tbuckley/cabot-search huggingface dataset:
Abstract 3058: AR-dependent anticancer action of BF175 in hormone sensitive prostate cancer
Authors: Lakshmi Sirisha Devarakonda, Prashanth Parupathi, Ekniel Francois, Bhasker C. Das, Avinash Kumar
Journal: Cancer Research (2025)

Abstract Androgen receptor (AR) is a well established key biological contributor to prostate cancer progression. Despite significant efforts which have resulted in the therapeutic agents that target the AR signaling being the therapy of choice, prostate cancer remains one of the topmost causes of cancer-related deaths among men in the United States. Hence, development of novel targeted therapeutics that augment or supplant AR-based therapy remains a top priority. Sterol regulatory element binding proteins (SREBPs)are a family of transcription factors, consisting of SREBP-1 and SREBP-2, that control lipid synthesis. Available literature provides evidence for the cooperation between SREBPs and AR signaling in promoting prostate cancer progression. We observed that the SREBP expression is higher in LNCaP, C4, and C4-2 AR-positive/androgen-dependent compared to DU145, and PC3 AR-negative/androgen-independent prostate cancer cell lines. Therefore, we hypothesized that pharmacological targeting of SREBPs might be a promising therapeutic approach in hormone sensitive prostate cancer. We developed a novel boron-containing small molecule inhibitor of SREBPs, BF175, whose anticancer activity against prostate cancer has not been elucidated. In our study, we investigated the AR-dependent anticancer activity of BF175 in prostate cancer. We observed inhibition of viability, proliferation, and metastatic potential as well as induction of apoptosis in all prostate cancer cell lines treated with BF175. We also observed reduction in the levels of SREBPs in all prostate cancer cell lines treated with BF175. Notably, the anticancer action of BF175 was dependent on the AR status and BF175 demonstrated significantly more potent anticancer action in AR-positive/androgen-dependent compared to AR-negative/androgen-independent prostate cancer cell lines. Altogether, our data shows that BF175 may be a potential novel therapeutic agent for hormone sensitive prostate cancer. Citation Format: Lakshmi Sirisha Devarakonda, Prashanth Parupathi, Ekniel Francois, Bhasker C. Das, Avinash Kumar. AR-dependent anticancer action of BF175 in hormone sensitive prostate 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 3058.
Abstract 5889: Combined cfDNA and cfRNA enhanced gene fusion detection and drug resistance mechanism insights in mCRPC through combined cfDNA and cfRNA assays profiling
Authors: Haoran Tang, Feng Xie, Yue Zhang, Yutao Feng
Journal: Cancer Research (2025)

Abstract Background: Metastatic castration-resistant prostate cancer (mCRPC) is a complex disease characterized by distinct molecular features related to genomic instability and selective treatment pressures. Cell-free DNA and RNA (cfDNA and cfRNA) found in blood offer potential for disease diagnosis, monitoring, and interrogation of resistance mechanisms by detecting genomic alterations from tumors. Here, we introduce comprehensive cfDNA and cfRNA assays to profile the genomic landscape in mCRPC patients for the purposes of disease diagnosis and monitoring. Methods: In this retrospective study, plasma samples were collected from 52 patients with mCRPC at treatment baseline. For some patients, additional plasma samples were obtained at both cycle 1 day 1 (C1D1) and cycle 3 day 1 (C3D1) during androgen receptor inhibition therapy. We employed PredicineCARE, a 152-gene cfDNA assay, and PredicineRNA, an 88-gene cfRNA assay, to detect genomic alterations at both DNA and RNA levels in these samples. Results: The TMPRSS2-ERG fusion is a common genomic alteration in prostate cancer and serves as a potential diagnostic and prognostic indicator. In baseline samples from 52 patients, the cfDNA assay detected a TMPRSS2-ERG fusion positive rate of 25.0%, while the cfRNA assay detected a higher rate of 38.5%, although this difference did not reach statistical significance (McNemar's test, p = 0.065). Importantly, using a simultaneous testing strategy with both cfDNA and cfRNA increased the detection rate to 42.3%, which is comparable to the prevalence previously reported in tissue samples. Furthermore, by comparing the same androgen receptor (AR) mutations (W742C and T878A) detected by cfDNA and cfRNA assays at C1D1 and C3D1, this comprehensive analysis illustrates the potential biological mechanisms of acquired drug resistance. Conclusion: This study demonstrates that combining cfDNA and cfRNA assays enhances gene fusion detection in mCRPC patients and provides insights into the mechanisms of acquired drug resistance. These findings support comprehensive liquid biopsy approaches for improved diagnosis, monitoring, and personalized treatment strategies in mCRPC. Citation Format: Haoran Tang, Feng Xie, Yue Zhang, Yutao Feng. Combined cfDNA and cfRNA enhanced gene fusion detection and drug resistance mechanism insights in mCRPC through combined cfDNA and cfRNA assays profiling [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 5889.
Abstract 3270: Modulating the tumor microenvironment and boosting T cell immunity with smart enzyme-loaded virus-like particles
Authors: Orikeda Trashi, Jeremiah Gassensmith
Journal: Cancer Research (2025)

Abstract Virus-like particles (VLPs) are biomaterials engineered to structurally and functionally mimic viruses without carrying viral genetic material, making them non-infectious. These icosahedral structures, composed of coat proteins, offer a versatile platform for chemical and genetic modifications. In this project, we modify VLPs with receptors targeting the overexpressed Platelet-Derived Growth Factor Receptor Beta (PDGFRβ) in cancers such as lung, liver, and colorectal cancers, enabling precise tumor targeting. Additionally, we address the metabolic challenges posed by the Warburg effect, which leads to lactate accumulation, acidifying the tumor microenvironment and impairing T cell function. To counteract this, we encapsulate lactate oxidase (LOX) and catalase (CAT) within VLPs. LOX reduces lactate levels by converting it to pyruvate and hydrogen peroxide (H2O2), while CAT mitigates excess H2O2, alleviating oxidative stress and hypoxia. Together, these enzymes reprogram the tumor microenvironment, enhance anti-tumor immunity, and suppress tumor progression. This innovative strategy combines targeted tumor delivery and immune activation, positioning enzyme-loaded VLPs as a promising platform for next-generation cancer therapies. Citation Format: Orikeda Trashi, Jeremiah Gassensmith. Modulating the tumor microenvironment and boosting T cell immunity with smart enzyme-loaded virus-like particles. [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 3270.
Abstract 5057: Enhancing clinical applications by evaluation of sensitivity and specificity in whole exome sequencing
Authors: Chunghwan Hong, Youngbeen Moon, Hye Won Choi, Eun-Kyung Kang, Seo-Hyeon Ye, Jong-Kwang Kim, Young-Ho Kim, Hyeri Cho, Hana Choi, Dong-eun Lee, Yongdoo Choi, Tae-Min Kim, Seong Gu Heo, Namshik Han, Kyeong-Man Hong
Journal: Cancer Research (2025)

Abstract The cost-effectiveness of whole exome sequencing (WES) remains debated, primarily due to variability in variant calls. Evaluating the sensitivity and specificity of WES results may clarify this issue. WES was performed by three companies (AA, BB, and CC) using reference standards composed of DNA from Hydatidiform mole and individual blood at various ratios. Sensitivity was assessed by the detection rate of null-homozygote (N-H) alleles at expected variant allelic fractions, while false positive (FP) errors were counted for unexpected alleles. Sensitivity was approximately 20% for in-house results from BB and CC and around 5% for AA. Dragen analyses identified 1.34 to 1.71 times more variants, detecting over 96% of in-house variants, with sensitivity for common variants increasing to 5%. In-house FP errors varied significantly among companies (up to 13.97 times), while Dragen analyses minimized this variation. Despite Dragen showing higher FP errors for BB and CC, the increased sensitivity highlights the importance of effective bioinformatic conditions. We also assessed the potential effects of target enrichment and proposed optimal cutoff values for read depth and variant allele fraction in WES. Optimizing bioinformatic analysis based on sensitivity and specificity from reference standards can enhance variant detection and improve the clinical utility of WES. Citation Format: Chunghwan Hong, Youngbeen Moon, Hye Won Choi, Eun-Kyung Kang, Seo-Hyeon Ye, Jong-Kwang Kim, Young-Ho Kim, Hyeri Cho, Hana Choi, Dong-eun Lee, Yongdoo Choi, Tae-Min Kim, Seong Gu Heo, Namshik Han, Kyeong-Man Hong. Enhancing clinical applications by evaluation of sensitivity and specificity in whole exome sequencing [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 5057.
Abstract 4757: Elucidating novel pro-apoptotic consequences of ceramides in endocrine therapy-resistant breast cancer
Authors: Purab Pal, Godwin K. Sarpey, G. Ekin Atilla-Gokcumen, Jonna Frasor, Jonathan L. Coloff
Journal: Cancer Research (2025)

Abstract Endocrine Therapy (ET)-resistant breast cancer (BC) remains a clinical problem, with approximately 40% of patients experiencing disease relapse. Previously, we demonstrated that preclinical models of ET-resistant BC have an altered sphingolipidome, which is characterized by low levels of ceramides across multiple models of ET resistance. ET-resistant models are also more sensitive to ceramide-induced death compared to their ET-sensitive counterparts suggesting a functional significance of the low levels of ceramides. This study is designed to identify mechanisms by which ceramides preferentially kill ET-resistant BC models to identify novel therapeutic strategies to improve ET-resistant BC patient outcomes. We performed total RNA-seq of multiple ET-resistant BC cells with or without ceramides and found that ceramide exclusively induces genes associated with endoplasmic reticulum stress (EnRS), particularly in the PERK/peIF2A/ATF4 pathway, in multiple models of resistance but not in the parental ET-sensitive cells. Inhibitors of EnRS, PERK, and peIF2A partially reverse ceramide-induced cell death suggesting that ceramide-induced EnRS is lethal for ET-resistant cells. Since ceramides are well-known bioactive lipids, we hypothesized that ceramides interact with specific proteins that are instrumental in ET-resistant cell survival. To test this, we used a photoactivable-and-clickable ceramide probe and quantitative proteomics to identify differentially expressed ceramide-interacting proteins (CIPs) in ET-resistant BC cells. We found that ceramide interacts with a group of clinically relevant CIPs which are located in the endoplasmic reticulum (EnR) membrane. While most of these CIPs have yet to be implicated in ET resistance, a subset of the CIPs is known to be involved in attenuating EnRS. Knocking down one of the top CIPs, i.e., TRAM1, phenocopies ceramide treatment, suggesting that ceramides, by interacting with EnR-membrane proteins, such as TRAM1, may disrupt their function and induce a lethal level of EnRS in ET-resistant cells. Together, we find that ceramide induces preferential cell death in ET-resistant cells through interactions with a novel array of proteins leading to the inhibition of key survival proteins and a consequential activation of lethal levels of EnRS. Understanding how ceramides interact with and affect these proteins could lead to the development of novel strategies to selectively treat ET-resistant BC and to improve patient outcomes. Citation Format: Purab Pal, Godwin K. Sarpey, G. Ekin Atilla-Gokcumen, Jonna Frasor, Jonathan L. Coloff. Elucidating novel pro-apoptotic consequences of ceramides in endocrine therapy-resistant breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4757.
Abstract 7279: A novel humanized IL2 and IL15 receptor mouse model enables preclinical efficacy studies for IL-2 cancer therapeutics
Authors: Alexander Sercel, Linlin Wang, Suman Zhao, Zan Zhang, Zhenlan Niu, Yanling Wang, Xiaofei Zhou
Journal: Cancer Research (2025)

Abstract Recombinant human interleukin 2 (IL-2) is effective in treating metastatic renal carcinoma and melanoma, however, severe dose-limiting toxicity restricts patient treatment. There is conflicting evidence from human and murine studies on whether activation of natural killer (NK) cells leads to efficacy or toxicity and if activation of T or NK cells is associated with therapeutic benefit. The development of a humanized mouse model for this system is imperative to evaluate the safety and efficacy of IL-2 targets. Here, we generated a homozygous humanized hIL-2RB/hIL-2RG/hIL-15/hIL-15RA mouse model which constitutively expresses human IL-2RB, IL-2RG, IL-15, and IL-15RA proteins. The distribution of basal leukocyte subpopulations of blood, spleen, and lymph nodes in humanized B-hIL-2RB/hIL-2RG/hIL-15/hIL-15RA mice is similar and comparable to the distribution found in wild-type C57BL/6 mice. Functionally, the human IL-2 and IL-15/IL-15RA complex elicits a dose-dependent induction of pSTAT5 in humanized mice. Furthermore, using this model, we have detected modest efficacy of a human IL-2 drug in inhibiting MC38 tumor growth in vivo. In summary, B-hIL-2RB/hIL-2RG/hIL-15/hIL-15RA mice provide a powerful preclinical model to clear roadblocks towards in vivo evaluation of IL-2 drugs for cancer treatment. Citation Format: Alexander Sercel, Linlin Wang, Suman Zhao, Zan Zhang, Zhenlan Niu, Yanling Wang, Xiaofei Zhou. A novel humanized IL2 and IL15 receptor mouse model enables preclinical efficacy studies for IL-2 cancer therapeutics [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 7279.
Abstract 3059: Targeting tumor progression: The impact of SMR peptide and miRNA on exosome-inflammasome-EMT axis in breast cancer
Authors: Ming Bo Huang, Erica L. Johnson, Lily Yang, Jonathan Stiles, Aykut Uren, Fengxia Yan, Vincent C. Bond
Journal: Cancer Research (2025)

Abstract Background: In breast cancer, the interplay between exosomes, the inflammasome, and epithelial-mesenchymal transition (EMT) significantly influences tumor progression and metastasis. Exosomes carry molecules that affect cellular processes like inflammation and EMT. The inflammasome produces pro-inflammatory cytokines, promoting tumor-associated inflammation and stimulating EMT, which enhances cancer cell invasiveness. Exosomes also deliver miRNAs that modulate gene expression and promote EMT. Objective: This study investigates the role of the secretion modification region (SMR) peptide in regulating interactions between exosomes, the inflammasome, and EMT in breast cancer, focusing on miRNA influence on gene expression. Methods: MDA-MB-231 breast cancer cells were treated with tumor exosomes or exSMRwt. Exosomes were isolated and characterized using nanoparticle tracking analysis. Inflammasome activation was assessed by measuring caspase-1 and pro-inflammatory cytokines (IL-1β, IL-18). miRNA expression was evaluated using the nCounter Human miRNA assay. Results: The SMR peptide suppressed MDA-MB-231 cell activity and inhibited exosome release, crucial for cancer progression. exSMRwt-treated cells showed reduced inflammasome activity and altered miRNA expression, with significant upregulation and downregulation of specific miRNAs. Nine miRNAs were identified as closely related to breast cancer progression, inhibiting cell proliferation, EMT, migration, invasion, and metastasis. Conclusion: The SMR peptide is a promising therapeutic agent in breast cancer, targeting multiple pathways involved in tumor progression. It inhibits inflammasome activation, reduces pro-inflammatory cytokine production, and modulates exosome-mediated signaling. The peptide also influences miRNA regulation, suppressing inflammation and inhibiting tumor growth and metastasis. This study highlights the therapeutic potential of the SMR peptide and provides direction for further miRNA research in breast cancer. Citation Format: Ming Bo Huang, Erica L. Johnson, Lily Yang, Jonathan Stiles, Aykut Uren, Fengxia Yan, Vincent C. Bond. Targeting tumor progression: The impact of SMR peptide and miRNA on exosome-inflammasome-EMT axis in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3059.
Abstract 5525: YTHDF3 and RAS-ERK1/2 pathway generate a negative feedback loop to maintain phosphorylation cascade and contribute to EGFR-TKI resistance
Authors: Jaeik Oh, Sung-Yup Cho
Journal: Cancer Research (2025)

Abstract About half of East Asian patients with lung adenocarcinoma harbor EGFR mutations, which lead to dramatic initial response to EGFR tyrosine kinase inhibitors (EGFR TKI); however, the resistance to these therapies is ultimately inevitable. Several previous studies on EGFR TKI that typically utilized genomic, epigenomic and transcriptomic data of resistant tumors from patients attributed their resistance to bypass signal activation or downstream target mutations, however, mostly failed to overcome resistance by targeting such signals. The gap between RNA and protein expression, which obscures changes in actual phosphorylation cascade, is one plausible explanation for the previous failures of multi-layer omics studies and genome-wide screening. Given that posttranslational modification contributes to this gap, N6-Methyladenosine, which is dynamically regulated and present in the mRNAs of various genes in the RAS pathway, has emerged as an intriguing target for studying its role in EGFR TKI resistance. Here, we demonstrated that the phosphorylation cascade of EGFR-RAS-ERK1/2 and YTHDF3 regulate each other and are composed of a negative feedback loop between two independent systems. We identified blocking the EGFR signal decreased the protein stability of YTHDF3 while negative regulation of YTHDF3 intensified EGFR-RAS-ERK1/2 signaling. Our findings reveal that YTHDF3 plays a critical role in modulating EGFR TKI resistance, suggesting its potential as a therapeutic target to overcome resistance in lung cancer treatment. Citation Format: Jaeik Oh, Sung-Yup Cho. YTHDF3 and RAS-ERK1/2 pathway generate a negative feedback loop to maintain phosphorylation cascade and contribute to EGFR-TKI resistance [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 5525.
Abstract 3197: Macrophage-ferritin-drug conjugates: a novel approach to overcome glioblastoma drug resistance and induce long-term tumor immunity
Authors: Maciej Białasek, Miaomiao Sun, Bartłomiej Taciak, Tomasz Rygiel, Michael Weller, Tobias Weiss, Magdalena Krol
Journal: Cancer Research (2025)

Abstract Glioblastoma (GBM) remains a major clinical challenge due to its resistance to conventional therapies and immunosuppressive tumor microenvironment. To address these challenges, we developed Macrophage-Ferritin-Drug Conjugates (MDCs), leveraging the unique ability of macrophages to infiltrate gliomas and transfer therapeutic ferritin-drug complexes directly to cancer cells. In orthotopic glioma models (GL-261 and CT-2A), MDC-735, consisting of macrophages loaded with ferritin conjugated to inhibitor of tubulin polymerization, demonstrated significant tumor reduction and improved survival compared to controls, including unloaded macrophages or cell-free ferritin-drug conjugates. MDC-735 also outperformed current standard treatments such as temozolomide, radiation, and second-line agents like lomustine, which fail to achieve long-term survival. Remarkably, rechallenge studies showed that mice treated with MDC-735 developed immunological resistance to tumor regrowth, indicating a role for adaptive immunity. In vitro co-culture experiments revealed that MDC-735-loaded macrophages induced T-cell activation and pro-inflammatory cytokine production. In vivo, MDC-735 enhanced tumor-infiltrating lymphocyte populations, reduced exhaustion marker expression, and decreased regulatory T-cell frequencies, further supporting its immune-modulating effects. Functional validation in immunodeficient models confirmed the critical involvement of lymphocytes in MDC-735's therapeutic efficacy. To explore clinical potential, we produced cryopreserved human MDC-735 using macrophages differentiated and loaded via automated platforms. MDC-735 administration in human glioblastoma-bearing mice was well-tolerated and led to tumor regression and survival benefits. Patient-derived glioblastoma samples co-cultured with MDC-735 exhibited preferential ferritin transfer to glioma cells and enhanced phagocytosis, underscoring its selective anti-tumor activity. These findings highlight MDC-735 as a promising immunotherapeutic strategy for GBM, capable of targeting drug-resistant cancer cells, modulating the tumor microenvironment, and inducing durable anti-tumor immunity. Importantly, MDC-735 is designed as an allogeneic, off-the-shelf cell-based therapy, enabling scalable and timely delivery for clinical applications, addressing a significant unmet medical need in glioblastoma treatment. Citation Format: Maciej Białasek, Miaomiao Sun, Bartłomiej Taciak, Tomasz Rygiel, Michael Weller, Tobias Weiss, Magdalena Krol. Macrophage-ferritin-drug conjugates: a novel approach to overcome glioblastoma drug resistance and induce long-term tumor immunity [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 3197.