tbuckley/cabot-search huggingface dataset:
Abstract 4285: Modulation of spliceosomal protein hnRNPH1 in BRAF, NRAS, and triple-wild type melanoma induces immunogenicity and in vivo immune response
Authors: Maab Sultan, Sadeeshkumar Velayutham, Vladimir Beljanski, Keiran S.M. Smalley, Nhut Minh Nguyen, Shweta Shah, Tulsi Desai, Aveta Singh, Jun Yong Choi, Dmitriy Minond
Journal: Cancer Research (2025)

Abstract Background: We previously reported that treating WM266-4 with H1 siRNA, followed by RNAseq, resulting in increased immune related pathways. Additionally, we reported novel melanoma leads, 2155-14 and 2155-18, which act via downregulation of spliceosomal heterogenous nuclear ribonuclear proteins hnRNPH1/H2 (H1/H2) and demonstrated efficacy in an in vivo model of A375 BRAF mutation. This study aimed to determine the effect of H1 modulation on immune-related genes in vitro across melanoma cell lines with diverse mutational backgrounds and in vivo using a syngeneic mouse model. Methods: To assess in vivo immune response, 2155-14 and 2155-18 were tested in the B16F10 C57BL/6J syngeneic mouse model (n=5). In vitro, we knocked down H1/H2 in BRAF-mutant, NRAS-mutant, and triple-wild type melanoma cell lines and treated BRAF and NRAS cell lines with both compounds to evaluate immune responses to spliceosomal modulation. Data from in vivo experiments were analyzed using one-way ANOVA to compare means, followed by Sidak’s multiple comparisons for significant differences. Statistical significance was set at p &amp;lt; 0.05. For NanoString experiments, a 1.4-fold change and p-value &amp;lt;0.05 (n=3) were used as thresholds. Results: Treatment of B16F10 syngeneic melanoma mouse model with 2155-14 and 2155-18 resulted in increased tumor infiltration of macrophages (p-value &amp;lt;0.01), dendritic cells (p-value &amp;lt;0.05), B cells (p-value &amp;lt;0.05), and CD4+ T cells (p-value &amp;lt;0.05) as determined by flow cytometry analysis. Moreover, NanoString gene expression analysis of both transfected and treated samples confirmed upregulation of interferon signaling and cellular immune responses, processes known to enhance cellular immunogenicity. Conclusion: These findings highlight the therapeutic promise of targeting spliceosomal proteins H1 and H2, and they underscore the potential of 2155-14 and 2155-18 as promising drug candidates for melanoma treatment. Furthermore, the results suggest that spliceosomal inhibition can enhance immune system activation, presenting an opportunity to combine these therapies with FDA-approved immunotherapies to achieve improved treatment outcomes. Citation Format: Maab Sultan, Sadeeshkumar Velayutham, Vladimir Beljanski, Keiran S.M. Smalley, Nhut Minh Nguyen, Shweta Shah, Tulsi Desai, Aveta Singh, Jun Yong Choi, Dmitriy Minond. Modulation of spliceosomal protein hnRNPH1 in BRAF, NRAS, and triple-wild type melanoma induces immunogenicity and in vivo 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 4285.
Abstract 4286: CHK1 as a novel therapeutic target for pleural mesothelioma
Authors: Kazumasa Akagi, Hirokazu Taniguchi, Hiromi Tomono, Midori Matsuo, Hiroshi Gyotoku, Shinnosuke Takemoto, Yasuhiko Nakao, Seiji Yano, Kazuto Ashizawa, Hiroshi Mukae
Journal: Cancer Research (2025)

Abstract Background: Pleural mesothelioma (PM) is a rare thoracic malignant tumor with poor prognosis. First line nivolumab plus ipilimumab prolonged overall survival compared to standard chemotherapy, however its clinical benefit is limited and development of therapeutic strategy with novel mechanisms is strongly desired. In this study, we focused on CHK1, one of the major molecules involved in the DNA damage repair, as a candidate for novel therapeutic target since one of the hallmarks of PM is DNA damage repair, such as BAP1 loss or TP53 mutation. Method: The prognostic impact of CHK1 mRNA expression on PM was analyzed using RNAseq data of The Cancer Genome Atlas (TCGA). The anti-tumor effect of CHK1 inhibitor using human PM cell lines were evaluated by MTT assay and annexin V assay. The protein expression was evaluated by Western blotting and the mRNA expression was evaluated by qRT-PCR. The anti-tumor effects of CHK1 inhibitor in vivo were evaluated with subcutaneous tumor model that was established by injecting mouse PM cells subcutaneously in immunodeficient Balb/c nu/nu mice, and the pleural carcinomatosis model that was also established with injecting the mouse PM cells into the intrapleural space of immunocompetent Balb/c mouse. Results: The low CHK1 expression group demonstrated significantly longer overall survival than the high CHK1 expression group in PM cases of TCGA. CHK1 inhibitor had anti-tumor effect and induced apoptosis in a dose-dependent manner. CHK1 inhibitor increased micronuclei formation, activated STING pathway, and induced mRNA expression of type I and II interferons, CCL5, and CXCL10, suggesting CHK1 inhibitor activated anti-tumor immune response. PD-L1 expression was also increased by CHK1 inhibitor. CHK1 inhibitor demonstrated significantly suppressed tumor growth combined with cisplatin compared to CHK1 inhibitor alone in the subcutaneous mouse model. Furthermore, CHK1 inhibitor combined with anti-PD-L1 antibody significantly prolonged overall survival in the pleural carcinomatosis model. Conclusion: The CHK1 inhibitor showed immunostimulatory effect on PM in addition to direct anti-tumor effect. Furthermore, the therapeutic benefit was enhanced when combined with cisplatin or anti-PD-L1 antibody. Citation Format: Kazumasa Akagi, Hirokazu Taniguchi, Hiromi Tomono, Midori Matsuo, Hiroshi Gyotoku, Shinnosuke Takemoto, Yasuhiko Nakao, Seiji Yano, Kazuto Ashizawa, Hiroshi Mukae. CHK1 as a novel therapeutic target for pleural mesothelioma [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 4286.
Abstract 4284: Determining selectivity of MYC inhibitors via transcriptional monitoring of sentinel genes
Authors: Susanne Stockinger, Sabine Hartl, Manfred Koegl, Johannes Zuber, Matthias Samwer
Journal: Cancer Research (2025)

Abstract MYC is a key transcription factor with essential roles in development and tissue maintenance. Deregulation of MYC has been described in many cancers and several MYC inhibitors have been published, but their selectivity has often remained unclear. A key challenge is the short half-life of MYC mRNA and protein, making MYC particularly sensitive to general transcriptional and translational stress. Therefore, discrimination between on- and off-target effects on MYC and its transcriptional output is critical. Here, we used SLAMseq-derived direct target genes of MYC to establish a panel of sentinel genes to quantify direct and selective effects on MYC. Changes in transcriptional output of MYC are measurable within a few hours after various treatments and can discriminate between on-target MYC perturbation and off-target cytotoxic effects. We then used the assay to benchmark selectivity of various pre-clinical MYC inhibitors. Importantly, the assay principle can be transferred to other important transcription factor drug targets. Citation Format: Susanne Stockinger, Sabine Hartl, Manfred Koegl, Johannes Zuber, Matthias Samwer. Determining selectivity of MYC inhibitors via transcriptional monitoring of sentinel genes [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 4284.
Abstract 5759: Unraveling the roles of mTORC2 signaling in promoting aggressive glioblastoma characteristics through multi-omics analysis
Authors: Nuttiya Kalpongnukul, Rungnapa Bootsri, Gea A. Ecoy, Tankun Bunlue, Napatsakon Youngsanbhu, Chatchapon Chuenjit, Nuanwan Songcharoen, Trairak Pisitkun, Naphat Chantaravisoot
Journal: Cancer Research (2025)

The mechanistic target of rapamycin complex 2 (mTORC2) is a pivotal component of the mTOR signaling pathway, regulating critical cellular processes such as growth, proliferation, differentiation, survival, motility, and metabolism. Notably, mTORC2 facilitates actin cytoskeleton reorganization, cell motility, survival, and DNA damage repair. Aberrations in mTORC2 signaling are strongly associated with aggressive features of cancers, including glioblastoma (GBM), driving metastasis, drug resistance, recurrence, and tumor progression. However, unlike mTORC1, the molecular mechanisms governing mTORC2 functions remain less understood. To address this gap, we employed a comprehensive multi-omics approach—integrating transcriptomics, proteomics, phosphoproteomics, and interactomics—to investigate mTORC2-driven mechanisms underlying GBM aggressiveness. By leveraging computational big data analyses, we aimed to uncover therapeutic targets, identify biomarkers, and explore chemotherapy resistance mechanisms. Our findings reveal that mTORC2 signaling is intricately linked to key GBM hallmarks, including enhanced invasion, metastasis, genome instability, deregulated metabolism, and phenotypic plasticity. Disrupting mTORC2 profoundly altered intracellular regulatory mechanisms controlling these traits. Importantly, our analyses identified key molecular players driving these processes. Furthermore, we demonstrated that ATP-competitive inhibitors of mTOR kinase significantly enhanced the efficacy of temozolomide in GBM spheroid models, offering a promising strategy to overcome chemoresistance. These findings highlight the potential of targeting mTORC2-mediated pathways to develop more effective therapeutic strategies for aggressive cancers. Citation Format: Nuttiya Kalpongnukul, Rungnapa Bootsri, Gea A. Ecoy, Tankun Bunlue, Napatsakon Youngsanbhu, Chatchapon Chuenjit, Nuanwan Songcharoen, Trairak Pisitkun, Naphat Chantaravisoot. Unraveling the roles of mTORC2 signaling in promoting aggressive glioblastoma characteristics through multi-omics analysis [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 5759.
Abstract 3593: Effect of regular antidepressants use on cancer morbidity and mortality: A propensity score matched cohort study
Authors: Jing He, Yue Ma, chenyang Li, Fubin Liu, Yaogang Wang, Fengju Song
Journal: Cancer Research (2025)

Abstract Background—Antidepressant use is rising globally and has shown potential anticancer properties in vitro, but findings from observational studies have been inconsistent. We aimed to investigate the association between regular antidepressant use and cancer risk in a large prospective cohort with long-term follow-up. Methods—A total of 421, 529 participants without cancer or cardiovascular disease at baseline were obtained from the UK Biobank, recruited between 2006 and 2010 from 22 assessment centres across the UK. Regular antidepressant users were matched to nonusers using propensity score matching (PSM), adjusting for 21 key covariates, including age, sex, race, socioeconomic status, lifestyle factors, and medical history. The primary outcomes were overall cancer morbidity and mortality, with site-specific cancer morbidity as a secondary outcome. The association between different antidepressant subtypes and cancer risk was also examined. Findings—The median follow-up was 13.6 years. Of the participants, 26, 796 were regular antidepressant users and 394, 733 were nonusers. After 1:1 PSM, 26, 372 matched pairs were identified. Regular antidepressant use was associated with a reduced risk of overall cancer morbidity (HR 0.83, 95% CI 0.79-0.88), particularly for colorectal cancer (HR 0.75, 95% CI 0.65-0.86), and lower cancer-related mortality (HR 0.91, 95% CI 0.84-0.99) compared with nonusers. Among antidepressant subtypes, selective serotonin reuptake inhibitors (SSRIs) were associated with a 17% reduced risk of overall cancer morbidity (HR 0.83, 95% CI 0.79-0.88), especially for fluoxetine, citalopram, and sertraline. SSRIs were also associated with a 23% reduced risk of cancer-related mortality (HR 0.77, 95% CI 0.70-0.85), particularly with fluoxetine and citalopram. However, tricyclic antidepressants (TCAs) were linked to an increased risk of cancer-related mortality (HR 1.19, 95% CI 1.07-1.32), especially for amitriptyline. Interpretation—These findings provide important evidence for the potential repurposing of antidepressants in cancer prevention and treatment. However, TCAs, such as amitriptyline, were associated with an increased risk, warranting caution. Further research is needed to confirm these findings. Citation Format: Jing He, Yue Ma, chenyang Li, Fubin Liu, Yaogang Wang, Fengju Song. Effect of regular antidepressants use on cancer morbidity and mortality: A propensity score matched cohort study [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 3593.
Abstract 3038: Preclinical evaluation of combination therapy of HJ-037 with anti-PD-1 antibody treating KRASG12C mutated tumors
Authors: Na Guo, Xiangyu Yang, Longjun Yang, Fengtian Du, Huiqiao Ling, Ke Xue, Lina Zhang, Jianxin Ji, Zhigang Wu
Journal: Cancer Research (2025)

Abstract Background: The development and clinical application of KRASG12C inhibitors have made significant progress in recent years and some groundbreaking clinical results have been reported. However, overcoming resistance of KRASG12C-OFF covalent blockade remains a key focus in the fight against KRASG12C mutated cancers. Combination therapy may be one of the best treatment strategies to overcome the resistance. Methods and Results: HJ-037 is an orally available, potent, and highly selective covalent KRASG12C inhibitor, which showed significantly superior inhibitory activities against NCI-H358 and Mia PaCa-2 cells to current marketed KRASG12C inhibitors, and favorable safety profile was observed in pre-clinical study, providing a good safety foundation for its combination with PD-1 inhibitor. In a Colon Cancer CT26-mKRASG12C cell line subcutaneous syngeneic model, animals treated with HJ-037 plus anti-PD-1 antibody showed complete tumor regression without recurrence. A proof-of-concept clinical trial combining HJ-037 with PD-1 inhibitor is currently ongoing, and preliminary data shows a positive trend in efficacy and safety profile. Conclusions: Preclinical study results indicate that the combination therapy of HJ-037 with PD-1 inhibitor could enhance the intensity and duration of antitumor activity compared to monotherapy, with satisfactory safety, therefore possessing a better potential for the treatment of cancer patients harboring KRASG12C mutation. Citation Format: Na Guo, Xiangyu Yang, Longjun Yang, Fengtian Du, Huiqiao Ling, Ke Xue, Lina Zhang, Jianxin Ji, Zhigang Wu. Preclinical evaluation of combination therapy of HJ-037 with anti-PD-1 antibody treating KRASG12C mutated tumors [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 3038.
Abstract 4381: Preclinical studies of HEC211909, an orally bioavailable, high potent pan-KRAS inhibitor
Authors: Haiwang Liu, Hongming Xie, Fuxing Tan, Ning Kang, Ming Li, Yingjun Zhang
Journal: Cancer Research (2025)

Abstract Background: KRAS is the most commonly mutated oncogene, which is the driver in nearly 23% human cancers, and are especially prevalent in colorectal, lung, and pancreatic tumors. The KRAS signaling pathway is often hyperactivated in cancer cells due to KRAS gene mutations. This hyperactivation leads to uncontrolled cell proliferation, ultimately leading to the development and progression of cancer. There has been an urgent and unmet need to target KRAS mutations in KRAS-driven cancer. Methods: Biochemical HTRF assay was used to measure the inhibition of HEC211909 to both GDP-bound and GTP-bound state of various KRAS mutant. CellTiter-Glo assay was performed to determine the effects on proliferation of tumor cell lines. Several KRAS dependent tumor models were employed to study the in vivo pharmacodynamic and anti-tumor effects. Results: HEC211909 is a potent and orally bioavailable small molecule inhibitor of the KRAS oncogene, such as KRAS G12D, KRAS G12C, KRAS G12V, KRAS Q61H, KRAS G13D and KRAS wild-type amplifications. HEC211909 inhibits both active (GTP-bound) and inactive (GDP-bound) forms of multiple KRAS mutant protein with single-digit nanomolar IC50 values. HEC211909 has a strong anti-proliferative activity in a panel of KRAS mutant cancer cell lines and KRAS wild-type amplifications cancer cell lines in vitro with sub-nanomolar IC50 values, as well as significant inhibition of ERK1/2 phosphorylation with sub-nanomolar IC50 values. HEC211909 is highly selective for KRAS vs HRAS or NRAS, and is expected to be well-tolerated in normal tissues. In vivo, HEC211909 demonstrated dose-dependent anti-tumor activity with tumor regressions at 30 or 60 mg/kg given orally twice daily in KRAS-mutant xenograft models, such as PK59(KRAS G12D), HPAC(KRAS G12D), H358(KRAS G12C) xenograft models, and shows good tolerability during 21 days of treatment. Conclusions: HEC211909 is a highly potent and selective orally pan-KRAS(ON/OFF) inhibitor against KRAS G12D, KRAS G12C, KRAS G12V, KRAS Q61H, KRAS G13D mutations and also displays high selectivity over WT HRAS and NRAS, thus providing an expanded therapeutic index. Citation Format: Haiwang Liu, Hongming Xie, Fuxing Tan, Ning Kang, Ming Li, Yingjun Zhang. Preclinical studies of HEC211909, an orally bioavailable, high potent pan-KRAS 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 4381.
Abstract 5765: Illuminating the kinase activity starmap in NSCLC via tyrosine phosphoproteomics
Authors: Naizhong Zheng, Yi Liu, Jinfeng Yuan, Ying Hu, Yilin Wang, Tianhui Zhang, Aijuan Yu, Hui Zhou, Chao Zhou, Junjie Hou, Yinyin Xu, Xinxin Xu, Huan Ding, Yuxin Zhang, Rujie Zhong, Mengjie Yang, Chunyan Chang, Hongxuan Yan, Yuanyuan Shang, Weicong Ren, Shanshan Li, Hongdong Zhong, Yun Xiao, Zhang Zhang, Ming Han, Yu Pang
Journal: Cancer Research (2025)

In lung cancer treatment, understanding kinase activity, particularly tyrosine phosphorylation, is crucial but incomplete. We studied tyrosine phosphoproteomics in 74 patients with non-small-cell lung cancer (NSCLC) using SH2-Superbinder and data-independent acquisition mass spectrometry. We identified 1,048 tyrosine phosphosites, the highest number reported in lung cancer research. We constructed a tyrosine phosphorylation starmap, enabling a novel and intuitive analysis of tumors versus normal adjacent tissues, revealing kinases driving tumor progression and metastasis. Subsequently, patients were stratified by kinase activity for multiple precision medicine perspectives. “Cold” and “hot” tumors were divided based on immune kinase activity, while cancer driver kinase profiling revealed vulnerability to BRD4 inhibitors in wild-type lung cancer cells. EGFR-L858R mutations benefited from combining MEK and EGFR inhibitors. Two distinct kinase activity panels predicted patient survival across different mutation backgrounds. Our findings underscore the diverse kinase activities in NSCLC and highlight the need for personalized therapy based on these profiles. Citation Format: Naizhong Zheng, Yi Liu, Jinfeng Yuan, Ying Hu, Yilin Wang, Tianhui Zhang, Aijuan Yu, Hui Zhou, Chao Zhou, Junjie Hou, Yinyin Xu, Xinxin Xu, Huan Ding, Yuxin Zhang, Rujie Zhong, Mengjie Yang, Chunyan Chang, Hongxuan Yan, Yuanyuan Shang, Weicong Ren, Shanshan Li, Hongdong Zhong, Yun Xiao, Zhang Zhang, Ming Han, Yu Pang. Illuminating the kinase activity starmap in NSCLC via tyrosine phosphoproteomics [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 5765.
Abstract 4386: HJ-099, a novel, orally bioavailable pan-KRAS (ON) non-covalent inhibitor, demonstrates significant antitumor activity in multiple preclinical models with KRAS mutations
Authors: Xiangyu Yang, Fengtian Du, Na Guo, Huiqiao Ling, Shuai Luo, Xiaorong Yu, Qingqing Qian, Ruisi Wu, Jingyu Tian, Jianxin Ji, Li Zhang
Journal: Cancer Research (2025)

Abstract Background: KRAS is one of the most common mutated oncogenes in cancer, which primarily stimulates tumor growth by activating the MAPK pathway. Tumors with non-KRASG12C mutations, such as KRASG12D, KRASG12V, and other codon mutation subtypes, currently lack compelling precision medicines. Therefore, the development of pan-KRAS inhibitor is an unmet and pressing clinical need. Methods and Results: Here, we report a novel, orally bioavailable pan-KRAS (ON) inhibitor HJ-099, designed to treat various KRAS mutation-driven tumors. HJ-099 exhibited significant anti-proliferative activity against multiple KRAS mutated cancer cell lines, including SW620, MAI PaCa-2, NCI-H358, AsPC-1, and NCI-H441, with IC50 &amp;lt;1.5 nM. In multiple KRAS mutated xenograft mouse models, HJ-099 showed significant inhibition on tumor growth. Tissue distribution study in tumor-bearing murine model showed that HJ-099, after oral administration, were mainly detected in the tumors, and the long-lasting accumulation of HJ-099 in tumor tissues resulted in more potent and durable antitumor activity in vivo. Conclusions: The study indicates that HJ-099 is a novel, highly active pan-KRAS (ON) inhibitor that shows significant tumor suppression activity against major KRAS mutation subtypes, and merits clinical evaluation. Citation Format: Xiangyu Yang, Fengtian Du, Na Guo, Huiqiao Ling, Shuai Luo, Xiaorong Yu, Qingqing Qian, Ruisi Wu, Jingyu Tian, Jianxin Ji, Li Zhang. HJ-099, a novel, orally bioavailable pan-KRAS (ON) non-covalent inhibitor, demonstrates significant antitumor activity in multiple preclinical models with KRAS mutations [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 4386.