tbuckley/cabot-search huggingface dataset:
Abstract 4380: HBW-016-K, a novel orally available pan-KRAS inhibitor targeting both “ON” and “OFF” states, is potent, selective, efficacious, safe, and high tissue-penetrant
Authors: Ning Lee, Yingfu Li, Guanfeng Liu, Jiang Li, Mao Yang, Zhiguan Song
Journal: Cancer Research (2025)

Purpose: This study aimed to develop a novel, orally available pan-KRAS inhibitor capable of targeting both the “ON” and “OFF” states of KRAS, addressing drug resistance and expanding treatment options for KRAS-mutant cancers. Methods: Through medicinal chemistry efforts, we designed and optimized a pan-KRAS inhibitor that selectively targets various KRAS mutant subtypes while sparing wild-type KRAS, NRAS, and HRAS. The lead compound was further evaluated for its pharmacokinetic (PK) properties and safety profile. Its anti-tumor efficacy was assessed in multiple KRAS mutant mouse models following oral administration. Results: HBW-016-K demonstrated potent inhibition of various KRAS mutant cell lines with excellent selectivity for KRAS wild-type and other RAS isoforms. This compound effectively targets both the “ON” and “OFF” conformations of KRAS G12D. Additionally, HBW-016-K exhibits favorable PK properties and significant tissue penetration, particularly in lung, intestine, and pancreas. In a KRAS G12V mouse xenograft model, HBW-016-K exhibited dose-dependent anti-tumor activity. At the highest dose of 30 mg/kg (BID, PO), tumors shrank by 84.1% compared to baseline, with sustained tumor regression. HBW-016-K also demonstrated potent anti-tumor activity in KRAS G12D and G12C mouse models. Preliminary toxicity studies revealed a favorable safety profile for HBW-016-K, including minimal off-target effects, negative mutagenicity, and excellent tolerability in a 14-day rat toxicity study. Conclusion: HBW-016-K is a promising novel pan-KRAS inhibitor with superior potency, selectivity, and efficacy. Its favorable PK profile and safety profile support its advancement into clinical development. HBW-016-K has the potential to significantly impact the treatment of KRAS-driven cancers, particularly those with limited therapeutic options, such as lung, colorectal, and pancreatic cancer. Citation Format: Ning Lee, Yingfu Li, Guanfeng Liu, Jiang Li, Mao Yang, Zhiguan Song. HBW-016-K, a novel orally available pan-KRAS inhibitor targeting both “ON” and “OFF” states, is potent, selective, efficacious, safe, and high tissue-penetrant [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 4380.
Abstract 5798: Characterization of neoantigen peptides reveals key factors for sequence design to achieve immunogenicity
Authors: Piriya Wongkongkathep, Worawan Bunrasmee, Jirattha Siriluksana, Korn Chotirosniramit, Pimpayao Sodsai, Nattiya Hirankarn, Trairak Pisitkun
Journal: Cancer Research (2025)

Abstract Immunotherapy has become a powerful approach by utilizing immune systems to combat cancer. Therapeutic cancer neoantigen vaccines targeting tumor-specific antigen (TSA) have demonstrated promising results in several clinical trials, particularly in adjuvant settings. Neoantigens are tumor-specific antigens that are derived primarily from somatic mutations or non-canonical sequences, which can be presented on major histocompatibility complex (MHC) complexes to stimulate T cells. However, selecting mutations and designing neoantigen sequences to achieve high immunogenicity remains challenging. Compared with RNA-based vaccines, the peptides are more difficult to design due to solubility issues. We have analyzed immune response data from an enzyme-linked immunospot (ELISpot) assay collected from patients enrolled in Phase I clinical trial of neoantigen peptide vaccine at Faculty of Medicine, Chulalongkorn University, Thailand. A total of 12 patients with metastatic melanoma and renal cell carcinoma were treated with neoantigen synthetic long peptides, derived from 15-20 patient-specific somatic variants. The patients received neoantigen vaccine alone, intramuscularly administered in 5-7 injections, without combination with immune checkpoint inhibitors. A total of 239 peptides have been tested by ELISpot. We have characterized several contributing factors to immune response. Notably, we found no significant difference in immunogenicity based on peptide solubility, gene expression levels, variant allele frequency, or sites of injection. However, neoantigen peptides derived from indel mutations exhibited slightly stronger immune responses, than those from single nucleotide variants (SNVs) or frameshift variants. In conclusion, we identified some key factors that can assist in the design of neoantigen peptide sequence, and help prioritize neoantigen candidates for cancer treatments. Citation Format: Piriya Wongkongkathep, Worawan Bunrasmee, Jirattha Siriluksana, Korn Chotirosniramit, Pimpayao Sodsai, Nattiya Hirankarn, Trairak Pisitkun. Characterization of neoantigen peptides reveals key factors for sequence design to achieve immunogenicity [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 5798.
Abstract 4389: HJ-093, a novel, orally bioavailable, and potent pan-RAS inhibitor, for the treatment of various RAS mutation-driven cancers
Authors: Fengtian Du, Xiangyu Yang, Shuai Luo, Jingyu Tian, Li Zhang, Huiqiao Ling, Na Guo, Ruisi Wu, Qingqing Qian, Li Tao
Journal: Cancer Research (2025)

Background: RAS mutations dominate tumorigenesis as they account for approximately 30% of human cancer cases, and are common in various solid tumor types such as pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), and colorectal cancer (CRC). Nowadays, in the field of RAS mutated tumors treatment, only KRASG12C selective inhibitors have been approved, nonetheless, patients are prone to acquire resistance to those inhibitors. Yet there is still a lack of innovative treatments for cancers harboring other RAS mutation subtypes. Methods and Results: Here, we report a novel, orally bioavailable, and potent pan-RAS inhibitor HJ-093, for the treatment of different subsets of RAS mutations. HJ-093 exhibited significant anti-proliferative activity across various RAS mutated 3D cancer cell models including SW480, HCT116, NCI-H358, and AsPC-1, with IC50 &amp;lt;2 nM. In multiple RAS mutated xenograft mouse models, HJ-093 showed significant antitumor activity. HJ-093 significantly suppressed tumor growth in CT26 CRC syngeneic model either alone or in combination with anti-PD-1 antibody. Tumor regression was achieved when combined with PD-1 blockade. Conclusions: HJ-093 is a potent pan-RAS inhibitor with the potential to be developed as a targeted therapy for various RAS mutation-driven cancers. Citation Format: Fengtian Du, Xiangyu Yang, Shuai Luo, Jingyu Tian, Li Zhang, Huiqiao Ling, Na Guo, Ruisi Wu, Qingqing Qian, Li Tao. HJ-093, a novel, orally bioavailable, and potent pan-RAS inhibitor, for the treatment of various RAS mutation-driven cancers [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 4389.
Abstract 4074: A 10 million cell atlas of cytokine-stimulated PBMCs via high-throughput combinatorial single cell RNA sequencing
Authors: Joey Pangallo, Efthymia Papalexi, Simone Marrujo, Bryan Hariadi, Crina Curca, Alexa Suyama, Maria Nigos, Oliver Sanderson, Hoai Nguyen, Vuong Tran, Ajay Sapre, Olivia Kaplan, Sarah Schroeder, Alec Salvino, Ryan Koehler, Gokhan Demirkan, Gary Geiss, Charles Roco, Alexander Rosenberg
Journal: Cancer Research (2025)

Abstract Cytokines, secreted by immune cells, are essential for coordinating immune responses against pathogens and abnormal cells, such as those found in cancer. Despite their critical role, a comprehensive understanding of how many different types of immune cells respond to individual cytokines remains elusive. To begin to address this challenge, we created a comprehensive single cell atlas of immune responses to 90 cytokines, profiling the single cell transcriptomes of 10 million PBMCs from 12 donors after 24 hours of treatment. We identified 18 cell types, resulting in the analysis of 19, 440 experimental conditions. Our analysis revealed gene expression changes that are both cell type- and donor-specific, uncovering responses even in rare immune cell populations that are difficult to capture in smaller datasets. Furthermore, we also identified a small number of cytokines that induced changes in cell type proportions after cytokine treatment. Given the limited number of publicly available large-scale single cell studies, we also provide an updated, detailed analysis workflow to encourage researchers to produce similarly scaled-up datasets. By sharing this comprehensive dataset and methodology, we aim to empower the scientific community to scale single cell experiments and drive advancements in immunology, immuno-oncology, cancer biology, and beyond. Citation Format: Joey Pangallo, Efthymia Papalexi, Simone Marrujo, Bryan Hariadi, Crina Curca, Alexa Suyama, Maria Nigos, Oliver Sanderson, Hoai Nguyen, Vuong Tran, Ajay Sapre, Olivia Kaplan, Sarah Schroeder, Alec Salvino, Ryan Koehler, Gokhan Demirkan, Gary Geiss, Charles Roco, Alexander Rosenberg. A 10 million cell atlas of cytokine-stimulated PBMCs via high-throughput combinatorial single cell RNA 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 4074.
Abstract 5780: Prognostic implications of prostatic gonadotropin releasing hormone receptor and androgen receptor expression in non-metastatic prostate adenocarcinoma
Authors: Donghyun Kim
Journal: Cancer Research (2025)

Abstract Background: Suppression of pituitary gonadotropin releasing hormone receptor (GnRHR) is the mainstay systemic therapy for prostate cancer. GnRHR is also expressed in the prostate and its correlation with direct anti-tumorigenic effects have been demonstrated. The inhibition of prostatic androgen receptor (AR) signaling is another potent therapeutic option. Despite their crucial role in prostate cancer proliferation, prognostic implications of prostatic GNRHR and AR expressions remain uncertain. To investigate the prognostic utility of GNRHR and AR expressions, a public prostate cancer transcriptomic profile and progression-free survival (PFS) data were reviewed. Methods: The Cancer Genome Atlas (TCGA) Pan-Cancer project batch-corrected treatment-naïve primary tumor mRNA expression profiles (RNA Seq V2 RSEM) of 324 non-metastatic (M0) prostate adenocarcinoma cases and their associated clinical data were retrieved from the cBioPortal. Log-rank Kaplan-Meier was used for survival analysis. The “low” vs. “high” expression cutoffs for GNRHR and AR were defined as the cohort’s lower 30th and 25th percentiles, respectively. Results: Prostatic GNRHR and AR mRNA expressions were heterogeneous, but apart from low AR expression in Gleason grade group (GGG) 1, levels were similar across age, anatomical T N stage or all other GGGs. For T2b-4 N0 disease, neither GNRHR nor AR expression alone was significantly associated with PFS. However, in a subgroup of patients with T2b-3a N0 disease with high GNRHR, those with concomitant low AR (n=21) were associated with superior 4-year PFS compared to high AR (n=119) with hazard ratio (HR) 0.28 (95% CI 0.080-0.976, p=0.046). The composition of GGG was similar between these groups. GNRHR or AR expression-dependent differential PFS was not observed in patients with T3b-4 N0 disease. For N1 disease, high GNRHR (n=38) was associated with superior 4-year PFS compared to low GNRHR (n=25) with HR 0.32 (95% CI 0.12-0.85, p=0.007), independent from AR expression levels. Conclusions: High GNRHR and low AR expression were associated with superior PFS in an anatomical stage-dependent manner. The superior PFS of low AR was more pronounced for localized T2b-3a N0 disease, while high GNRHR was most pronounced in regional node-positive N1 disease. Prostatic GNRHR and AR mRNA expression levels may allow tailored strategies in utilizing GnRH agonist/antagonist and AR signaling inhibitors in treating non-metastatic castrate-sensitive disease. Further investigation is warranted. Citation Format: Donghyun Kim. Prognostic implications of prostatic gonadotropin releasing hormone receptor and androgen receptor expression in non-metastatic prostate 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 5780.
Abstract 4406: Temozolomide-resistant glioblastoma cells promote proteolytic activities of MMPs and PAI-1 to manifest invasive potentials
Authors: Hien Thanh Duong, Thang Huu Nguyen, Seongwook Jeong, Kyung-Sub Moon, Chaeyong Jung
Journal: Cancer Research (2025)

Abstract Glioblastoma (GBM) is the most lethal and treatment-resistant tumor among brain cancers. Temozolomide (TMZ) is the standard chemotherapeutic agent for GBM, but the majority of patients experience recurrent tumors, leading TMZ-resistant cells to evade the cytotoxic effects of TMZ and continue to invade surrounding tissues. We have recently reported that transient treatment of high-dose TMZ in GBM cells upregulates matrix metalloproteinases 9 (MMP9), resulting in increased tumor cell migration and invasion through the activation of p38 and JNK MAPK pathways. To confirm potential adverse effects caused by TMZ, in this study, we constructed TMZ-resistant GBM cells through repeated culturing of cells by gradually doubling the TMZ concentration (12.5-300 µM). TMZ-resistant cells were analyzed for proteome profiling, revealing altered expression of several proteases including MMP2/9 and PAI-1. Compared to parental cells, resistant cells showed a significant increase in migration and invasion in vitro and either inhibition of JNK or suppression of MMP9 and PAI-1 dramatically counteracted the invasive potential of resistant cells. At the same time, media collected from TMZ-resistant cells significantly activated the migration and invasion potentials of normal fibroblasts. Further mechanistic studies demonstrated that TMZ-resistant cells retain higher promoter activities of MMP9 and PAI-1 through the regulation of MAPKs and β-catenin/TCF pathways. Since resistance to TMZ in GBM tumors leads to poor treatment outcomes and low survivability for patients, results from our study about potential adverse effects from ensuing TMZ-resistant cells may contribute to these malignant processes of GBM cells. Citation Format: Hien Thanh Duong, Thang Huu Nguyen, Seongwook Jeong, Kyung-Sub Moon, Chaeyong Jung. Temozolomide-resistant glioblastoma cells promote proteolytic activities of MMPs and PAI-1 to manifest invasive potentials [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 4406.
Abstract 4390: HJ-119, a novel, highly selective, orally bioavailable small molecule KRASG12D inhibitor
Authors: Fengtian Du, Huiqiao Ling, Shuai Luo, Li Zhang, Ruisi Wu, Zhenlong Gao, Na Guo, Li Tao
Journal: Cancer Research (2025)

Background: KRAS mutations are present in approximately 25% of human cancers, among which KRASG12D is the most common hotspot mutation subtype, accounting for 20%-50% of all KRAS mutations. KRASG12D mutation frequently occur in cancers such as pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and non-small cell lung cancer (NSCLC). Currently, no drug directly targeting KRASG12D has been approved. An effective therapy for KRASG12D mutant cancers represents a significant unmet need. Methods and Results: We developed a novel, highly selective, orally bioavailable small molecule inhibitor of KRASG12D, denoted as HJ-119, and evaluated its antitumor activities in both in vitro and in vivo studies. In vitro, HJ-119 exhibited effective antiproliferative activities against various KRASG12D mutant cell lines, including AsPC-1, A427, and GP2D, with IC50 &amp;lt; 15 nM. Consistent with the in vitro data, in AsPC-1 xenograft mouse model, tumor growth was significantly inhibited after HJ-119 treated and favorable safety profile was presented. Conclusions: Our findings demonstrate the potent antitumor activity of HJ-119, and manifest a promisingly therapeutic prospect for patients suffering from KRASG12D mutant tumors. Citation Format: Fengtian Du, Huiqiao Ling, Shuai Luo, Li Zhang, Ruisi Wu, Zhenlong Gao, Na Guo, Li Tao. HJ-119, a novel, highly selective, orally bioavailable small molecule KRASG12D inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4390.
Correction to: Neutrophil CRACR2A Promotes Neutrophil Recruitment in Sterile Inflammation and Ischemic Stroke
Authors: Jingu Lee, Brett Balzraine, Alexis Schweizer, Vasilisa Kuzmanova, Yousang Gwack, Babak Razani, Jin-Moo Lee, Deane F. Mosher, Jaehyung Cho
Journal: Circulation (2025)
Abstract 4404: BRPF1 inhibition restores chemosensitivity in triple negative breast cancer via ribosomal pathway modulation
Authors: Ozlem Yedier Bayram, Ahmet Cingöz, Ebru Yilmaz, Ali Cenk Aksu, Beril Esin, Nareg Pinarbaşi-Degirmenci, Ayşe Derya Cavga, Beyza Dedeoglu, Buse Cevatemre, Hamzah Syed, MArtin Philpott, Adam P. Cribbs, Udo Opperman, Nathan A. Lack, Ceyda Açılan Ayhan, Tamer T. Onder, Tugba Bagci Onder
Journal: Cancer Research (2025)

Abstract Triple-negative breast cancer (TNBC) is an aggressive cancer subtype lacking targeted therapies, leaving chemotherapy as the primary treatment option. However, acquired resistance to drugs like paclitaxel (Taxol) poses a significant challenge, often driven by complex genetic and epigenetic changes. Our study identifies bromodomain and PHD finger-containing protein 1 (BRPF1) as a critical epigenetic regulator of Taxol resistance in TNBC cells, linking it to ribosome biogenesis and ABCB1-mediated drug resistance. We developed Taxol-resistant TNBC cell lines using an escalating dose protocol. These cells exhibited sustained resistance to high doses of Taxol, accompanied by significantly elevated expression of ABCB1. Epigenome-wide CRISPR/Cas9 screens revealed that BRPF1 is required for the survival of Taxol-resistant cells. Genetic depletion or pharmacological inhibition of BRPF1 using small-molecule inhibitors sensitized resistant cells to Taxol. RNA sequencing and functional assays demonstrated that BRPF1 loss led to the downregulation of ribosomal biogenesis and translation-related genes, impairing global protein synthesis. Notably, BRPF1 was found to directly bind the ABCB1 promoter, regulating the elevated ABCB1 levels. These findings highlight BRPF1’s dual role in maintaining translation machinery integrity and modulating ABCB1-driven chemoresistance. In conclusion, our work identifies BRPF1 as a novel therapeutic target for combating Taxol resistance in TNBC. Targeting BRPF1 disrupts ribosome biogenesis and reverses ABCB1-mediated drug resistance, offering a promising strategy to overcome chemotherapy failure in aggressive breast cancers. This work was supported by The Scientific and Technological Research Council of Turkey (TUBITAK) 1003-216S461 and 1001-221S419. Citation Format: Ozlem Yedier Bayram, Ahmet Cingöz, Ebru Yilmaz, Ali Cenk Aksu, Beril Esin, Nareg Pinarbaşi-Degirmenci, Ayşe Derya Cavga, Beyza Dedeoglu, Buse Cevatemre, Hamzah Syed, MArtin Philpott, Adam P. Cribbs, Udo Opperman, Nathan A. Lack, Ceyda Açılan Ayhan, Tamer T. Onder, Tugba Bagci Onder. BRPF1 inhibition restores chemosensitivity in triple negative breast cancer via ribosomal pathway modulation [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 4404.
Abstract 4407: Taurine's potential role in tamoxifen resistant MCF-7 cells
Authors: Yazan I. Hamadneh, Mohammad Alwahsh, Aya Hasan, Ala A. Alhusban, Osama M. Younis, Roland Hergenröder, Lama Hamadneh
Journal: Cancer Research (2025)

Abstract Taurine is a non-proteinogenic amino acid synthesized from cysteine. Although taurine does not contribute to protein synthesis, it regulates glutathione metabolism, upregulates proliferative and anti-oxidative pathways, downregulates pro-apoptotic pathways, and improves mitochondrial function in normal tissues. However, the role of taurine in tumorigenesis and resistance development in cancer, especially breast cancer, is not widely understood. We aim to study metabolic and cellular changes associated with the taurine metabolism pathway in tamoxifen resistant (TAM-R) MCF-7 breast cancer cell lines. Methods: Three TAM-R MCF-7 models were developed using two strategies. The first was achieved by incrementally increasing the dose until reaching a predetermined dose (TAM-P). The second was achieved by taking cell lines from the first method and continuously treating them with 1μM of tamoxifen (TAM-C). NMR was used to quantify the levels of intracellular metabolites, and HPLC/MS-MS was used to calculate taurine uptake by the cells from media. Gene expression levels of ESR1, PI3KCA and PTEN were measured by RT-PCR. GSCA: Gene Set Cancer Analysis platform was used to check the association of a gene set consisting of taurine metabolism pathway genes (CDO1, ADO, GAD1, GAD2, CSAD) with the regulation of cancer related pathways. Results: Taurine, choline, and glutathione concentrations were significantly higher in TAM-C compared to tamoxifen-sensitive control and TAM-P, while cystine was lower in TAM-C. Taurine uptake from the media in TAM-C and control were slightly higher than TAM-P. ESR1 was 40 folds overexpressed in TAM-C and down regulated in TAM-P, while PI3KCA was overexpressed and PTEN was down regulated in both TAM-C and TAM-P. Moreover, there was a positive correlation between taurine metabolism pathway gene set and activation of ER pathway. Conclusion: The significant increase in taurine and decrease in cysteine in the TAM-C group cannot be explained by the marginal increase in taurine uptake alone, which necessities increased synthesis of the taurine. Overexpression of ESR1 in TAM-C could be caused by upregulation of the taurine synthesis pathway. However, overexpression of PI3KCA and down regulation of PTEN indicates reliance on PI3K/AKT/PTEN pathway instead of estrogen signaling pathway. Moreover, increased glutathione and choline concentrations increased antioxidative capacity, mitochondrial function, and resistance to oxidative stress. Citation Format: Yazan I. Hamadneh, Mohammad Alwahsh, Aya Hasan, Ala A. Alhusban, Osama M. Younis, Roland Hergenröder, Lama Hamadneh. Taurine's potential role in tamoxifen resistant MCF-7 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 4407.