tbuckley/cabot-search huggingface dataset:
Abstract 6779: The plant derived compound Simalikalactone D is a potent anticancer agent in triple negative breast cancer cells
Authors: Joshua Nieves, Annelis Sanchez, Claudia Ospina, Pablo Vivas-Mejia
Journal: Cancer Research (2025)

Abstract Despite recent advances in systemic therapy, Triple Negative Breast Cancer (TNBC)—accounting for 10-20% of breast cancer cases—remains the subtype with the worst prognosis, marked by a high risk of distant recurrence and death; thus, novel treatments are urgently needed for this deadly disease. Simalikalactone D (SKD) is a potential anticancer compound from Simarouba tulae, an endemic plant of Puerto Rico. We observed that the TNBC cells, MDA-MB 231 and MDA-MB 468 respond differently when treated with SKD. Thus, it is critically important to investigate the mechanism of action of SKD in TNBC cells. This study involved a comparative analysis in MDA-MB 231 and MDA-MB 468 cells, and their differential response to treatment with SKD. We performed Tandem Mass Tag (TMT)- based quantitative proteomics, followed by Ingenuity Pathway Analysis (IPA) protein expression analysis to identify distinctly active networks and signaling pathways along with different cellular behaviors between the TNBC cell lines.In the MDA-MB 468 cell line, SKD appeared to play a role in inducing apoptosis through Caspase 3 activation, with apparent PD-1/PD-L1 signaling in Death Receptor pathways. This correlates with reduced cell migration and adhesion in this cell line, which could suggest an apoptotic-mediated loss of integrity. Alternatively, the MDA-MB 231 cells did not show Caspase 3 activation, instead they exhibited an activation of autophagy pathways, including Macroautophagy and Late Endosomal Microautophagy (LEMA). After treatment of cells with SKD, LEMA appeared to act as a compensatory mechanism of survival when Autophagy was impaired. This emphasizes the role of cellular stress responses for maintaining cell viability under SKD treatment.This study highlights the influence of genetic and molecular differences on TNBC cell responses to SKD, reinforcing the clinical importance of personalized medicine. Therapeutic strategies using the genetic and molecular profiles of a patient’s tumor could enhance treatment efficacy and improve outcomes, particularly for aggressive cancers like TNBC. Citation Format: Joshua Nieves, Annelis Sanchez, Claudia Ospina, Pablo Vivas-Mejia. The plant derived compound Simalikalactone D is a potent anticancer agent in triple negative breast 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 6779.
Abstract 6778: Targeting the YAP-TEAD interaction in brain metastatic breast cancer cells
Authors: Caitlyn C. Castillo, Mohamed Haloul, Philana Phan, Zongmin Zhao, Ekrem E. Er
Journal: Cancer Research (2025)

Abstract Breast cancer metastasis to the brain is a devastating stage of breast cancer that presents with cognitive decline and seizures, and currently there are no treatments available. Brain metastases are resistant to immunotherapy, chemotherapy, and targeted therapies. This is partly because the blood-brain barrier and the blood-tumor barriers prevent effective delivery of these treatment modalities at clinically safe doses and partly because we do not know enough about the molecular mechanisms that govern breast cancer brain metastasis. Recent work in mouse models of breast cancer brain metastases revealed that the interaction between Yes Associated Protein (YAP) and Transcriptional Enhanced Association Domain (TEAD) family of transcription factors is an essential step in outgrowth of disseminated cancer cells. Here, we demonstrate a series of time-lapse imaging assays and luminescence based viability assays that we optimized to investigate the impact of YAP-TEAD inhibitors and chemotherapeutic agents on the viability of brain metastatic breast cancer cells in vitro. Our results will guide the prioritization of these treatment modalities in pre-clinical in vivo models. We will specifically investigate whether one or more of these agents can be loaded onto nanoparticle-engineered macrophages to better overcome blood-brain and blood-tumor barriers for effective delivery and targeted destruction of brain metastases. Citation Format: Caitlyn C. Castillo, Mohamed Haloul, Philana Phan, Zongmin Zhao, Ekrem E. Er. Targeting the YAP-TEAD interaction in brain metastatic breast 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 6778.
Abstract 6780: Discovering novel inhibitors of the chaperone Hsp90 for cancer treatment: A plant-based approach
Authors: Chidera P. Ogbu, Taoufik Llbiyi, Vamsi Krishna Kommalapati, Ahmed Chadli
Journal: Cancer Research (2025)

Abstract We investigated the effect of small molecules extracted from the latex of Calotropis procera (CPPE) to act as inhibitors of Heat Shock Protein 90 (HSP90), a key molecular chaperone co-opted by cancer cells for survival and proliferation. Current HSP90 inhibitors often activate the heat shock response, reducing their long-term efficacy. While CPPE has been shown to have toxic effects on cancer cells, its exact mechanism of action, including its potential to inhibit HSP90, has yet to be evaluated. Using flow cytometry, gene expression and protein quantification analysis, and mass spectroscopy techniques, we evaluated the effects of CCPE small molecules on triple-negative breast cancer cells (TNBCs) compared to 17-AAG, a known HSP90 inhibitor. We observed a dose-dependent increase in cell death with graded doses of CPPE compared to 17-AAG. Additionally, our findings from the MTT assay and flow cytometry demonstrated that treatment with CPPE led to a decrease in cell viability and the initiation of cell death pathways such as apoptosis and necrosis. Notably, western blot analysis suggests the absence of heat shock responses in cells treated with CPPE compared to 17-AAG. These findings support our hypothesis, indicating that small molecules present in CPPE show promise as candidates for HSP90 inhibitors. Further investigations to gain deeper insights into CPPE mechanisms as well as characterizing its bioactive compounds are ongoing. This research highlights the importance of natural product-based drug discovery in cancer treatment Citation Format: Chidera P. Ogbu, Taoufik Llbiyi, Vamsi Krishna Kommalapati, Ahmed Chadli. Discovering novel inhibitors of the chaperone Hsp90 for cancer treatment: A plant-based approach [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 6780.
Abstract 6772: Heterogeneity of <i>ex-vivo</i> tumor responses in primary ovarian cancer tissues
Authors: Chiara Maestri, Ivan Trus, Rajeshwar Nitiyanandan, Jahanvi Kumar, Ricardo J. Parker, William Cance, Christian Apfel
Journal: Cancer Research (2025)

Abstract Background: While most stage III and IV ovarian cancer patients respond to neo-adjuvant carboplatin and paclitaxel, not all do. Some experience recurrence within 6 months (platinum-resistant), others after 6 months, and a minority achieve remission beyond 5 years. Apart from BRCA mutations, genomic testing offers little guidance on patient-to-patient heterogeneity in tumor responses. To address this, we developed an internally validated functional profiling platform in a CLIA-certified and CMS accredited lab. Our goal was to measure in-vitro heterogeneity of tumor responses to NCCN-recommended treatments to identify the most suitable therapies for patients. Methods: Ovarian cancer biopsies were shipped overnight and processed the same day using our proprietary functional profiling platform in a physiological culture system with around 2, 000 viable cells per well. Tissues were exposed to up to 24 NCCN recommended therapies on the day after for 4 days, cytotoxicity readout with dose response curves within 7 days. Heterogeneity was assessed by the interquartile ratios of the EC50 drug concentrations. Not requiring organoid-like cell growth offers two advantages: a) actionable results for almost all patients and b) a fast turnaround time with an issued report within 10 days. Heterogeneity was evaluated using interquartile ratios of EC50 drug concentrations. Results: A total of 17 ovarian cancer tissues were processed and exposed to up to 24 NCCN recommended therapies. Interquartile ratios (IQRs) of carboplatin and paclitaxel were 3.62 and 5.22 for the individual drugs, the IQR for the carboplatin/paclitaxel combination was 91.1, suggestive for synergy between both drugs in some, but not other cancer tissues. Gemcitabine’s and cisplatin/gemcitabine IQRs were 39.8 and 17.9, respectively, suggestive that patient benefits to gemcitabine or platinum/gemcitabine combination may vary greatly. IQRs for doxorubicin and olaparib were only 5.8 and 3.2, owing to many tissues not showing any tumor response. All p-value comparisons for EC EC50s heterogeneity of tumor responses were &amp;lt;0.001. Conclusions: Consistent with the clinically known patient-to-patient heterogeneity of tumor responses, such heterogeneities were also observed in our in-vitro tissue culture platform. Thus, these results warrant external validation of this already internally validated laboratory developed test (LDT). Citation Format: Chiara Maestri, Ivan Trus, Rajeshwar Nitiyanandan, Jahanvi Kumar, Ricardo J. Parker, William Cance, Christian Apfel. Heterogeneity of ex-vivo tumor responses in primary ovarian cancer tissues [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 6772.
Abstract 2417: N-Orbit: An interpretable, distance-based framework for comparison of tumor microenvironments and beyond
Authors: Barbara Xiong, Yuxuan Hu, Kai Tan
Journal: Cancer Research (2025)

Abstract The tumor microenvironment (TME) plays a major role in cancer progression and treatment resistance. Advances in single-cell resolution spatial omics technologies have facilitated the exploration of the TME and its role in these processes. Recent developments in quantitative methods for tissue cellular neighborhood (TCN) detection have provided further insights into the organization of spatial heterogeneity within individual tissue samples. Yet a theoretical framework for modeling and comparing tissue architecture across time points and clinical subtypes remains lacking. We introduce, N-Orbit, a mathematical model that captures both cell type composition and spatial relationships within tissue cellular neighborhoods, encoding this information in a vector format for computationally efficient distance metric calculations. We benchmark our N-Orbit-based neighborhood distance metric on spatial omics datasets with manually annotated ground truth anatomical regions and on patient datasets with corresponding clinical variables. We also demonstrate that N-Orbit neighborhood distances recapitulate transitions across treatment phases and can be used to identify resistance-enriched neighborhood clusters in triple-negative breast cancer. Additionally, N-Orbit enhances model interpretability by allowing these neighborhood clusters to be traced back to enriched cell-cell interactions. N-Orbit holds significant potential for deepening our understanding of how TMEs, as well as tissue microenvironments more broadly, evolve across treatment timelines and clinical subtypes. Citation Format: Barbara Xiong, Yuxuan Hu, Kai Tan. N-Orbit: An interpretable, distance-based framework for comparison of tumor microenvironments and beyond [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 2417.
Abstract 5815: Both CD4 and CD8 T cells mediate antitumor immunity to prevent development of neoantigen-expressing autochthonous sarcomas
Authors: Sabelo Mndeni Lukhele, David G. Kirsch, Jonathon E. Himes
Journal: Cancer Research (2025)

Sarcoma is a rare, aggressive and highly metastatic disease. The efficacy of current treatment approaches including surgery, chemotherapy and radiation is limited hence the recent focus in novel immunotherapy. However, immunotherapy research for sarcoma is impeded by our limited understanding of the antitumor immune responses, largely due to the lack of faithful mouse models expressing known sarcoma neoantigens. Here, we combined CRISPR/Cas9 and sleeping beauty transposase technology to develop an autochthonous orthotopic murine sarcoma model that allows the tumor to coevolve with the immune system and expresses MHCI (mLama4) and/or MHCII (mItgb1) sarcoma neoantigens. We show that expression of mLama4 and/or mItgb1 neoantigens prevented tumor development in a T-cell dependent manner. Indeed, tumors expressing both neoantigens only developed following depletion of both CD4 and CD8 T cells. Similarly, growth of mItgb1-expressing tumors was observed only in CD4 T cell deficient mice. Tumor-specific T cells were detected, using MHC-mLama4/mItgb1 tetramers, as early as ten days post tumor induction and persisted for more than three months. Both CD4 and CD8 tumor-specific T cells were activated, in cycle, and produced effector cytokines IFNγ and TNFα, suggesting that they both mediate antitumor immunity in part by direct killing of tumor cells. Thus, CD4 and CD8 T cells independently contribute to cancer immunosurveillance leading to clearance of neoantigen-expressing sarcomas. Citation Format: Sabelo Mndeni Lukhele, David G. Kirsch, Jonathon E. Himes. Both CD4 and CD8 T cells mediate antitumor immunity to prevent development of neoantigen-expressing autochthonous sarcomas [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 5815.
Abstract 6515: <i>Candida</i>-associated microbiome in pancreatic ductal adenocarcinoma
Authors: Carlos H.F. Chan, Casandro J. Chan, Ashutosh K. Mangalam, Po Hien Ear
Journal: Cancer Research (2025)

Abstract Candida species are commonly found in bile collected during surgery in pancreatic ductal adenocarcinoma (PDAC) patients. We have previously shown that bile and tumor-associated Candida albicans are associated with higher pathological stage, worse pathological response to neoadjuvant chemotherapy, worse overall survival, and epithelial-mesenchymal transition gene signature. Here we investigated the association between Candida species and other commonly found bacterial species in the biliary system of PDAC patients with biliary stents. Patients undergoing pancreatectomy with available intraoperative bile cultures (aerobic, anaerobic and fungal) were identified in a prospective single-institution cohort. 16S rRNA and ITS sequencing was performed using available frozen banked bile samples from these patients. Relative abundance (RA) was determined as the ratio of an individual microbial count over the total microbial count in a given sample. Bile acid contents in these bile samples were determined using LC-MS methods. Of 135 patients with preoperative biliary stenting, the most commonly found bacteria were Enterococcus (56%), Streptococcus (47%), Klebsiella (47%), Enterobacter (26%), Escherichia (25%), Prevotella (22%), and Clostridioides (15%). Candida species were found in 36% of these patients. 76% of patients without preoperative biliary stenting had negative bacterial cultures. Using 16S rRNA and ITS sequencing data (N=27), the presence of Candida (RA &amp;gt; 0) was significantly associated with the presence of Enterococcus species (RA of 24.8% in Candida+ samples vs. 7.8% in Candida- samples, P=0.046). Enterococcus was also found to be associated with more unconjugated bile acids in the bile samples (unconjugated/conjugated bile acid ratios: cholic acid, 3.07 vs. 0.30, P=0.089; deoxycholic acid, 3.57 vs. 0.39, P=0.029; chenodeoxycholic acid, 2.54 vs. 0.35, P=0.045). Our data show Candida and Enterococcus species frequently co-exist in the biliary system of PDAC patients with biliary stents and that Enterococcus species may be responsible for bile acid deconjugation within the biliary system. Whether Enterococcus species and unconjugated bile acids promote the colonization and survival of Candida within the biliary system remains to be determined in future investigation. Citation Format: Carlos H.F. Chan, Casandro J. Chan, Ashutosh K. Mangalam, Po Hien Ear. Candida-associated microbiome in pancreatic ductal 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 6515.
Abstract 1719: Constitutive aryl hydrocarbon activity promotes resistance to bortezomib which is exacerbated by leptin and potentially involves Src phosphorylation by JAK2 in prostate cancer cells
Authors: Kofi K. Khamit-Kush, Daniel J. Walters, Nathan J. Bowen, Jeffrey A. Handy, Joann B. Powell
Journal: Cancer Research (2025)

Abstract The aryl hydrocarbon receptor (AhR) plays a role in regulating diet-induced obesity and is a nuclear transcription factor involved in the transcriptional regulation of target genes, such as enzymes of xenobiotic metabolism (CYP1, UGTs) or genes involved in the transcriptional regulation. Induced enzymes facilitate the metabolism of various endogenous compounds and drugs, such as bortezomib. We report that the constitutive activity of AhR promotes drug resistance which is exacerbated in the presence of leptin and potentially involves AhR-mediated Src phosphorylation by JAK2 in a prostate cancer in vitro model. Leptin is known to contribute to cancer progression and has an emerging role in chemoresistance. Of note, both leptin receptor and aryl hydrocarbon receptor are overexpressed in prostate cancer cell lines. Additionally, our lab previously reported an integrative bioinformatics analysis using TCGA data (n=498) which revealed a positive correlation in AHR and LEPR mRNA expression in patients with prostate cancer. Our in vitro results also show AhR protects androgen-insensitive C4-2 cells but not LNCaP cells from apoptosis induced by anti-androgens, suggesting AhR activity leads to androgen independence and potentially multi-class chemoresistance. Further investigation into AhR as a drug target in obesity-associated conditions for the treatment of advanced prostate cancer upon entering the phase of drug resistance coupled with failure of first-line androgen deprivation therapy. Citation Format: Kofi K. Khamit-Kush, Daniel J. Walters, Nathan J. Bowen, Jeffrey A. Handy, Joann B. Powell. Constitutive aryl hydrocarbon activity promotes resistance to bortezomib which is exacerbated by leptin and potentially involves Src phosphorylation by JAK2 in prostate 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 1719.
Abstract 6519: Tumor sidedness of colorectal cancer shows differential abundance of tumor microbiota and plausible implications
Authors: Kuo-Hsing Chen
Journal: Cancer Research (2025)

Abstract Background: The tumor microbiota in colorectal cancer (CRC) plays a significant role in carcinogenesis, progression and metabolic interaction. Studies have shown the microbiota composition may be different between left-sided and right-sided CRC (LCRC and RCRC). Materials and methods: We conducted a multi-cohort study to investigate the role of tumor microbiota in CRC in Taiwan. Cohort 1 included 140 CRC pairs from the National Taiwan University Hospital biobank. Cohort 2 was a prospective study to recruit patients with newly diagnosed CRC and collect their surgical specimens and physical activity status. Cohort 3 included 30 colon polyps. The V3-V4 regions of the bacterial 16S ribosomal RNA gene were amplified, and the amplicons were sequenced using the MiSeq system. Left-sided (LCRC, descending colon to rectum) and right-sided (RCRC, cecum to splenic flexture of transverse colon) CRC were defined according to the location of primary tumor. An integrated analysis of clinicopathological characteristics and tumor microbiota was conducted. Co-occurrence networks was used to understand the relationships and interactions between different microbial species within a community. Results: Among 140 CRC in cohort 1, 93 (66.4%) of them were left-sided. There were significantly more CIMP-high tumors in LCRC than in RCRC (p = 0.0002). The diversity of microbiota was not different between LCRC and RCRC. LefSe (Linear discriminant analysis Effect Size) analyses revealed many bacteria had significantly higher abundance in LCRC and RCRC (LDA score ≥ 2, p &amp;lt; 0.05). The top 3 microbiota were Bacillaceae, Sphingomonadaceae, Propionibacteriacea in LCRC and Enterococcus, Enterococcaceae, Lachnospiraceae in RCRC. Clinically, high abundance of Flavobacterium was significantly correlated to absence of high body mass index (BMI ≥ 27.5 kg/m2) (p = 0.0019) and low abundance of Lachnoclostridium was significantly associated with late-stage (stage 3 and 4) (p = 0.0363) in right-sided CRC. Co-occurrence networks and pathway analysis showed Flavobacterium was negatively associated with multiple nutrients metabolism. Conclusion: The microbiota composition between LCRC and RCRC was different. The clinical implications of Flavobacterium and Lachnoclostridium warrants further validation. Citation Format: Kuo-Hsing Chen. Tumor sidedness of colorectal cancer shows differential abundance of tumor microbiota and plausible implications [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 6519.