tbuckley/cabot-search huggingface dataset:
Abstract 5142: Role of UCA1 in Warburg effect during anoikis resistance in colorectal carcinoma
Authors: Ricardo Pequeno Bracho, Salique H. Shaham, Yamile Abuchard Anaya, Sophia Leslie, Kyle Doxtater, Bilal B. Hafeez, Tamer Oraby, Subhash C. Chauhan, Manish K. Tripathi
Journal: Cancer Research (2025)

Abstract Colorectal carcinoma (CRC) remains the second leading cause of cancer-related deaths in the United States. The survival rate for CRC patients drops precipitously from 90% for localized disease to only 14% upon metastasis. Approximately, 40-50% of CRC cases progress to metastasis, a multifaceted process requiring the acquisition of anoikis resistance as one of the critical steps. This anoikis or anchorage-independent resistance enables cancer cells to survive detachment from the extracellular matrix, migrate through vascular and lymphatic systems, and establish secondary tumor sites. A deeper understanding of the molecular mechanisms underlying anoikis resistance, particularly in the context glucose metabolism, is crucial for advancing therapeutic strategies in CRC metastasis. Cancer cells frequently exhibit the Warburg Effect, a metabolic adaptation characterized by preferential glycolysis over oxidative phosphorylation, even under normoxic conditions. This metabolic reprogramming supports proliferation and may promote survival under anchorage-independent conditions. Our preliminary data suggests that the long non-coding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1), which is overexpressed in CRC and correlates with poor prognosis, may play a pivotal role in metastasis and glucose metabolism. Utilizing isogenic a CRC cell line model SW480 (primary tumor-derived) and SW620 (metastasis-derived), we have developed stable UCA1-overexpressing (SW480+UCA1) and UCA1-knockdown (SW620+shUCA1) experimental models. In vitro characterization of the cell lines via phenotypic assays showing invasion, migration, and cell proliferation by xcelligence and colony formation to be enhanced through UCA1 overexpression and reduced by its knockdown. Furthermore, our data indicates that UCA1 overexpression enhances glucose uptake, lactate production, and anchorage-independent survival, suggesting its involvement in promoting anoikis resistance through metabolic reprogramming. Moreover, these cell lines will be subjected to anchorage-independent growth conditions to assess alterations in cell cycle, pro-survival, and stemness-related markers. Furthermore, glucose metabolism will be evaluated using Seahorse XFp metabolic analysis parameters. Citation Format: Ricardo Pequeno Bracho, Salique H. Shaham, Yamile Abuchard Anaya, Sophia Leslie, Kyle Doxtater, Bilal B. Hafeez, Tamer Oraby, Subhash C. Chauhan, Manish K. Tripathi. Role of UCA1 in Warburg effect during anoikis resistance in colorectal 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 5142.
Abstract 4369: Preclinical characterization of a dual-state pan-KRAS Inhibitor
Authors: Kevin Gaida, Tao Osgood, Ying-Chu Chen, Deanna Mohn, Anne Y. Saiki, Gilbert Diaz, Monica Leavitt, Upendra Dahal, Amit Vaish, Jason DeVoss, Karen Rex, Ryan Wurz, Brian A. Lanman, Paul E. Hughes, Rati Verma
Journal: Cancer Research (2025)

Abstract Activating mutations in KRAS occur in greater than twenty percent of all cancers encompassing several solid tumors with significant unmet medical need, including lung, colon, pancreatic, endometrial and stomach cancers. While mutations of codon 12 of KRAS (encoding glycine) are the most common, activating missense mutations are also observed at codons 13 and 61. Guided by our experience in the successful development of the covalent KRAS G12C mutant-selective inhibitor, sotorasib, we leveraged structure-based design to identify a new class of reversible, pan-KRAS inhibitors capable of targeting an expanded set of hot spot mutations prevalent in the above tumor types (e.g., KRAS G12D, G12V, G13D and Q61H). These reversible inhibitors potently inhibit both the GDP(OFF)- and GTP(ON)-states of KRAS while sparing H/NRAS. Dual ON/OFF-state activity facilitates the inhibition of mutant alleles that rapidly cycle between ON and OFF states (e.g., KRAS G12C) as well as those demonstrating slower cycling (e.g., KRAS G12V &amp; KRAS Q61H), which predominantly reside in the GTP-bound state. Mechanistically, these inhibitors block the interaction of KRAS with its downstream effectors, such as c-RAF, and potently inhibit ERK phosphorylation. In vivo profiling demonstrated promising preclinical efficacy in KRAS G12D and KRAS G12V xenograft models, and good tolerability, illustrating the potential of pan-KRAS inhibitors to extend therapeutic benefit to tumors beyond those with KRAS G12C mutations. Citation Format: Kevin Gaida, Tao Osgood, Ying-Chu Chen, Deanna Mohn, Anne Y. Saiki, Gilbert Diaz, Monica Leavitt, Upendra Dahal, Amit Vaish, Jason DeVoss, Karen Rex, Ryan Wurz, Brian A. Lanman, Paul E. Hughes, Rati Verma. Preclinical characterization of a dual-state pan-KRAS Inhibitor [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 4369.
Abstract 5155: A novel lipid nanoparticle for delivering sgRNA and mRNA to develop lung cancer model mice
Authors: Bingxin Liu, Yutaka Maeda
Journal: Cancer Research (2025)

Abstract Background: Genetically engineered mouse models (GEMMs) that develop autochthonous lung tumors are suitable to study lung tumor initiation and the tumor microenvironment involved in immune cells. However, GEMMs require lengthy mouse breeding with multiple crossing of genetic lines to develop mice carrying multiple alleles of specific genes. A more convenient approach to develop these GEMMs will facilitate lung cancer research. Methods: We have recently developed a novel lipid nanoparticle PEG-PBAE/4A3-SC8/DOPE/Cholesterol/DOTAP (hereafter, LNP) that can deliver mRNA into lung epithelial cells in mice by intratracheal (IT) injection (Liu et al., bioRxiv 2024; https://doi.org/10.1101/2024.08.22.608643). Using this LNP, we delivered different sgRNAs and/or Cre mRNA into Cas9 mice that constitutively express Cas9 (or KrasLSL-G12D/+;Cas9 mice) by IT injection and sought to develop lung cancer model mice. Results: The LNP delivery of sgRNAs targeting Eml4 (sgEml4) and Alk (sgAlk) into Cas9 mice produced autochthonous lung tumors induced by the driver oncogene EML4-ALK two months after IT injection. The LNP delivery of Cre mRNA along with sgRNA targeting the lung lineage transcription factor Nkx2-1 (sgNkx2-1) into KrasLSL-G12D/+; Cas9 mice produced autochthonous invasive mucinous adenocarcinomas of the lung (IMA) that carry KrasG12D with loss of NKX2-1 and de novo expression of the gastrointestinal transcription factor HNF4A while the LNP delivery of only Cre mRNA into KrasLSL-G12D/+; Cas9 mice produced autochthonous non-mucinous adenoma/adenocarcinoma two months after IT injection. Conclusion: Delivery of our novel LNPs encapsulating sgRNAs and/or Cre mRNA into Cas9 or KrasLSL-G12D/+;Cas9 mice by IT injection successfully resulted in producing autochthonous lung tumors driven by EML4-ALK or KRASG12D similar to traditional GEMMs. This approach using our LNPs will allow for agile development of lung cancer mouse models for investigating novel lung cancer therapeutics. Citation Format: Bingxin Liu, Yutaka Maeda. A novel lipid nanoparticle for delivering sgRNA and mRNA to develop lung cancer model mice [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 5155.
Abstract 1349: Single-cell transcriptomic architecture deciphering the complexity of tumor microenvironment in ampulla of Vater carcinoma
Authors: Hyemin Kim, Young Hoon Choi, Hyoung-oh Jeong, So Jeong Yoon, Yo Han Jeon, Hongbeom Kim, Sang Hyun Shin, Jin Seok Heo, In Woong Han, Kee-Taek Jang, Se-Hoon Lee, Kwang Hyuck Lee, Kyu Taek Lee, Jong Kyun Lee, Semin Lee, Joo Kyung Park
Journal: Cancer Research (2025)

Abstract Background: Ampulla of Vater carcinoma (AVC) is a rare gastrointestinal tumor that is associated with a high mortality rate and it’s often diagnosed at later stages due to lack of clinical symptoms. Elucidating complex ecosystems and molecular features of AVC is pivotal to proactive cancer prevention and optimal therapeutic intervention. Methods: We performed single-cell RNA sequencing (scRNA-seq) of treatment-naïve AVC biopsies (N=8), and bulk RNA sequencing of surgically resected tissues (N=62) to investigate the transcriptomic signature in tumor microenvironment (TME) of AVC. Results: We analyzed the single-cell transcriptome of 34, 672 cells and epithelial cells were classified into 4 subtypes by consensus non-negative matrix factorization (cNMF) based on their gene expression profiles. Among them, the KRAShigh subtype showed more increased copy number variation than other subtypes and was less differentiated with a high stemness score. Moreover, the KRAShigh subtype was reversely related to overall survival (OS) and enriched with granzyme K+ CD8 T cells. Deconvolution of bulk RNA-seq data validated the poor OS and progression-free survival (PFS) in the AVC patients with the KRAShigh subtype. Also, it was revealed that this subtype was associated with early tumor recurrence in AVC. Conclusions: We understood the heterogenous TME of AVC and found the prognostic biomarker to predict postoperative recurrence and survival in AVC. Citation Format: Hyemin Kim, Young Hoon Choi, Hyoung-oh Jeong, So Jeong Yoon, Yo Han Jeon, Hongbeom Kim, Sang Hyun Shin, Jin Seok Heo, In Woong Han, Kee-Taek Jang, Se-Hoon Lee, Kwang Hyuck Lee, Kyu Taek Lee, Jong Kyun Lee, Semin Lee, Joo Kyung Park. Single-cell transcriptomic architecture deciphering the complexity of tumor microenvironment in ampulla of Vater 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 1349.
Abstract 5141: ADAR1 maintains cancer stem cell proliferation in a mouse model of TNBC-derived breast cancer brain metastases
Authors: Teresa Sposito, Emma Klacking, Jessica Pham, Roman Sasik, Inge van der Werf, Najla Kfoury-Beaumont, Alexander Khalessi, Thomas Whisenant, Catriona Jamieson
Journal: Cancer Research (2025)

Abstract Background: Essential for preventing autoinflammation, adenosine deaminase acting on double-stranded RNA (ADAR1) is also a recognized driver of epi-transcriptomic remodeling and tumor immune silencing. High levels of ADAR1 have been associated with a worse prognosis and reduced survival in patients with high-grade breast cancer (BC), especially in the HER2+ and triple-negative BC (TNBC) subgroup, which are the most likely to develop brain metastasis (BrM), arising in up to 30% of TNBC and HER2+ cases. Nevertheless, the role of ADAR1 in the metastatic context is only partially understood. We have hypothesized that ADAR1 activation and upregulation of the p150 isoform play a pivotal role in promoting BC-BrM invasion by maintaining BC stem cell metastatic niches. We focused on the brain, one of the most aggressive and less studied metastatic sites. Methods: We developed a BC-BrM model based on intracerebroventricular implants of MDA-MD-231 TNBC and primary BC-BrM patient cells in Rag2-/-γc-/- mice. Before implantation, tumor cells were transduced with a nanoluc-GFP reporter for tracing ADAR1 enzymatic activity in the brain niche, or shRNA vectors for ADAR1 down regulation studies. Results: Upon establishment of BrM, scRNA sequencing and qRT-PCR revealed that ADAR1 p150 was upregulated, alongside WNT/β-Catenin pathway activation, a switch in the CD47 isoforms, and extra cellular matrix remodeling. Preliminary results from FFPE imaging of patient samples further suggested a correlation between ADAR1 and WNT/β-Catenin activation, showing that high levels of ADAR1 are associated with nuclear translocation of β-Catenin. Additionally, sc-RNA sequencing of ADAR1 knocked-down TNBC-derived BrM compared to scrambled controls, identified a cluster with increased protein stress and arrest of growth-related processes, predominantly represented by the ADAR1 KD cells. These findings suggest that ADAR1 is essential for maintaining cancer cell proliferation in the brain. Future Directions: We are now further validating the role of ADAR1 and its molecular interactors in maintaining the metastatic brain niche through scRNA-sequencing of BC-BrM patient samples collected from UCSD hospitals. Overall, this study provides new insights into the molecular role of ADAR1 deaminase activity in establishing and maintaining metastatic niches. Citation Format: Teresa Sposito, Emma Klacking, Jessica Pham, Roman Sasik, Inge van der Werf, Najla Kfoury-Beaumont, Alexander Khalessi, Thomas Whisenant, Catriona Jamieson. ADAR1 maintains cancer stem cell proliferation in a mouse model of TNBC-derived breast cancer brain metastases [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 5141.
Abstract 1413: Dissecting the biology of mutant p53 with the Cellular Thermal Shift Assay (CETSA)
Authors: Tomas Friman, Merve Kacal, Laurence Arnold, Daniel Martinez Molina
Journal: Cancer Research (2025)

The tumor suppressor protein p53 is one of the most important safeguards against malignant transformation of mammalian cells, but it is also one of the most frequently mutated proteins in cancers. Therefore, p53 constitutes an attractive drug target in oncology. However, there has been little success in finding clinical candidate drugs that directly manipulate the function of p53. The p53 protein offers several challenges for investigators wanting to manipulate its function e.g., the absence of accessible binding pockets, lack of enzymatic activity, and its intracellular location. Moreover, another complication with p53 is the plethora of mutations that alter the protein’s characteristics. Most mutational changes in p53 result in a loss of function, but there are also examples of gain of function mutations in p53. We have applied the Cellular Thermal Shift Assay (CETSA) for screening of new chemical hit matter for binding to p53. As CETSA exploits the compound induced changes in protein melting behavior it is important to know the melting characteristics of the protein under investigation. Since p53 displays a wide variety of mutational variants, we decided to investigate three different variants present in three separate breast cancer cell lines: SK-BR-3 (p53R175H), BT-474 (p53E285K), and MCF-7 (p53WT). The melting behavior of p53 protein was similar irrespective of genomic status of p53 in intact cells. However, in lysed cells there was striking difference in p53 protein melting between MCF-7 cells that carry WT p53 and the two other breast cancer cell lines that carry mutations in the gene coding p53. The melting temperature for WT p53 was nearly the same in both lysate and intact cells, whereas there was 3 to 4°C difference between intact cells and lysates derived from the two cell lines that expressed mutated p53. Both of the mutated forms of p53 found in SK-BR-3 cells and BT-474 cells displayed greater thermal stability in lysate compared to MCF-7. Intrigued by this difference we set out to investigate its cause. It is known that certain mutated forms of p53 are rescued from proteasomal degradation by associating with chaperone proteins like Hsp90. Therefore, the different breast cancer cell lines were treated with inhibitors of Hsp90 function and protein melting of the respective form of p53 was assessed. Hsp90 modulation by Geldanamycin had a much more potent effect on thermal stability of mutant p53 compared to the WT counterpart, which indicates that Hsp90 could be involved in conferring increased thermal stability of mutant p53. Citation Format: Tomas Friman, Merve Kacal, Laurence Arnold, Daniel Martinez Molina. Dissecting the biology of mutant p53 with the Cellular Thermal Shift Assay (CETSA) [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 1413.
Abstract 4370: Synthetic cell penetrating RAS-binding peptide for the treatment of RAS mutated cancer
Authors: Gookjin Yoon, Beom Soo Jo, Dong Woo Lee, Moonsil Choi, Eui Kyun Jeong, Hoo Cheol Lee, Yu-Bin Kim, Sanghui Seok, Yoon Shin Park, Jue-Yeon Lee, Chong Pyung Chung, Yoon Jeong Park
Journal: Cancer Research (2025)

Abstract The RAS-RAF-ERK1/2 signaling pathway plays a critical role in cancer progression and is a primary target for anticancer drug development, given its frequent activation in various human cancers. MAPK, a key molecule within this pathway, is vital for eukaryotic cells to process external stimuli, leading to cancer cell proliferation. The MDA-MB-231 cell line, which represents triple-negative breast cancer, carries a G13D KRAS mutation, rendering it resistant to numerous treatments. This mutation drives abnormal MAPK pathway activation, fueling tumor progression. To address this, a synthetic cell-penetrating peptide called RAS-binding peptide (RBP) was designed to selectively bind RAS with high affinity in MDA-MB-231 cells. Experimental results revealed that RBP effectively inhibited RAS-RAF interaction, leading to reduced cell proliferation and suppression of ERK1/2 phosphorylation in MDA-MB-231 cells. Additionally, RBP significantly decreased cell migration and invasion, indicating potential anti-metastatic properties. In both chicken egg and mouse xenograft models, RBP treatment markedly inhibited tumor growth and metastasis. Histopathological analysis further demonstrated enhanced immune cell infiltration, while immunohistochemistry confirmed reduced expression of Ki-67, a marker for tumor cell proliferation. Collectively, these findings highlight RBP as a promising therapeutic candidate for targeting RAS-driven cancer by inhibiting tumor growth and metastasis. Citation Format: Gookjin Yoon, Beom Soo Jo, Dong Woo Lee, Moonsil Choi, Eui Kyun Jeong, Hoo Cheol Lee, Yu-Bin Kim, Sanghui Seok, Yoon Shin Park, Jue-Yeon Lee, Chong Pyung Chung, Yoon Jeong Park. Synthetic cell penetrating RAS-binding peptide for the treatment of RAS mutated 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 4370.
Medicaid Accountable Care Organization Implementation and Perinatal Claims Documentation of Social Risk Factors
Authors: Kevin H. Nguyen, Sarah H. Gordon, Kenneth Lim, Kathryn D. Thompson, Collette N. Ncube, Megan B. Cole
Journal: JAMA Network Open (2025)

Importance Addressing social risk factors (eg, food insecurity) during the perinatal period has the potential to improve pregnancy-related outcomes. While social risk factor diagnosis codes (ie, International Statistical Classification of Diseases, Tenth Revision, Z codes) were introduced in 2016, adoption in claims has been slow. In 2018, Massachusetts’ Medicaid program implemented an accountable care organization (ACO) model, including a requirement that all ACOs screen for social risks. Objective To assess claims documentation of Z codes in the perinatal period for Medicaid enrollees and evaluate changes in documentation following implementation of Massachusetts’ Medicaid ACO program. Design, Setting, and Participants This cross-sectional study used the Massachusetts All-Payer Claims Database to identify all Medicaid-enrolled live deliveries between January 31, 2016, and December 31, 2020, among people 18 years or older. A difference-in-differences (DiD) approach was used to compare Z code documentation before (2016-2017) vs after (2018-2020) ACO implementation for Medicaid ACO vs non-ACO deliveries. Data were analyzed between August 23, 2024, and January 27, 2025. Exposures Attribution to a Medicaid ACO (vs non-ACO), determined based on whether an enrollee’s primary care physician participated in an ACO. Main Outcomes and Measures The primary outcome was claims documentation of any Z code, measured separately for the prenatal period, 60 days post partum, 12 months post partum, and the full perinatal period. Secondary outcomes included documentation of specific Z codes (eg, housing, food insecurity). Results The study sample included 79 293 deliveries (mean [SD] age of Medicaid-enrolled pregnant people, 28.2 [5.7] years), of which 69 535 (87.7%) were in a Medicaid ACO. Among all Medicaid deliveries from 2016 to 2020, 4.45% had claims documentation of a Z code in the prenatal period; 1.14%, within 60 days post partum; and 3.31%, within 12 months post partum. Within the prenatal period, Medicaid ACO implementation was associated with statistically significant increases in documentation of any Z code (DiD, 1.09 [95% CI, 0.38-1.80] percentage points [PP]), housing or economic circumstances codes (DiD, 1.52 [95% CI, 1.07-1.97] PP), and food insecurity codes (DiD, 0.58 [95% CI, 0.42-0.73] PP). The Medicaid ACO was associated with few changes in Z code documentation in the postpartum period. Conclusions and Relevance In this cross-sectional study of Medicaid-enrolled live births in Massachusetts, ACO implementation was associated with increased claims documentation of Z codes during the perinatal period, driven by increases in the prenatal period. While Z code documentation remains low, implementation of care delivery models that incentivize screening and documentation of social risk factors among Medicaid enrollees may help to identify the care needs of pregnant and postpartum people.