tbuckley/cabot-search huggingface dataset:
Abstract 5796: Inhibition of oxidative phosphorylation leads to immunogenic cell death in ovarian cancer
Authors: Mayra A. Betancourt Ponce, Nicha Boonpattrawong, Alex J. Fagan, Manish Patankar, Lisa Barroilhet
Journal: Cancer Research (2025)

Abstract Developing new therapies that are effective against localized and disseminated epithelial ovarian cancer (EOC) is imperative. Oxidative phosphorylation (OXPHOS) has been linked to chemoresistance and stemness in EOC, making it an interesting treatment target for this disease. Our laboratory has previously demonstrated that the OXPHOS inhibitor atovaquone has antitumorigenic effects against EOC. However, the precise mechanisms underlying these effects have not been fully elucidated. We adopted an RNA sequencing approach to characterize the transcriptional changes induced by atovaquone in EOC cells. Our findings revealed that atovaquone not only disrupts pathways associated with cellular homeostasis and metabolism but also activates stress responses and primes immune recognition. We show that atovaquone leads to the activation of the Protein Kinase RNA-Like ER Kinase (PERK) branch of the ER stress response, which has been linked to immunogenic cell death. During ER stress, the ER protein calreticulin is translocated to the plasma membrane where it functions as a Damage-Associated Molecular Pattern (DAMP). DAMPs are intracellular molecules that have been translocated to the plasma membrane or released into the extracellular environment where they activate a cascade of immune responses. Our findings suggest that calreticulin is upregulated in the plasma membrane of EOC cells treated with atovaquone. In parallel, we also found an increase of other DAMPs, including High Mobility Group Box 1 (HMGB1) and Mitochondrial Transcription Factor A (TFAM), in the supernatant of atovaquone-treated cells, suggesting that these injured cells are releasing immunogenic molecules. Moreover, we demonstrate that natural killer cells co-cultured with atovaquone-treated EOC cells have increased activity when compared to those co-cultured with vehicle-treated EOC cells. Altogether, we show that the disruption of the OXPHOS converges with the activation of ER stress to promote immunogenic cell death and activate innate immune responses. Atovaquone’s potential to boost cellular immunotherapies opens a new avenue for its use as a combination agent for the treatment of EOC. Citation Format: Mayra A. Betancourt Ponce, Nicha Boonpattrawong, Alex J. Fagan, Manish Patankar, Lisa Barroilhet. Inhibition of oxidative phosphorylation leads to immunogenic cell death in 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 5796.
Abstract 4492: Covalent ligands that selectively disrupt CDK4-CDC37/HSP90 interactions in cancer cells
Authors: Zachary Eugene Potter, Bruno Melillo, Kristen E. DeMeester, Benjamin F. Cravatt
Journal: Cancer Research (2025)

The Heat-Shock family of Proteins (HSPs)—which are conserved in prokaryotic and eukaryotic organisms—are molecular chaperones that regulate protein folding and stability, and in turn cellular homeostasis. In human cancers and hematological malignancies, HSPs are often upregulated. Additionally, many oncogenic proteins are HSP90 client proteins. Thus, decades of research have focused on inhibiting HSP90’s function as a potential anti-cancer therapeutic strategy. However, the clinical application of HSP90 inhibitors has been hampered by dose-limiting toxicity due to the systemic disruption and subsequent dysregulation of HSP90 client proteins. Hence, the selective targeting of individual cancer-relevant client:chaperone interactions could represent a more tractable therapeutic strategy. Using activity-based protein profiling (ABPP), we have identified a stereoselective and site-specific covalent liganding event at an isotype-restricted cysteine on CDK4 located in proximity to the interface for binding the HSP90 co-chaperone CDC37. Alterations to the CDK4/CDK6/Rb signaling pathway are common in almost all tumors, and typically arise via the overexpression of CCND1, or loss of the CDK4/CDK6-specific inhibitor p16INK4a—either event increases CDK4/CDK6 activity and leads to uncontrolled cell proliferation. Importantly, CDK4 stability is highly dependent on interactions with CDC37 and HSP90. We show that the covalent ligands selectively disrupt the CDK4:CDC37:HSP90 chaperone complex while sparing other kinase:CDC37:HSP90 interactions; the selective disruption of this chaperone complex leads to the partial degradation of CDK4 in breast cancer cells. The ligand-induced disruption of CDK4-chaperone interactions and CDK4 stability are both stereoselective (not observed with an inactive enantiomeric compound) and site-specific (not observed with a C135S mutant CDK4 protein). Given CDK4’s validated role in regulating the growth of hormone-sensitive cancer cells, compounds that can selectively disrupt chaperone regulation and stability of this kinase may have therapeutic potential as precision medicines. Citation Format: Zachary Eugene Potter, Bruno Melillo, Kristen E. DeMeester, Benjamin F. Cravatt. Covalent ligands that selectively disrupt CDK4-CDC37/HSP90 interactions in 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 4492.
Abstract 6322: Lipid-soluble vitamin B1 derivatives prevent pancreatic cancer growth and migration
Authors: Nathan Kobus, Nancy Kaushal, Kota V. Ramana
Journal: Cancer Research (2025)

Abstract Pancreatic adenocarcinoma is a lethal type of cancer often diagnosed in the end stages, commonly leading to metastasis. Surgical resection and chemotherapy are not well curative, leading patients to seek alternative therapies via clinical trials. Lipid-soluble derivatives of thiamine, Benfotiamine (Ben), and Fursultiamine (FS) exhibit antioxidative and anti-inflammatory properties. However, their chemo-preventive efficacy is not well known. Therefore, we examined their chemo-preventive potential in pancreatic cancer cells. Human Pancreatic adenocarcinoma (MIA PaCa-2) and metastatic pancreatic adenocarcinoma (BxPC-3) cell lines were incubated for 24 h with varying concentrations (0-100 uM) of Ben and FS. Cell viability was determined by MTT assay. Our results indicate that both Ben and FS prevented the growth of MIA-PaCa2 and BxPC-3 cells in a time- and dose-dependent manner. Ben and FS treatments also increased the expression of caspase-3 and prevented the invasion and trans-well migration of pancreatic cancer cells. Further, human apoptosis array analysis indicates that Ben regulated the expression of various pro-apoptotic factors such as BAD and Bax and anti-apoptotic factors such as Bcl-xL and Bcl-2 in MIA PaCA-2 cells. In addition, human oncology array analysis indicates that Ben regulated the expression of various carcinogenic proteins such as amphiregulin, cathepsin D, HIF-1alpha, osteopontin, p27, and Kallikrein. Next, we planned to examine the in-vivo chemo-preventive efficacy of Ben using nude mice xenografts. So far, our data suggests that treatment with vitamin B1 derivatives is effective against pancreatic cancer cell growth in culture. Citation Format: Nathan Kobus, Nancy Kaushal, Kota V. Ramana. Lipid-soluble vitamin B1 derivatives prevent pancreatic cancer growth and migration [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 6322.
Abstract 4495: Inhibition of OTUD4/CD73 proteolytic axis by novel small molecule inhibitor ST80 reinvigorates tumor immune response
Authors: Kevin Li, Yueming Zhu, Yong Wan
Journal: Cancer Research (2025)

Despite the widespread utilization of immunotherapy, the poor clinical response by immune-suppressive tumors is an emerging challenge in the use of current immune checkpoint inhibitors. Recent research has revealed that CD73, or Ecto-5′-nucleotidase, is an enzyme overexpressed in many cancers, and works in concert with CD39 to produce immunosuppressive extracellular adenosine, subsequently inhibiting CD8+ T cell responses. Our multi-omics analysis identified CD73 and OTUD4, a deubiquitinase that stabilizes CD73 by counteracting its that counteracts its E3 ligase-mediated ubiquitination and degradation, as potential targets for enhancing anti-cancer immune responses. Using druggability and pharmacophore simulations, we developed ST80, a novel small molecule inhibitor that disrupts the OTUD4-CD73 interaction by binding to the hydrophobic OTUD4 binding site on CD73. Within in vitro models of triple-negative breast cancer, EGFR-mutant lung cancer, ovarian cancer, and colorectal cancer, ST80 demonstrates significant potential in overcoming immune evasion by reducing adenosine production in the tumor microenvironment, subsequently reinvigorating the tumor immune responses by enhancing CD8+ T cell proliferation and IFN-γ production. By targeting the CD73/OTUD4 proteolytic axis, ST80 presents a promising strategy for treating cancers with immune-suppressive properties, potentially enhancing the efficacy of current immunotherapies. Citation Format: Kevin Li, Yueming Zhu, Yong Wan. Inhibition of OTUD4/CD73 proteolytic axis by novel small molecule inhibitor ST80 reinvigorates tumor immune response [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 4495.
Abstract 2744: Interrogating the functional roles of differential CTCF-binding sites in IDH-mutant gliomas using a novel CRISPR library
Authors: Ebru Yilmaz, Alisan Kayabolen, Dogancan Ozturan, Tahsin E. Tekoglu, Ester Calvo Fernández, Sedef Sarac Yalcinkaya, Nathan A. Lack, Mario L. Suvà, Tugba Bagci Onder
Journal: Cancer Research (2025)

Abstract Isocitrate dehydrogenase (IDH) mutations are frequently observed in gliomas, and their mutation status is accepted as a CNS tumor classification marker. IDHs are enzymes that convert isocitrate into alpha-ketoglutarate (α-KG). Mutations in IDHs cause neomorphic enzymatic activity, by which D-2-hydroxyglutarate (2- HG), the oncometabolite, is produced from α-KG. This leads to the inhibition of α-KG-dependent enzymes, such as DNA and histone demethylases, thus altering chromatin structure and gene expression profile. CTCF is a methylation-sensitive structural protein that recognizes specific DNA motifs. It dimerizes, together with cohesin, forms chromatin loops, and determines the boundaries of topologically associated domains. Previous work demonstrated that IDH-mutant gliomas have hypermethylation at CTCF-binding sites, leading to reduced CTCF binding and permitting a constitutive enhancer to interact aberrantly with a glioma oncogene. Despite the unique epigenetic features of IDH-mutant gliomas and the ever-increasing importance of IDH mutation in patient prognosis, there has been no comprehensive study on the functional roles of CTCF binding sites in these tumors.We reanalyzed publicly available CTCF ChIP-seq data of three IDH-wild type (wt) and three IDH-mutant glioma cell lines, determined differential CTCF ChIP-seq regions, and aimed to explore their functional roles in glioma survival. To investigate the effect of methylation and demethylation of a specific CTCF binding site in both IDH-wt and -mutant gliomas, we developed a novel paired gRNA library targeting the left and right sides of these differential regions, which consists of 899 paired gRNAs. The CRISPR droplet screens are being conducted using dCas9-fused DNMT3A&amp;3 and TET1 effector proteins, causing DNA methylation and demethylation, respectively. Beyond the alterations of gRNAs in the population, the single-cell transcriptomic readout will be obtained at the end of the screen.Our library design offers advantages over available libraries as it can be utilized with different CRISPR approaches. This high-throughput epigenome editing approach will allow for identifying regulatory interactions leading to tumor cell survival in IDH-wild type and -mutant gliomas. Citation Format: Ebru Yilmaz, Alisan Kayabolen, Dogancan Ozturan, Tahsin E. Tekoglu, Ester Calvo Fernández, Sedef Sarac Yalcinkaya, Nathan A. Lack, Mario L. Suvà, Tugba Bagci Onder. Interrogating the functional roles of differential CTCF-binding sites in IDH-mutant gliomas using a novel CRISPR library [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 2744.
Abstract 4514: The impact of Project Optimus and FDA guidance on study design of early-phase clinical trials
Authors: Deepak Bhamidipati, Suzanne Jones, David Spigel, Gerald Falchook, Manish Patel, Howard Burris, Vivek Subbiah
Journal: Cancer Research (2025)

Abstract Methods: All early phase protocols activated at Sarah Cannon Research Institute between 2021-2023 were reviewed (n=286 protocols). Information such as class of therapy, study design, and dose optimization plan (if applicable) were extracted from review of each protocol. Fisher’s exact test was used to compare proportions across categories and a p-value &amp;lt;0.05 was considered statistically significant. Results: 268 unique protocols including 215 first in human trials (80%) were initiated with 179 different sponsors between 2021 and 2023. Trial classification by mechanism of action included 114 targeted therapies (43%), 109 immunotherapies (41%), 29 antibody drug conjugates (11%), 12 Immune effector cellular therapies (4%), and 4 chemotherapies (1%). Most trials employed a Bayesian dose escalation design (53%) versus rule-based (3+3), and this did not vary significantly year-over-year. 32% of trials (N=86) had a dose optimization plan. 47 trials (18%) included a dose optimization plan with randomization while 39 trials (14%) discussed optimization without randomization. The percentage trials with a dose optimization plan increased annually from 2021-2023 (22%, 29%, and 47% respectively; p=0.002). There was an increase in the proportion of trials which included backfill cohorts from 2021 (60%) to 2022-2023 (76%) (p=0.007) in addition to the proportion of protocols which allowed intra-patient dose escalation (45% in 2021 versus 57% in 2022-2023, p&amp;lt;0.001). The number of additional patients required in the trials with a dose optimization plan ranged from 12 - 200 with a median of 40. The inclusion of patient reported outcomes in early phase protocols was low at 12% from 2021-2023 and only 3 protocols (1%) addressed enrollment of underrepresented groups in the protocol. Conclusion: Overall, there has been a trend towards increased implementation of a dose optimization plan within early phase protocols since the announcement of the FDA’s Project Optimus initiative in 2021. Moreover, Bayesian designs, backfill cohorts, and intra-patient dose escalation are common in contemporary dose escalation studies. However, patient-centered outcomes and underrepresented populations are not routinely addressed in these protocols. Updated analysis including early phase clinical trials activated in 2024 is planned. Citation Format: Deepak Bhamidipati, Suzanne Jones, David Spigel, Gerald Falchook, Manish Patel, Howard Burris, Vivek Subbiah. The impact of Project Optimus and FDA guidance on study design of early-phase clinical trials [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 4514.
Abstract 6289: SCplot: an interactive platform for single-cell RNA-seq analysis in colorectal cancer
Authors: William Kothalawala, Balazs Gyorffy
Journal: Cancer Research (2025)

Background: Single-cell RNA sequencing (scRNA-seq) is a powerful tool for detailed characterization of the processes driving cancer and the interactions between different cell types in neoplastic tissues. However, the large volume of resulting data and the complexity of downstream analytic software and statistical approaches can make it challenging for researchers and clinicians without bioinformatics expertise to extract meaningful insights. To address this need, we developed SCplot, an integrated database and interactive online analysis platform for single-cell colorectal cancer (CRC) RNA-seq data. Methods: SCplot allows users without prior programming experience to explore an integrated single-cell dataset. We compiled eight publicly available raw scRNA-seq CRC datasets from GEO, performed quality control and normalization, combined the datasets, and annotated the cell types. The complete database includes among others 102,195 cancer cells, 19,942 vascular endothelial cells, 25,027 cancer associated fibroblasts, and 7,438 smooth muscle cells. The platform available at www.scplot.com enables downstream analysis features, including differential gene expression, volcano plots, expression heatmaps, and gene-gene correlation analyses across various cell types. Results: To demonstrate SCplot’s utility, we investigated correlations of VEGFA between cancer cells and vascular endothelial cells, cancer-associated fibroblasts, and smooth muscle cells. Notably, the transcription factor JUND was among the top five positively correlated genes to VEGFA in cancer cells in each of these cell types (Pearson’s correlation coefficient: 0.27-0.37, p&amp;lt;0.001). Other strongly positively correlated genes included those involved in cell signaling (TCF4, CALCRL, GNAS) and angiogenesis (MCAM, COL4A1, SOX18). Conversely, negatively correlated genes were associated with immunoregulation (B2G, FKBP2), iron metabolism (FTL, FTH1), apoptosis (SOD1), and cell differentiation (PPDPF). Conclusions: These findings provide new insights into VEGF-driven interactions in CRC, revealing potential therapeutic targets to modulate the tumor microenvironment and disrupt angiogenesis. The SCplot platform can be mined to uncover, visualize, and validate cellular interactions in CRC. Citation Format: William Kothalawala, Balazs Gyorffy. SCplot: an interactive platform for single-cell RNA-seq analysis in colorectal 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 6289.
Abstract 4892: Tools for screening for social determinants of health in head and neck cancer: a scoping review
Authors: Rebecca A. Zasloff, Alexandra Hunter, Ayush Khanna, Huda Haque, Elizabeth R. Blackwood, Nosayaba Osazuwa-Peters
Journal: Cancer Research (2025)

Abstract Methods: We conducted a systematic literature search of Medline, Embase, and Web of Science databases on July 24, 2024. The included studies were US-based, written in English, and examined a validated tool to assess SDoH among HNC patients. Tools were categorized by the five primary SDoH domains as defined by the Healthy People 2030 Initiative: Economic Stability, Education Access and Quality, Social and Community Context, Health Care Access and Quality, and Neighborhood and Built Environment. Subdomains within each primary domain were used to further categorize the included tools. Results: After screening 272 articles, 5 studies that evaluated 4 unique SDoH screening tools were included in the analysis. The number of questions in any given SDoH assessment tool ranged from 2 to 33 (mean: 16). Economic Stability (n = 3, 75%) and Health Care Access and Quality (n =2, 50%) were the only 2 SDoH domains assessed by the tools. Most tools evaluated one domain (n =3, 75%). Poverty (n = 3, 75%) and Access to Health Services (n = 2, 50%) were the most commonly assessed SDoH sub-domains. Only one study proposed a specific intervention to address SDoH. Conclusion: This review found that most SDoH screening tools in HNC care focus on assessing Economic Stability, but do not capture several other Healthy People 2030 domains. Ultimately, the limited number of validated SDoH tools fail to assess the wide-reaching spectrum of HNC patient experiences, making it difficult to comprehensively address the social needs of HNC patients. In addition to the development of tools to screen other SDoH domains, future studies are needed to integrate adequate public health interventions in order to address social need particularly among racial/ethnic minority and marginalized populations. Citation Format: Rebecca A. Zasloff, Alexandra Hunter, Ayush Khanna, Huda Haque, Elizabeth R. Blackwood, Nosayaba Osazuwa-Peters. Tools for screening for social determinants of health in head and neck cancer: a scoping review [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 4892.
Abstract 4493: Exploring APE1-G4 interactions and FACT complex inhibition to overcome therapy resistance in pediatric medulloblastoma
Authors: Ritesh Dey, Yingling Chen, Sutapa Ray, Kishor Bhakat
Journal: Cancer Research (2025)

Abstract Medulloblastoma or MB is the most common malignant brain tumor in children. Tumor recurrence and therapy resistance remain critical obstacles for the treatment of MB. Although surgical resection followed by high doses of chemotherapies and ionizing radiation IR has considerably improved the survival rates. Resistance of residual tumor to IR and chemotherapies often leads to tumor recurrence. Despite advances in standard therapies, survival rates for relapsed MB patients have remained stagnant for over three decades, leaving clinicians and families with limited options. Previous reports have demonstrated that APE1, a key protein involved in repairing AP sites and single-strand breaks SSBs in DNA, is overexpressed in MB, and its activity is associated with tumor progression. Knockdown of APE1 enhances sensitivity of MB cells to radiation and chemotherapy, suggesting that APE1 mediates IR/chemo resistance. We have recently demonstrated that IR or cisplatin treatment induced APE1 interaction which Facilitates Chromatin transcription FACT complex, and treatment with CBL0137, a FACT targeted small molecule, improves the potency of cisplatin and radiation in vitro and in intracranial orthotopic MB xenograft model. Our current study discovered that recombinant APE1 binds to non-canonical four stranded DNA secondary structure called G quadruplexes or G4 DNA in the genome of MB cells and interacts with G4 in cells. Inhibition of APE1 binding to G4 by small molecules affects damage repair in cells. Treatment with these small molecules dose-dependently affects MB tumor cell growth in vitro. Further, we have delineated a mechanistic link of G4 with APE1 mediated drug resistance. Our project unraveled a novel mechanism by which APE1 and G4 promote therapy resistance and identify a promising strategy to improve the efficacy of IR and cisplatin and prevent tumor recurrence. Citation Format: Ritesh Dey, Yingling Chen, Sutapa Ray, Kishor Bhakat. Exploring APE1-G4 interactions and FACT complex inhibition to overcome therapy resistance in pediatric medulloblastoma [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 4493.