tbuckley/cabot-search huggingface dataset:
Abstract 6654: Investigating the role of fructose-1,6-bisphosphatase in soft tissue sarcoma
Authors: Bailey Nance, Brian Keith, Celeste Simon
Journal: Cancer Research (2025)

Abstract Glucose metabolism is commonly dysregulated in cancer and other pathological contexts. Fructose-1, 6-bisphosphatase (FBP) is a key rate-limiting gluconeogenic enzyme that converts fructose-1, 6-bisphosphate to fructose-6-phosphate, which produces glucose and glycogen from noncarbohydrate substrates. Two FBP isoforms, FBP1 and FBP2, are differentially expressed in human tissues. FBP1 is expressed in the primary gluconeogenic organs (liver and kidney) to maintain blood glucose levels under fasting conditions. In contrast, FBP2 expression is primarily restricted to striated muscle where it regulates glycogen synthesis. Our recent work demonstrates that both FBP isoforms function as metabolic tumor suppressors and are significantly downregulated in multiple cancers. In sarcoma cells, ectopic FBP2 decreases cytosolic glycolytic flux and FBP2 interacts with nuclear c-Myc to repress transcription of the gene encoding mitochondrial transcription factor A (TFAM), a transcription factor essential for mitochondrial biogenesis. We aim to expand on the roles of FBP2 expression in sarcomas by investigating its binding partners and the role of its catalytic activity in vitro and in vivo. To explore this, we have ectopically expressed wildtype FBP2 and catalytically inactive FBP2-E98A at similar levels to human skeletal muscle in sarcoma cell lines and observed their impacts on proliferation, glucose metabolism, colony formation, invasion, gene expression, and tumor growth. Interestingly, both enzymatically wildtype FBP2 and catalytically inactive FBP2 can suppress proliferation and colony formation in vitro suggesting that FBP2 has additional non-catalytic functions contributing to its repressive role in cancer cells. To explore additional roles of FBP2 outside of its catalytic function, we have developed a FBP2-BioID2 fusion protein and performed immunoprecipitation mass spectrometry to identify novel binding partners of FBP2. Surprisingly, our RNAseq and proteomics data suggest that ectopically expressed wildtype FBP2 may enrich for gene sets and putatively bind with components of the cytoskeleton. Furthermore, to investigate the role of FBP2 loss in sarcomagenesis, we have also utilized autochthonous and injury-induced murine models of undifferentiated pleiomorphic sarcoma with and without Fbp2 loss. We aim to fully characterize these models to elucidate the possible roles of FBP2 in tumor latency, size, and metastasis in sarcoma. Overall, our work will further define the moonlighting roles of FBP2 by elucidating its interactome and the role of FBP2 in coordinating metabolic transitions in sarcomagenesis. Citation Format: Bailey Nance, Brian Keith, Celeste Simon. Investigating the role of fructose-1, 6-bisphosphatase in soft tissue sarcoma [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 6654.
Abstract 3027: Killing two birds with one stone: veratridine functions as a dual inhibitor of both hyperactive mTORC2 and mitochondria in colon cancer cells
Authors: Morgan Eikanger, Khosrow Rezvani
Journal: Cancer Research (2025)

Abstract Despite considerable advances to improve colorectal cancer (CRC) survival over the last decade, therapeutic challenges remain due to the rapid metastatic dissemination of primary tumors. There has been an increase in early-onset CRC (patients under age 50) incidences in all ethnicities. Early-onset CRC introduces another major health challenge as these patients are commonly diagnosed with advanced, metastatic forms of CRC, resulting in higher mortality rates, showing the clear need to develop safer and more effective therapies. There has been significant progress in understanding the tumorigenic pathways responsible for the invasion and metastasis of human CRC. Current evidence indicates that overactive mitochondria and hyperactivation of the Rictor-mTORC2-AKT signaling pathway drive key metastatic players and support the formation and progression of metastatic cells in diverse malignant tumors, including early-onset CRC. Small molecule inhibitors that selectively interfere with these key metastatic pathways have become a primary focus of targeted therapy as they control proteins involved in tumor dissemination without affecting normal cells. Selective mTORC2 inhibitors are becoming a potential optimal treatment strategy for patients with CRC because they eliminate therapeutic limitations and drug resistance reported for mTORC1 and mTORC1/mTORC2 inhibitors. Veratridine (VTD), a lipid-soluble alkaloid extracted from Liliaceae plants, can transcriptionally increase UBXN2A, a ubiquitin-like protein. UBXN2A's E3 ubiquitin ligase partners enable UBXN2A to target dually and selectively induce 26S proteasomal degradation of the following substrates: mitochondrial HSP70 (mortalin) proteins and Rictor in the mTORC2 signaling pathway. This study explains the dual-action molecular mechanisms of the VTD-UBXN2A axis in patient-derived xenograft (PDX) cell lines. Longitudinal analysis of cells after completing real-time cell analysis using xCELLigence technology and generating a 3D spheroid CRC model using PDX cells indicate that VTD can effectively restrict cell migration. Additionally, Seahorse bioenergetic assays showed that VTD reduces mitochondria respiration and glycolysis. These results indicate the dual-targeting efficiency of VTD on metastatic cancer cells. This study opened a new platform for repurposing VTD, a supplemental anti-hypertension molecule, into an effective targeted therapy in CRC tumors. Citation Format: Morgan Eikanger, Khosrow Rezvani. Killing two birds with one stone: veratridine functions as a dual inhibitor of both hyperactive mTORC2 and mitochondria in colon 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 3027.
Abstract 7094: Financial risks in southeast asian patients with cancer
Authors: Nguyen H. Tran, Jordan Mason, Wendy Hanson, Kimberly Steinbert, Minji Lee, Robert McWilliams
Journal: Cancer Research (2025)

Abstract Background: Financial toxicity can have devastating long-term effects for cancer patients (pts) and their family members which may impact their access to care, adherence and, ultimately, outcomes. Identifying those at greatest risk is key to mitigating costs and distress to pts. Here we report results from a screening questionnaire on financial risks among Southeast Asian (SE-A) pts. Methods: This retrospective review included pts on the cancer patient registry at Mayo Clinic (Arizona, Florida, Minnesota, Wisconsin, and Iowa) who had completed a clinical visit in an oncology-related department (hematology, medical oncology, radiation oncology, etc) within the past 270 days prior to 6/4/24. Pts completed an electronic social determinant of health questionnaire of which financial risks and transportation needs are the focus of this study: 1) how hard is it for you to pay for the very basics like food, housing, medical care, and heating? 2) in the past 12 months, has lack of transportation kept you from medical appointments or from getting medications. Our primary endpoints include the association between financial risks, active bad debts (defined as having &amp;gt;$5000 owed for high active bad debt, $0-$5000 for some active bad debt), pre-appointment review (PAR) flag status and transportation needs. Descriptive statistics and Chi-square were used to analyze factors associated with financial risks. Results: We identified 81, 731 pts who completed the questionnaire, among whom 387 were SE-A. Compared to non-SE-A and White, 6.5% have some active bad debt vs 3.3% and 3.6% (p&amp;lt;0.001), and 1.0% had high active bad debt vs 0.8% and 0.7% (p&amp;lt;.001); 58.4% had low financial risk vs 60% and 66% (p&amp;lt;0.001) and 2.3% with high risk vs 1.5% and 1.6% (p&amp;lt;0.001), 4.1% declined to answer and 29.7% were unknown. Bad debt was associated with PAR flag (P &amp;lt;0.001) and financial risk (P&amp;lt;0.001). For transportation among SE-A, 2.3% had unmet transportation needs, 1.8% declined/unable to answer, while 17.8% were unknown. Those with transportation needs were associated with active debt and financial risk (p&amp;lt;0.001). Conclusion: In this cohort, we identified SE-A with highest rates of active debt and higher financial risks compared to Non-SE-A and White. A large percentage of patients declined to answer or are unknown. Future pilot questionnaire is in development to identify pts concerns for medical costs, financial strain and the receptivity to be connected to resources/referrals to address them. Citation Format: Nguyen H. Tran, Jordan Mason, Wendy Hanson, Kimberly Steinbert, Minji Lee, Robert McWilliams. Financial risks in southeast asian patients with 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 7094.
Abstract 7092: The change in Asian American/Native American/Pacific Islander demographics in interventional clinical trials in Hawai'i
Authors: Aiesha Pradhan, Jangsoon Lee, Naoto T. Ueno, Toshiaki Iwase
Journal: Cancer Research (2025)

Abstract Asian Americans, Native Hawaiians, and Pacific Islanders (AA/NH/PI) contribute significantly to the state’s ethnic diversity. Despite their substantial presence, these groups face considerable health disparities, particularly in access to and participation in clinical trials. Furthermore, detailed accrual data based on ethnicity is missing as national datasets often aggregate AA/NH/PI populations into a single racial category. The aim of this study is to investigate change in accrual rates to interventional oncology clinical trials over time and determine the patient demographic factors that caused disparities in the trial participation. Through the Clinical Trial Management System at the University of Hawai'i Cancer Center, we collected patient enrollment data for NCI-funded interventional clinical trials (i.e., National Cancer Trials Network, NCTN and NCI Community Oncology Research Program, NCORP trials) conducted within the Hawai'i Cancer Consortium (HCC) between 2005 and 2020. The HCC is constituted by seven entities, including 2 major healthcare organizations in Hawai'i. The dataset comprised of demographic details such as biological sex, age, and race. Among 2, 341 study participants who were identified by screening, 870 were enrolled in non-therapeutic studies, while 1, 471 were involved in therapeutic trials. Nearly 50% identified as Asian American, 25% as White, and 12% as Native Hawaiian, and 3% as Pacific Islander. The remaining 10% were categorized as Black, American Indian, Multiracial, Other, or Unknown. The number of Asian American participants showed a declining trend until 2014, after which it began to recover. The number of Native Hawaiian and Pacific Islander participants has been stable over this time period. Female participation consistently exceeded male participation over the study period. The annual enrollment of all participants remained low until 2014 but steadily increased, reaching its peak in 2019. This study revealed that local AA/NH/PI accrual has a different trend from the national accrual over time. While the findings suggest that local, continuous community outreach efforts have been effective, male patient accrual remains inequitable. To address this disparity, our center is currently implementing an educational program aimed at Native Hawaiian men to help eliminate mistrust in clinical trial participation. Citation Format: Aiesha Pradhan, Jangsoon Lee, Naoto T. Ueno, Toshiaki Iwase. The change in Asian American/Native American/Pacific Islander demographics in interventional clinical trials in Hawai'i [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 7092.
Abstract 7117: Short-term surgical outcomes for colon adenocarcinoma: Racial-ethnic comparisons in the Military Health System
Authors: Yvonne L. Eaglehouse, Sarah Darmon, Michele M. Gage, Craig D. Shriver, Kangmin Zhu
Journal: Cancer Research (2025)

Abstract Background: Racial-ethnic disparities in receipt of treatment and survival outcomes of colon cancer have been documented in the general U.S. population, with access to care identified as a contributor to the disparities. Less is known about disparities in quality aspects of colon cancer surgery, such as achievement of negative surgical margins, adequate lymphadenectomy, and complication rates. We aimed to study colon cancer surgery and postoperative outcomes in the Military Health System (MHS), which provides access to care regardless of patient demographic or socioeconomic characteristics, to better understand racial-ethnic disparities in surgical oncology care in an equal access setting. Material and Methods: We used the MilCanEpi database to identify patients aged 18 or older who were diagnosed with stage I-III colon adenocarcinoma between 2001 and 2014 and received colectomy as primary surgical treatment. The occurrence of positive surgical margins, inadequate lymphadenectomy (&amp;lt12 nodes examined), 30-day complications (general: surgical site infection, hemorrhage, myocardial infarction, stroke, thrombosis; or gastrointestinal: bowel obstruction or intra-abdominal abscess), and 30-day inpatient admissions were captured. Multivariable logistic regression models estimated the adjusted odds ratios (AORs) and 95% confidence intervals (CIs) in association with race-ethnicity for each outcome. Results: The study included 157 Asian, 257 non-Hispanic Black, 110 Hispanic, and 1115 non-Hispanic White patients. Overall, the frequency of positive margins (7.6%), inadequate lymphadenectomy (28.9%), 30-day complications (33.1%), or 30-day inpatient admissions (14.3%) did not differ significantly between racial-ethnic groups (all AORs and their 95% CIs included 1.00). By complication type (general or gastrointestinal), Hispanic patients had a significantly lower likelihood of bowel obstruction (AOR=0.48, 95% CI=0.25, 0.95) compared to non-Hispanic White patients, with no other statistically significant racial-ethnic differences. Conclusions: In the equal access MHS, there were no overall significant racial-ethnic differences in margins, lymphadenectomy, or 30-day outcomes of colectomy for non-metastatic colon cancer. Our findings highlight the role of access to care in minimizing racial or ethnic disparities in colon cancer surgery and postoperative outcomes in the U.S. Citation Format: Yvonne L. Eaglehouse, Sarah Darmon, Michele M. Gage, Craig D. Shriver, Kangmin Zhu. Short-term surgical outcomes for colon adenocarcinoma: Racial-ethnic comparisons in the Military Health System [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 7117.
Abstract 5390: Metabolic reprogramming and glutamine addiction in squamous cell carcinoma driven by mutant cyclin D1
Authors: Shuyuan Zhang, Polly Phillips-Mason, J. Alan Diehl
Journal: Cancer Research (2025)

Abstract Cyclin D1 overexpression contributes to abnormal cell proliferation and tumor development in multiple cancer types. Cyclin D1 overexpression occurs at the highest frequency in head and neck squamous cell carcinoma (HNSCC). Biological events that trigger cyclin D1 overexpression include CCND1 amplification, mutations that impair cyclin D1 degradation, and inactivation of the SCF E3 ubiquitin ligase, Fbxo4 which controls cyclin D1 degradation. We focused on a mutant, cyclin D1T286A, which blocks the nuclear export of cyclin D1 and its subsequent degradation by the 26S proteasome. Cyclin DT286A expression can drive a variety of cancer types murine models including endometrial and mammary carcinoma as well as B-cell lymphoma. However, the molecular mechanisms whereby cyclin DT286A drives cancer progression remain to be fully identified. Here, we demonstrate that cyclin D1T286A drives metabolic reprogramming in squamous cancer cells resulting in glutamine addiction via activation of CDK4/6. Notably, cyclin D1T286A triggers downregulation of IDH3 contributing to cell glutamine dependency to enforce oxidative carboxylation benefiting both generation of biosynthetic intermediates and ATP. A decrease of NAD+/NADH ratio induced by decreased IDH3 results in cellular ATP imbalance and compromised mitochondria which promote cell death under glutamine restriction. Finally, we demonstrate that cyclin D1T286A cooperates with mutant p53 to promote head and neck squamous tumor development in a genetically engineered mouse model. In conclusion, we have uncovered the novel mechanism whereby that cyclin D1T286A drives metabolic reprogramming and HNSCC and our results highlight the potential for targeting glutamine metabolism in cyclin D1-positive HNSCCs. Citation Format: Shuyuan Zhang, Polly Phillips-Mason, J. Alan Diehl. Metabolic reprogramming and glutamine addiction in squamous cell carcinoma driven by mutant cyclin D1 [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 5390.
Abstract 3936: CDK12 tumor suppressor function and therapeutic targeting in newly developed mouse models of serous ovarian cancer
Authors: Jean Ching-Yi Tien, Yali Zhai, Rong Wu, Yuping Zhang, Yu Chang, Yunhui Cheng, Abigail J. Todd, Christina Wheeler, Shuqin Li, Rahul Mannan, Caleb Cheng, Somnath Somnath Mahapatra, Xuhong Cao, Yuanyuan Qiao, Lanbo Xiao, Marcin Cieslik, Ding Ke, Kathleen R. Cho, Arul M. Chinnaiyan
Journal: Cancer Research (2025)

Abstract Adenocarcinoma of the ovary is the fifth leading cause of cancer death among American women. Most mortality results from high-grade serous ovarian carcinoma (HGS-OvCa)—a disease type resistant to conventional chemotherapy, and therein requiring urgent preclinical modeling for pharmaceutical testing. We generated a novel serous ovarian carcinoma model by employing Ovgp1-driven Cre recombinase to catalyze CRISPR-Cas9-medicated ablation of the Trp53, Rb1 and Nf1 tumor suppressor genes in the mouse ovary (sgPRN mice). The gene encoding cyclin dependent kinase 12 (CDK12) is among the most frequently inactivated in HGS-OvCa. Its loss corresponds with increased mortality, DNA damage (including tandem duplications) and tumor immunogenicity. Co-ablation of Cdk12 in the sgPRN model (“sgPRN-Cdk12KO mice”) accelerated tumor progression leading to bona fide HGS-OvCa, and early mortality. In a conventional (Cre-lox-medicated) Trp53/ Nf1/ Rb1 triple knockout model, Cdk12ablation (“PRN-Cdk12KO mice”) effected immune infiltration characterized by CD3, CD8, CD4, and Granzyme B positivity like that seen in clinical HGS-OvCa. We observed recapitulation of this immunogenic phenotype—with corresponding sensitivity to immune checkpoint blockade—in a novel syngeneic allograft model derived from these animals. To screen for synthetic lethal interactions with Cdk12 loss, we conducted a CRISPR-Cas9 screen in PRN-Cdk12KO cell lines. The gene encoding CDK12 paralog CDK13 emerged as the most depleted, suggesting CDK13 could be targeted to promote paralog-induced synthetic lethality as previously demonstrated in CDK12-mutant prostate cancer. Indeed, sgPRN-Cdk12KO and PRN-Cdk12KO -derived cell lines exhibited enhanced sensitivity to the CDK13/12 degrader YJ1206. Our work defines CDK13-targeting as a novel treatment modality for CDK12-inactive HGS-OvCa while establishing biological resources for the in vivo modeling of this disease. Citation Format: Jean Ching-Yi Tien, Yali Zhai, Rong Wu, Yuping Zhang, Yu Chang, Yunhui Cheng, Abigail J. Todd, Christina Wheeler, Shuqin Li, Rahul Mannan, Caleb Cheng, Somnath Somnath Mahapatra, Xuhong Cao, Yuanyuan Qiao, Lanbo Xiao, Marcin Cieslik, Ding Ke, Kathleen R. Cho, Arul M. Chinnaiyan. CDK12 tumor suppressor function and therapeutic targeting in newly developed mouse models of serous ovarian 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 3936.
Abstract 111: Detection of clonal hematopoietic APOBEC3-mediated splicing deregulation
Authors: Inge van der Werf, Jane Isquith, Emma Klacking, Jessica Pham, Thomas Whisenant, Ludmil Alexandrov, Catriona Jamieson
Journal: Cancer Research (2025)

Abstract Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell (HSC)-derived disorders that often arise as a result of JAK2/STAT3 signal activating mutations. In the setting of microenvironmental inflammatory cytokines, MPNs also acquire splicing alterations that are associated with progression to rapidly lethal secondary acute myeloid leukemia (sAML) (reviewed in Jamieson, Weisman. NEJM. 2023). By performing whole genome and RNA sequencing analyses of MPN hematopoietic stem and progenitor populations (HSPCs), we discovered that inflammatory cytokine inducible APOBEC3C upregulation was associated with IL6ST and ADAR1p150 splice isoform overexpressing progenitor proliferation and progression to sAML (Jiang⋯Jamieson. Cell Reports. 2021). Thus, we sought to investigate the role of APOBEC3 activation as a driver of clonal hematopoietic progenitor splicing deregulation and propagation. We cloned human APOBEC3 family genes into pCDH lentiviral vectors and transduced cord blood derived immunomagnetic bead selected CD34+ cells with APOBEC3A, B, C, D, G or H, or pCDH lentiviral backbone controls for whole genome and whole transcriptome analyses. Additionally, CD34+ cells derived from aged normal bone marrow (ABM), collected according to IRB approved protocols, were transduced with APOBEC3C for whole genome and whole transcriptome analyses, coupled with functional assays to assess the effects of APOBEC3 overexpression on RNA splicing and editing deregulation. Following lentiviral APOBEC3B, APOBEC3C, and APOBEC3G transduction of CD34+ cells, gene set enrichment analysis (GSEA) revealed splicing pathway alterations. Significantly altered APOBEC3-responsive pathways involved genes crucial for hematopoiesis, including ZRSR2, U2AF1, and SRSF2. Additional analysis of RNA sequencing data of CD34+ HSPCs derived from aged normal bone marrow overexpressing APOBEC3C, and CD34+ HSPCs derived from MPNs further confirmed these splicing pathway alterations and revealed a correlation with APOBEC expression levels. Moreover, we observed that lentiviral APOBEC3C wild-type overexpression in ABM-derived CD34+ cells resulted in differential exon usage using splicing reporter assays. Together, these results suggest that detection of APOBEC3-mediated splicing deregulation may inform the development of diagnostic and therapeutic strategies aimed at preventing splicing-mediated MPN progression. Citation Format: Inge van der Werf, Jane Isquith, Emma Klacking, Jessica Pham, Thomas Whisenant, Ludmil Alexandrov, Catriona Jamieson. Detection of clonal hematopoietic APOBEC3-mediated splicing deregulation [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 111.