cobblestone epithelial morphology of parental OVCA429 and clones with region A deletion. These changes corresponded with the altered expression of known EMT markers. RNA-seq analysis showed a significant shift in the EMT scores of OVCA429_PER2_B towards a Mes-like profile. Hi-C analysis was done in OVCA429_PER2_B to decipher the 3D genome architecture. Changes at compartments, topologically associated domains (TADs), and long-range DNA interaction loops were explored. Our findings highlighted that alternative enhancer usage is crucial in EM plasticity and subtype conversion, offering genome level insights into EMT regulatory mechanisms in cancers. Citation Format: Yi-Chia Chiu, Qing You Pang, Tuan Zea Tan, Wendy W. Hwang-Verslues, Ruby Y. J. Huang. Alternative enhancer usage of PER2 locus regulating 3D genome architecture in epithelial-mesenchymal states [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 2750.
Abstract 2737: Enhancing the efficacy of DNA methyltransferase inhibitors in colon cancer through dual targeting of EZH1 and EZH2
Authors: Rochelle Tiedemann, Alison Chomiak, Ashley Wiseman, Yanqing Liu, Scott Rothbart
Journal: Cancer Research (2025)

Abstract DNA methyltransferase inhibitors (DNMTis) have shown limited success in solid tumors, despite the prevalence of aberrant DNA methylation and associated tumor suppressor gene silencing. Colon cancer cells exposed to DNMTi accumulate lysine 27 tri-methylation on histone H3 (H3K27me3), and we and others have proposed this EZH2-dependent repressive histone modification limits DNMTi therapeutic potential. Recently we demonstrated that low-dose DNMTi treatment, which mimics solid tumor exposure in patients, sensitizes colon cancer cells to EZH2 inhibitors (EZH2is) and synergistically upregulates tumor suppressor genes and transposable elements (TEs). Importantly, the observed synergy varies among EZH2 inhibitors. Molecules targeting both EZH2 and its interchangeable catalytic counterpart, EZH1, demonstrate superior efficacy in tumor suppressor gene activation and cancer cell growth inhibition. In this study, we profiled the epigenomic landscapes that result from combination therapy with DNMTi and EZH1/2i to understand how these compounds alter the transcriptional states of solid tumors. We show that dual EZH1/2i reduces all states of H3K27 methylation (me1/me2/me3), providing additional substrates for p300/CBP deposition of H3K27 acetylation (H3K27ac) and enhancing transcriptional outcomes. Furthermore, H3K27ac is required for tumor suppressor gene activation observed with combination DNMTi and EZH1/2i treatment. These results underscore the therapeutic promise of combining DNMTi with dual EZH1/2i to reprogram the epigenetic landscape, restore tumor suppressor gene activity, and enhance the efficacy of epigenetic therapies in solid tumor treatment. Citation Format: Rochelle Tiedemann, Alison Chomiak, Ashley Wiseman, Yanqing Liu, Scott Rothbart. Enhancing the efficacy of DNA methyltransferase inhibitors in colon cancer through dual targeting of EZH1 and EZH2 [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 2737.
Abstract 1744: Preclinical efficacy of a selective, orally bioavailable HER2 small molecule inhibitor targeting HER2 alterations and Enhertu-resistant cancers
Authors: Jiyoung Jeon, Sun Young Jang, Ho Yeon Nam, HyungSeok Yoo, Jooyun Byun, Gunwoo Lee, Soye Jeon, Young Gil Ahn
Journal: Cancer Research (2025)

Abstract HER2 alterations, including overexpression, amplification, and other mutations are found in various solid tumors and have a significant impact on cancer cell growth and metastasis. To address this issue, HER2-targeted therapeutics are being developed and evaluated across multiple tumor types, including breast cancer, gastric cancer, HER2-positive cholangiocarcinoma, colorectal cancer, non-small cell lung cancer, and bladder cancer. Existing HER2 inhibitors inhibit not only HER2 alteration but also EGFRWT, causing issues with EGFR-related toxicity (skin rash, diarrhea, etc.). This highlights the need to develop selective HER2 inhibitors that specifically target HER2 and its mutations without affecting EGFRWT. The Hanmi compound selectively targets the HER2 receptor tyrosine domain via covalent binding, sparing EGFRWT and minimizing EGFR-related toxicity. The Hanmi compound inhibited both HER2 mutant and HER2WT cells and enzymes, had a DMPK profile compatible with oral administration. It also demonstrated potent antitumor activity as a single agent in various HER2 mutant xenograft models. Despite the good efficacy of Enhertu (trastuzumab deruxtecan), which is approved for the treatment of all HER2 cancers, resistance that develops within 12 months of drug administration remains a major clinical challenge. To address this unmet need, we evaluated a novel HER2 inhibitor in a preclinical model that acquired resistance to Enhertu. The Hanmi compound effectively inhibited tumor growth in Enhertu resistant NCI-N87 mouse models. In conclusion, Hanmi compound, an orally bioavailable small molecule inhibitor, showed high efficacy against both HER2 mutant and HER2WT tumors, while preserving EGFRWT and minimizing EGFR-related toxicities. Furthermore, it demonstrated the potential to overcome resistance to Enhertu by effectively inhibiting tumor growth in Enhertu-induced resistant xenograft mouse model, and these preclinical results support Hanmi compound as a promising treatment for HER2 altered cancers. Citation Format: Jiyoung Jeon, Sun Young Jang, Ho Yeon Nam, HyungSeok Yoo, Jooyun Byun, Gunwoo Lee, Soye Jeon, Young Gil Ahn. Preclinical efficacy of a selective, orally bioavailable HER2 small molecule inhibitor targeting HER2 alterations and Enhertu-resistant cancers [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 1744.
Abstract 3531: Development of a mRNA-LNP vaccine for Lynch syndrome
Authors: Yuri Koboziev, Ligia A. Pinto, Robert H. Shoemaker, Jason D. Marshall
Journal: Cancer Research (2025)

Abstract Lynch syndrome (LS) is a genetic disorder in which colorectal cancer is caused by mutations in DNA mismatch repair enzymes. Prophylactic mRNA vaccines have become the subjects of increasing interest as platforms for the potential prevention of such disorders. Several neoantigen sequences caused by defective mismatch repair were identified as expressed in a GEMM model of Lynch Syndrome, VCMsh2, and were also confirmed to be immunogenic for T and B cell responses in the background strain C57BL/6, as measured by IFN-g ELISPOT and ELISA in peptide/adjuvant-vaccinated mice. Vaccine mRNA constructs coding for 3 neoantigen peptides were designed with the HA signal peptide sequence and BioNTech 3’ and 5’ UTR regions and synthesized on the BioXp 3250 platform using pseudouridines. Monovalent mRNA vaccines were generated by encapsulating LS neoantigen mRNA into lipid nanoparticles (LNPs) on the NanoAssemblr Spark platform. High mRNA encapsulation efficiency was verified, and LNP size, polydispersity index, concentration, and zeta potential passed vaccine specifications. In vitro translation of vaccine mRNAs in transfected HEK-293 and RAW 264.7 cells were confirmed by FLAG Western Blot and mass spectrometry. The mRNA vaccines were administered 2X monthly via IM route to C57BL/6 mice. Substantial splenic CD4 T cell responses to the LS neoantigen peptides Nacad, Maz, and Senp6 were detected although lower than T cell responses to the corresponding peptide/adjuvant vaccine. In an attempt to adjuvant the mRNA vaccine, the TLR9 agonist CpG-2395 was encapsulated into LNPs via methods identical to mRNA packaging. In vitro testing on cell lines revealed that the CpG-LNPs enhanced Luciferase mRNA expression in RAW264.7 macrophages, triggered TLR9 signaling in mTLR9-HEK Blue reporter cells, and promoted IL-12 production by transfected RAW264.7. When LS neoantigen mRNA-LNPs were co-vaccinated with CpG-LNPs in C57BL/6 mice, T cell responses were augmented to be comparable to peptide-vaccinated T cell responses. Our current efforts involve optimizing the LNP lipid composition for uptake efficiency, optimizing the in vivo trafficking of the LNPs, and determining a suitable method for adjuvanting mRNA vaccines to boost T and B cell responses before evaluation in the VCMsh2 Lynch Syndrome GEMM model. Citation Format: Yuri Koboziev, Ligia A. Pinto, Robert H. Shoemaker, Jason D. Marshall. Development of a mRNA-LNP vaccine for Lynch syndrome [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 3531.
Abstract 1843: Therapeutic implication of pH/hypoxic responsive nanoencapsulated tunicamycin on pancreatic cancer by targeting K-RasG12D
Authors: Axel H. Breier, Debasmita Dutta, Anjali Kambhampati, Inamul Haque, Archana De, Sunil P. Upadhyay, Sushanta K. Banerjee, Mohiuddin Quadir, Snigdha Banerjee
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains one of the leading sources of cancer mortality worldwide, including US Veterans. An initial response to chemotherapy, such as Gemcitabine (GEM) alone or in combination with other chemotherapies, is often followed by emergent resistance, reflecting an urgent need for targeted therapies. PDAC cells are highly addicted to oncogenic K-RAS mutations for their growth, progression, immunosuppression, and drug resistance, but mutant K-RAS in PDAC is still tricky to target. A glycosylation inhibitor, Tunicamycin (TM), is a potent killer of PDAC cells. However, free-form TM is found to be very toxic in in vivo implication as a therapy. To repeal the limitation of TM, we have synthesized a pH/Hypoxic-responsive iRGD-tagged biodegradable nano-encapsulated TM (NPTM) that was found to inhibit PDAC cell growth parallel with blocking K-RASG12D expression and its downstream signaling pathways associated with desmoplasia, and program cell death ligand 1 (PD-L1) expression. Moreover, NPTM markedly reduced the xenograft tumor growth, increased intratumoral CD8+ T cells, and increased in overall survival of treated mice. Furthermore, NPTM treatment synergizes with GEM to further regress PDAC growth in a PDAC xenograft model. These studies provide insights into NPTM treatment with a potential clinical application. Citation Format: Axel H. Breier, Debasmita Dutta, Anjali Kambhampati, Inamul Haque, Archana De, Sunil P. Upadhyay, Sushanta K. Banerjee, Mohiuddin Quadir, Snigdha Banerjee. Therapeutic implication of pH/hypoxic responsive nanoencapsulated tunicamycin on pancreatic cancer by targeting K-RasG12D [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 1843.
Abstract 2264: Disparities in perceptions and uptake of genetic testing among the United States population: trends from 2011-2022
Authors: Ariana Naaseh, Mengyao Shi, Steven Tohmasi, Erin L. Linnenbringer, Julie A. Margenthaler, Graham A. Colditz, Yin Cao
Journal: Cancer Research (2025)

Background: Over the last decade, genetic testing has become more readily available, but it is not known whether this has translated to greater public awareness and usage over time. We aimed to evaluate patterns and temporal trends in genetic testing awareness and usage, along with their sociodemographic and cancer history correlates, in the United States (US) population. Methods: We performed a serial, cross-sectional analysis of nationally representative data from the National Cancer Institute’s Health Information National Trends Survey (HINTS). We analyzed survey responses from adults aged 18 or older from HINTS 4 Cycle 1 (2011), 4 Cycle 2 (2012), 4 Cycle 3 (2013), 4 Cycle 4 (2014), 5 Cycle 1 (2017), 5 Cycle 4 (2020), 6 (2022). Crude linear trend was evaluated using a linear regression model and multivariable logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs). Results: Data on 22,256 individuals (mean [SD] age, 46.7 [17.0] years; 13,208 (50.7%) female; non-Hispanic White 13,559 (65.2%)) were analyzed from 2011-2022 HINTS data. Awareness of genetic testing increased from 36.6% in 2011 to 81.7% in 2022 (p&amp;lt;0.001). Older adults, men, non-Hispanic Black individuals, non-Hispanic Asian individuals, Hispanic individuals, those with an education level less than some college, and individuals with annual household incomes less than $75,000 were significantly less likely to be aware of genetic testing. Uptake of genetic testing, however, lagged behind awareness with rates of 21.4% in 2020 and 35.6% in 2022. Uptake of genetic testing was significantly lower among non-Hispanic Asian individuals, those with household incomes under $35,000, and those without a personal history of cancer. Conclusion: Despite high levels of awareness, genetic testing uptake remains disproportionately low, with notable disparities across sociodemographic groups. Targeted educational interventions focused on genetic testing are necessary for marginalized populations and the providers caring for them. Further study is needed to understand genetic testing uptake patterns in the US. Citation Format: Ariana Naaseh, Mengyao Shi, Steven Tohmasi, Erin L. Linnenbringer, Julie A. Margenthaler, Graham A. Colditz, Yin Cao. Disparities in perceptions and uptake of genetic testing among the United States population: trends from 2011-2022 [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 2264.
Abstract 2767: Aneuploidy-induced VHL haploinsufficiency in lung squamous cell carcinoma and clear cell renal cell carcinoma
Authors: Joanna Kopko, Joan J. Castellano-Perez, Gayatri Bulsara, Alison Taylor
Journal: Cancer Research (2025)

Aneuploidy is present in 90% of solid tumors, making it a hallmark of cancer. Despite its prevalence, aneuploidy has been difficult to model in human cells due to the technical challenges of generating targeted events. One high-frequency aneuploidy alteration is chromosome 3p (chr3p) deletion, which is found in 80% of lung squamous cell carcinomas (LUSC) and 90% of clear cell renal cell carcinomas (ccRCC). Cells with chr3p deletion are missing one copy of the Von Hippel-Lindau (VHL) gene, a master regulator that targets Hypoxia Inducible Factor Subunit Alpha (HIF-α) for degradation. When HIF-α is not degraded, it promotes the transcription of genes involved in cell metabolism, cell survival, and proliferation. The role of VHL has already been extensively studied in ccRCC, but only using models with homozygous VHL loss, therefore the effect of heterozygous VHL loss is not known. I hypothesize that partial VHL loss is enough to stabilize HIF and activate transcriptional targets involved in tumor progression in LUSC. To study the effects of chr3p deletion, we developed a CRISPR-based approach to generate isogenic cell lines with and without the aneuploidy event in lung airway epithelial cells. Seven of eleven chr3p deleted clones had HIF-α protein stabilization in normoxic conditions. We also generated cells with smaller regions of chr3p deleted instead of whole arm loss. If the deletion region included VHL, we observed HIF-α accumulation. To test whether VHL haploinsufficiency was sufficient for this phenotype, we used CRISPRi to reduce VHL to 50% levels and found stabilization of HIF-α. In hypoxic conditions, VHL knockdown cells had increased HIF-α protein accumulation and gene expression of HIF-α targets GLUT1 and VEGF. These preliminary data suggest that VHL haploinsufficiency is enough to cause HIF-α stabilization. Additionally, we looked at VHL knockdown in renal epithelial cells and saw no HIF stabilization. This indicates that VHL haploinsufficiency and HIF stabilization may differ in lung vs. kidney cells. To our knowledge, our research is among the first to study VHL in lung cancer, and our results could have significant implications for drug development in LUSC. HIF-α inhibitors have recently been approved by the FDA, so determining the dose dependency of VHL on HIF-α activity will increase knowledge on treatment efficacy for patients with heterozygous deletion of VHL. Citation Format: Joanna Kopko, Joan J. Castellano-Perez, Gayatri Bulsara, Alison Taylor. Aneuploidy-induced VHL haploinsufficiency in lung squamous cell carcinoma and clear cell renal cell carcinoma [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 2767.
Abstract 1337: Androgen receptor mediates radioresistance through autophagy and DNA repair in AR-positive prostate cancer
Authors: Ken-ichi Kudo, Qianhua Feng, Maria Chosco, Leslie Wenning, Ziyi Huang, Jonathan Anzules, Jeshwanth Mohan, Nathan Lin, Zhao V. Wang, June-Wha Rhee, Yun Li
Journal: Cancer Research (2025)

Abstract Background: Androgen receptor (AR) is a critical therapeutic target in prostate cancer (PC) and androgen blockade is known to act synergistically with radiotherapy (RT), however, the mechanisms through which AR modulates RT response is complex and remains poorly elucidated. Aims and Methods: We compared the radiation responses in LNCaP (AR-positive), PC3 (AR-negative), and HEK293T (non-malignant) cells by analyzing DSB induction, cell cycle arrest, and apoptosis. Mechanistic studies, including AR silencing and inhibition, were validated through RNA sequencing and IHC analysis of cell lines and irradiated patient-derived prostate tumors. Results: At 24-hours post-RT, the apoptotic rate increased by 6-fold in HEK293T and PC3 cells versus LNCaP cells. Cell viability at 48-hours post-RT was decreased to less than 10% in HEK293T, remaining at ∼60% in LNCaP cells. Moreover, over 70% of LNCaP cells were arrested in the G1 phase post-RT, accompanied by rapid p53 activation and p21 induction within 3-hours. AR silencing significantly increased radiosensitivity and reduced cell proliferation in LNCaP but did not alter the expression of p53 downstream genes, eg. BAX and p21. Interestingly, AR silencing reduced the phosphorylation of DNA-PKcs, a critical mediator of non-homologous end joining (NHEJ) repair, suggesting that AR facilitates NHEJ. This was further supported by the comet assay results showing that LNCaP repaired RT-induced DSBs more efficiently than PC3 cells. Moreover, AR regulates autophagy post-RT as AR silencing decreased autophagy-related gene (ATG) expression, and macroautophagy was augmented in LNCaP cells post-RT through LC3-II expression and autophagic vacuole formation. Bulk transcriptome analysis revealed significant upregulation of 11 ATGs, including ULK1 and ATG2, at 24-hours post-RT. Moreover, IHC analysis of patient-derived PC ex vivo irradiated tumors consistently showed that RT-induced autophagy supports the survival of AR-positive PC cells. Discussion and Conclusion: Our results demonstrate that AR plays an essential role in mediating radioresistance in AR-positive PC by enhancing both autophagy and DNA repair, with ongoing spatial transcriptome analysis to further explore these mechanisms in patient-derived tumors. Citation Format: Ken-ichi Kudo, Qianhua Feng, Maria Chosco, Leslie Wenning, Ziyi Huang, Jonathan Anzules, Jeshwanth Mohan, Nathan Lin, Zhao V. Wang, June-Wha Rhee, Yun Li. Androgen receptor mediates radioresistance through autophagy and DNA repair in AR-positive 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 1337.