tbuckley/cabot-search huggingface dataset:
Abstract 419: Chromosomal instability and oncogene dosage variations underlying KRAS G12C inhibition therapy resistance in lung cancer
Authors: Dingcheng Gao, Yingzhuo Liu, Yi Ban
Journal: Cancer Research (2025)

Abstract KRAS G12C inhibitors (G12Ci), including the FDA-approved Sotorasib and Adagrasib, represent a significant advancement in targeted cancer therapies. As their use in non-small cell lung cancer patients expands, addressing the pervasive challenge of drug resistance is critical. Resistance mechanisms can be innate, acquired, or both, often coexisting within complex scenarios. Recent studies have highlighted various resistance mechanisms to G12Ci, such as oncogene amplification, activation of alternative signaling pathways, additional mutations in KRAS or its associated networks, and adaptive processes like epithelial-to-mesenchymal transition. Identifying the primary drivers and predominant mechanisms of resistance is crucial for developing effective countermeasures. To tackle these challenges, we developed Oligo-CALL, an innovative cellular barcoding technology that employs antisense oligonucleotide-inducible CRISPRa for lineage labeling. This technique allows for precise clonal tracking and the retrospective isolation of clones. Using Oligo-CALL, we analyzed tumor clonal heterogeneity and traced the evolution of resistance in lung cancer cells treated with G12Ci. Treatment with Sotorasib resulted in reduced clonal diversity, indicative of strong selective pressure. Similar clonal compositions across different replicates suggest that intrinsic mechanisms significantly contribute to G12Ci resistance. Notably, about 30% of resistant clones showed increased expression of the Kras G12C allele, primarily due to genomic gains, pointing to chromosomal instability (CIN) as a key factor in resistance development. Comprehensive analyses including fluorescent karyotyping, whole-genome, and transcriptome sequencing of isolated tumor clone pairs, revealed extensive genomic complexity and increased heterogeneity under G12Ci treatment. Resistant clones exhibited specific increases in copy number variations, chromosomal structure variations, and additional single nucleotide mutations, further underscoring CIN as a driving force behind G12Ci resistance. Clones that underwent drug treatment displayed higher CIN scores compared to their treatment-naïve counterparts. Intriguingly, cells resistant to G12Ci demonstrated increased sensitivity to PARP inhibitors, suggesting that targeting DNA repair pathways could induce synthetic lethality, offering a potential strategy to overcome resistance in lung cancer cells. Citation Format: Dingcheng Gao, Yingzhuo Liu, Yi Ban. Chromosomal instability and oncogene dosage variations underlying KRAS G12C inhibition therapy resistance in lung 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 419.
Abstract 1086: Introducing the Florida Cancer Research (FL CARES) Network and the Platform for Accelerating Collaborative Computational Cancer Research (PAC3R)
Authors: Michael Sinclair, Carlos Obregon, Caty Chung, Dusica Vidovic, Lukas Rupprecht, Jeronimo Pissinis, Marcin Pilarczyk, Franklin Sotolongo, Kathleen M. Jagodnik, Till Krenz, Erin Kobetz, Mondal M. Ananda, Ling Cen, Xuefeng Wang, Appu Rathinavelu, Stuart Chalk, Jiang Bian, Ji-Hyun Lee, Qianqian Song, Vasileios Stathias, Stephan C. Schürer
Journal: Cancer Research (2025)

Abstract Florida ranks second in cancer burden in the United States. The Florida CAncer RESearch (FL CARES) Network (https://floridacancernetwork.org/) is a statewide collaboration dedicated to advancing cancer research and improving patient outcomes through education, collaborative research initiatives, and a focus on reducing health disparities by leveraging advanced computational approaches. Funded by the State of Florida Bankhead-Coley Cancer Research Program, FL CARES comprises six research organizations, including Florida's three NCI-designated Cancer Centers. The Network has established a collaborative research consortium with unified policies, coordinated data and metadata standards, and diverse datasets. It incorporates tools like SCAN360, developed at Sylvester Comprehensive Cancer Center, to explore the impact of social determinants of health and environmental factors on cancer outcomes across Florida communities. To further collaborative computational research, FL CARES is developing the Platform for Accelerating Collaborative Computational Cancer Research (PAC3R). This advanced informatics system enables FAIR (findable, accessible, interoperable, reusable) data management, including standardization, harmonization, and integration of multimodal cancer datasets. PAC3R facilitates secure data sharing, scalable bioinformatics tools’ deployment, and collaborative analyses across the Network. Built on the Sylvester Data Portal (https://sdp.miami.edu/), a cloud-based multi-omics platform managing clinicogenomic and research data, PAC3R integrates diverse datasets such as transcriptional perturbation signatures, cell sensitivity data, small molecule interactions, and large-scale genomics from The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC). Citation Format: Michael Sinclair, Carlos Obregon, Caty Chung, Dusica Vidovic, Lukas Rupprecht, Jeronimo Pissinis, Marcin Pilarczyk, Franklin Sotolongo, Kathleen M. Jagodnik, Till Krenz, Erin Kobetz, Mondal M. Ananda, Ling Cen, Xuefeng Wang, Appu Rathinavelu, Stuart Chalk, Jiang Bian, Ji-Hyun Lee, Qianqian Song, Vasileios Stathias, Stephan C. Schürer. Introducing the Florida Cancer Research (FL CARES) Network and the Platform for Accelerating Collaborative Computational Cancer Research (PAC3R) [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 1086.
Abstract 623: Epigenetic age acceleration measures and chemotoxicity in older adults with early breast cancer
Authors: Jingran Ji, Canlan Sun, Marla Lipsyc-Sharf, Nikita V. Baclig, Yulia A. Zektser, Ali Al Saleem, Joseph D. Olivera, Kelly S. Synold, Lauren R. Zelman, Alexandra M. Binder, Mina S. Sedrak
Journal: Cancer Research (2025)

Abstract Background: Older adults with early breast cancer can have very different risks of chemotoxicity despite similar chronological age. This heterogeneity may be due to differences in biological age. However, few studies have evaluated whether epigenetic indicators of biological age can stratify the risk of chemotoxicity in older adults with early breast cancer. Methods: In a prospective multicenter study of 394 adults age &amp;gt;65 with stage I-III breast cancer treated with neo/adjuvant chemo, we analyzed DNA methylation patterns from peripheral blood to estimate epigenetic age acceleration (EAA) prior to chemo. We tested three generations of epigenetic age algorithms (1st gen: Horvath and Hannum; 2nd gen: PhenoAge and GrimAge; 3rd gen: DunedinPACE). We calculated EAA as the residual that results from regressing epigenetic age on chronological age. The primary endpoint was grade 2+ chemotoxicity (yes/no, yes defined as any grade 2+ toxicity attributed to chemo). Using multivariable logistic regression, we examined the association between EAA (analyzed as continuous and categorical [quartiles] variables) and grade 2+ chemotoxicity, adjusting for demographic, geriatric, and clinical covariates. Results: The median (range) pre-treatment chronological age was 70 (65-85), 65% had stage II/III disease, 38% had anthracycline, and 75% received G-CSF prophylaxis. A total of 334 (84.8%) participants experienced a grade 2+ toxicity. After adjusting for age, cell composition, stage, race/ethnicity, education, regimen, organ function, and geriatric assessment variables, there was no significant association between the measures of EAA and grade 2+ chemotoxicity (Table). Conclusions: In this cohort of older adults with early breast cancer, there was no significant association between pre-treatment EAA and grade 2+ chemotoxicity. Further research is needed to examine how measures of biological age can be translated to the clinical care of older patients with breast cancer. Citation Format: Jingran Ji, Canlan Sun, Marla Lipsyc-Sharf, Nikita V. Baclig, Yulia A. Zektser, Ali Al Saleem, Joseph D. Olivera, Kelly S. Synold, Lauren R. Zelman, Alexandra M. Binder, Mina S. Sedrak. Epigenetic age acceleration measures and chemotoxicity in older adults with early breast 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 623.
Abstract 101: KPNA2 promotes the progression of lung adenocarcinoma
Authors: Seongran Cho, Inyoung Cheon, Seoree Kim, Yoon Ho Ko, Young-Ho Ahn
Journal: Cancer Research (2025)

Abstract KPNA2 (Importin α1) is a nuclear transporter that mediates the nuclear import of proteins, such as transcription factors and nuclear proteins. Previous studies have highlighted KPNA2 as an important factor influencing CAF activity, prompting us to explore its role and mechanisms in the migration, invasion, and metastasis of lung cancer cells. Immunohistochemistry on tumor samples from lung cancer patients revealed that higher expression of KPNA2 was linked to poorer survival outcomes. To further investigate its function, we used shRNAs to knock down KPNA2 in human and mouse lung cancer cells. This led to a reduction in cancer cell migration, invasion, and metastasis. In contrast, overexpressing KPNA2 enhanced cancer cell migration and invasion. RNA sequencing analysis showed that KPNA2 regulates focal adhesion and NF-κB signaling pathways. Additionally, protein microarray analysis identified Golgi-associated and RNA-associated proteins as potential KPNA2-binding partners, which require further study. These results indicate that KPNA2 plays a crucial role in promoting cancer cell migration, invasion, and metastasis, making it a promising therapeutic target in lung adenocarcinoma. Citation Format: Seongran Cho, Inyoung Cheon, Seoree Kim, Yoon Ho Ko, Young-Ho Ahn. KPNA2 promotes the progression of lung 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 101.
Abstract 1206: The molecular characterization initiative: Nationwide comprehensive clinical profiling of pediatric solid tissue malignancies at scale
Authors: Elaine R. Mardis
Journal: Cancer Research (2025)

Abstract The Molecular Characterization Initiative is an NCI-sponsored program being conducted in collaboration with the Children’s Oncology Group (COG), that seeks to enroll cancer patients from ages 0-25 with a primary diagnosis of a CNS malignancy, soft-tissue sarcoma, rare cancer or high-risk neuroblastoma onto Project Every Child. Subsequent to enrollment, the submission of a disease-involved specimen (cancer) and matched comparator normal (blood or buccal) is subjected to DNA and RNA (tumor) or DNA (normal) extraction by the Biopathology Center, followed by comprehensive clinical molecular profiling at The Institute for Genomic Medicine. To-date, over 4100 patients from 27 states in the United States, from Canada, Australia and New Zealand have been enrolled and studied since project inception in March 2022. Each patient sample set is evaluated by comparative tumor:normal exome analysis, fusion/ITD panel testing of RNA and by DNA methylation profiling, with return of results within 21 days from receipt of specimens at Nationwide Children’s Hospital. Subsequent to return of clinical results, each patient’s data are de-identified and submitted to the Childhood Cancer Database, a public repository managed by the NCI. The data in this repository are publicly available, with institutional sign-off, for the purposes of fueling future discoveries impacting pediatric cancer. The size and scope of the Molecular Characterization Initiative will be equivalent to or greater than other large-scale clinical profiling efforts conducted in Germany (INFORM) and in Australia (Zero Childhood Cancer). The current status and unique results from the MCI will be presented, along with future plans and ongoing challenges. Citation Format: Elaine R. Mardis, On behalf of The Institute for Genomic Medicine at Nationwide Children's Hospital. The molecular characterization initiative: Nationwide comprehensive clinical profiling of pediatric solid tissue malignancies at scale [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 1206.
Abstract 450: Discovery of a highly potent KAT6 Inhibitor for potential treatment of advanced, metastatic and refractory ER+Her2- breast cancers
Authors: Congcong Cai, Shiya Zhu, Linjun Wang, Shu Cai, Hongkun Li, Min Wen, Mingxin Qian, Shifeng Liu, Bin Shi, Hancheng Zhang
Journal: Cancer Research (2025)

Abstract Frequent genomic alteration of KAT6A and KAT6B have been found in a variety of cancer types. Histone acetyltransferases (HAT) KAT6A and KAT6B can acetylate lysine residues of histone H3 (including H3K23), leading to a relaxing state of chromatin and active transcription of genes regulating cell cycle, cellular senescence, and tissue development; to name a few, genes encoding ER (estrogen receptor), Myc, and Cyclin D1. Inhibition of these processes exerts an anti-tumor effect in many cancer types. We, Innogate Pharma (Innogate), have discovered a novel and highly potent series of small molecule KAT6 inhibitors with strong in vitro potency and robust in vivo anti-tumor efficacy. Innogate’s KAT6 preclinical candidate compound (PCC) exerts single digit nM IC50 activities against KAT6A/6B enzymes with good selectivity over KAT5, KAT7, KAT8. The molecule also demonstrated anti-proliferation activity at sub-nM IC50 in ZR-75-1 and T47D. We also tested enzyme kinetics and found the molecule have favorable binding profile to KAT6A in a fast-on-slow-off manner. The PCC molecule can be converted to salts with potential advantages in CMC development and showed a favorable solubility profile independent of GI pH variation. In ER+Her2-breast cancer ZR-75-1 xenograft models, the molecule at 0.3 mg/kg /PO/QD for 28 days leads to significant tumor growth inhibition and regression with TGI 129% at the termination day 28. Furthermore, in a fulvestrant resistant, ER+HER2- breast cancer PDX model, the molecule displayed excellent anti-tumor efficacy at 10 mg/kg /PO/QD, with tumors completely disappeared on day 22 and without safety issues observed, while the positive control compound still had palpable tumors on termination day 28 at the same dose. In other preclinical studies, the molecule holds good in vitro ADME properties and PK profiles in mice, rats and beagle dogs, favoring a potential once daily oral dose regime in the future clinical setting. The molecule also exhibited good in vitro safety profile in hERG and well tolerated in rodent study. Collectively, these results provide preclinical evidence that our PCC molecule could be a superior KAT6A/6B inhibitor to treat patients with advanced, metastatic, refractory, fulvestrant-sensitive or-resistant, ER+Her2- breast cancers. Citation Format: Congcong Cai, Shiya Zhu, Linjun Wang, Shu Cai, Hongkun Li, Min Wen, Mingxin Qian, Shifeng Liu, Bin Shi, Hancheng Zhang. Discovery of a highly potent KAT6 Inhibitor for potential treatment of advanced, metastatic and refractory ER+Her2- breast 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 450.
Abstract 996: Dietary patterns in plasma cell disorders: Opportunities for targeted interventions
Authors: Kadiatou Traore, Francesca Castro, Alankrita Taneja, Elan Gorshein, Andriy Derkach, Jorge Arturo Hurtado Martínez, Edith Serrano, Alexander Lesokhin, Jennifer M. Ahlstrom, Torin Block, Jay R. Hydren, Ana M. Sahagun Sanchez Aldana, Patricia Alejandra Flores Pérez, Cynthia A. Thomson, Saad Z. Usmani, Urvi A. Shah
Journal: Cancer Research (2025)

Abstract Background: Multiple myeloma (MM), the second most common hematologic malignancy in the US, has seen improved survival with therapeutic advancements. This presents an opportunity to enhance outcomes through diet and lifestyle. Poor dietary habits and obesity are linked to adverse outcomes in MM and its precursors—monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM)—potentially mediated by intestinal dysbiosis which affects the immune microenvironment. High Healthy Eating Index (HEI) scores, which reflect better adherence to the Dietary Guidelines for Americans, are associated with reduced mortality. However, data on the dietary habits of individuals with plasma cell disorders (PCDs) remains limited. Methods: We surveyed 443 individuals with MGUS, SMM, or MM on HealthTree Cure Hub using the Block Food Frequency Questionnaire (2022- 2023). We calculated HEI scores and analyzed by age, sex, race, BMI, PCD diagnosis, and education level. We also compared participants’ scores to the general US population by age, sex, and race. Results: Average HEI score was higher for participants (69) than for the US population (58) across all subgroups (p&amp;lt;0.001). Lower education was associated with lower HEI scores (p&amp;lt;0.001) and trended toward higher fruit and lower added sugar intake. Higher BMI trended toward lower HEI scores (p=0.052) and significantly increased fatty acid intake. Males consumed more calories with less vegetables, sodium, and fatty acid intake. Non-Hispanic Asians and Blacks consumed fewer calories but more fatty acids. MGUS and SMM participants consumed more vegetables and lower added sugar, but more sodium compared to MM patients. Conclusion: Individuals with PCDs have more healthful diets than the general US population. However, females, non-Hispanic Asians, non-Hispanic Blacks, individuals with higher BMIs, and those with less education may benefit from targeted dietary interventions to improve health outcomes. Citation Format: Kadiatou Traore, Francesca Castro, Alankrita Taneja, Elan Gorshein, Andriy Derkach, Jorge Arturo Hurtado Martínez, Edith Serrano, Alexander Lesokhin, Jennifer M. Ahlstrom, Torin Block, Jay R. Hydren, Ana M. Sahagun Sanchez Aldana, Patricia Alejandra Flores Pérez, Cynthia A. Thomson, Saad Z. Usmani, Urvi A. Shah. Dietary patterns in plasma cell disorders: Opportunities for targeted interventions [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 996.
Abstract 2465: Aperio manual scan software: beta testing for challenging slide imaging in research
Authors: Erica Pawlak, Shubham Dayal, Elizabeth Sullivan, Jacob Persky, Diane Robirds, Timothy Murphy-Stevens, Duff Pickering
Journal: Cancer Research (2025)

Abstract Purpose: The Aperio Manual Scan feature was developed to improve whole slide imaging for challenging samples, including faintly stained, sparse, or artifact-laden slides. This study evaluated the feature's usability and its ability to address imaging challenges. Experimental Procedures: Fifteen challenging slides, including cytospins, wet tissue touch preps, immunohistochemistry (IHC), and in situ hybridization (ISH) samples, were scanned during a beta test at a pharmaceutical research facility. Laboratory scientists and technicians used the manual scan feature to adjust scan areas, focus points, and calibration points. Participants provided feedback through a structured questionnaire. Results: Of 15 slides, 6 were successfully scanned using the automated workflow, while 9 required manual adjustments. The manual scan feature allowed successful imaging of sparse or faintly stained specimens, precise exclusion of artifacts, and focus optimization for multi-plane samples such as cell pellet arrays. Users highlighted the feature's intuitive interface and its ability to generate high-quality images for previously unscannable slides. Conclusions: The Aperio Manual Scan software enhances flexibility and precision in whole slide imaging, complementing the automated workflow. It allows researchers to overcome imaging challenges efficiently and is anticipated to benefit research facilities significantly. Citation Format: Erica Pawlak, Shubham Dayal, Elizabeth Sullivan, Jacob Persky, Diane Robirds, Timothy Murphy-Stevens, Duff Pickering. Aperio manual scan software: beta testing for challenging slide imaging in research [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 2465.
Abstract 420: On-target mutations confer resistance to WRN helicase inhibitors in Microsatellite Unstable Cancer Cells
Authors: Gabriele Picco, Yanhua Rao, Angham Al Saedi, Samantha J. Walker, Shriram Bhosle, Yang Lee, Sara F. Vieira, Gilberto Valdes Garcia, Kieron May, Francesco Sassi, Mamta Sharma, Cansu Dincer, Inigo Barrio Hernandez, Theo Bell, Anastasia Kavasakali, Maria Garcia-Casado, Ray Shenje, Cuthbert Martyr, Edward Brnardic, Nanhua Deng, Hristina Grigorova Dimitrova, Emre Karakoc, Emma Hitch, Katrina McCarten, Zoe Hewitson, Howard Lightfoot, Syd Barthorpe, Michael P. DeMartino, Phil Landis, Emanuel Gonçalves, Andrea Bertotti, Livio Trusolino, Geeta Sharma, Matthew A. Coelho, Jonathan Houseley, Benjamin Schwartz, Mathew J. Garnett
Journal: Cancer Research (2025)

Abstract Werner helicase inhibitors (WRNi) are in clinical development for treating patients with microsatellite-unstable (MSI) tumors characterized by defective DNA mismatch repair. Here, we investigate the impact of cancer cell evolutionary adaptation on WRN pharmacological inhibition with implications for understanding drug selectivity and potential clinical resistance. Coupling genome-wide CRISPR screens with WRN gene knockout, no suppressors of WRN dependency were identified, underscoring WRN’s essential non-redundant function in MSI cells. Pharmacogenomic screens pinpointed modulators of WRNi sensitivity, including SMARCAL1, linking it to WRN-MSI synthetic lethality. Semi-saturation mutagenesis of WRN and prolonged drug treatment identified on-target WRN mutations driving acquired resistance to multiple WRNi in vitro and in vivo. Specific resistance mutations induce cross-resistance to WRN inhibitors, whereas others preserve sensitivity to alternative WRNi. Our work guides next-generation strategies for targeting MSI cancers, enabling cross-resistance studies to evaluate current and novel WRNi efficacy and informing future clinical trial design. Citation Format: Gabriele Picco, Yanhua Rao, Angham Al Saedi, Samantha J. Walker, Shriram Bhosle, Yang Lee, Sara F. Vieira, Gilberto Valdes Garcia, Kieron May, Francesco Sassi, Mamta Sharma, Cansu Dincer, Inigo Barrio Hernandez, Theo Bell, Anastasia Kavasakali, Maria Garcia-Casado, Ray Shenje, Cuthbert Martyr, Edward Brnardic, Nanhua Deng, Hristina Grigorova Dimitrova, Emre Karakoc, Emma Hitch, Katrina McCarten, Zoe Hewitson, Howard Lightfoot, Syd Barthorpe, Michael P. DeMartino, Phil Landis, Emanuel Gonçalves, Andrea Bertotti, Livio Trusolino, Geeta Sharma, Matthew A. Coelho, Jonathan Houseley, Benjamin Schwartz, Mathew J. Garnett. On-target mutations confer resistance to WRN helicase inhibitors in Microsatellite Unstable Cancer Cells [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 420.