tbuckley/cabot-search huggingface dataset:
Abstract 4329: Developing oncogenic mutant-selective antisense oligonucleotide to treat PIK3CA-mutated cancers
Authors: Peng Ning, Yamu Li, Clemens Burda, Zhenghe Wang
Journal: Cancer Research (2025)

Abstract Phosphatidylinositol 3-kinases are heterodimers consisting of a p110 catalytic domain and a p85 regulatory domain. PIK3CA, which encodes the p110α catalytic subunit, is frequently mutated in human cancer. The FDA approved a WT p110-specific inhibitor, alpelisib, to treat PIK3CA-mutant breast cancer patients a few years ago. However, alpelisib and other WT p110α inhibitors could cause severe hyperglycemia in patients because WT p110α inhibitors block the intracellular action of insulin on the liver and skeletal muscle, thereby creating a transient state of insulin resistance. Most PIK3CA/p110α oncogenic mutations occur at two hot spot regions, one in the helical domain and the other in the kinase domain. Recently, a couple of PIK3CA/p110α kinase domain mutant-specific inhibitors have been developed. Early-phase clinical trials showed that the kinase domain mutant-specific inhibitors did not cause severe hyperglycemia in patients. Half of all p110α mutations are in the helical domain, and the E545K is the most frequent recurrent helical domain mutation. However, developing small molecule inhibitors against the PIK3CA/p110α helical domain mutations remains challenging. To this end, we have developed antisense oligonucleotides (ASOs) that preferentially degrade PIK3CA/p110α helical domain mutant mRNAs. In a cell-based assay, our lead ASO (ASO18) potently and preferentially degraded the PIK3CA E545K mutant allele at low nM concentrations. In multiple subcutaneous xenograft models, intra-tumor injection of ASO18 significantly inhibits the growth of tumors that harbor a PIK3CA E545K mutation but not a PIK3CA WT tumor. Based on our previous findings that p85β dissociates from PIK3CA/p110α E545K mutant protein and translocates into the nucleus to stabilize EZH2, we further demonstrated that a combination of ASO18 with an EZH2 inhibitor tazemetostat synergistically suppress xenograft growth of tumors harboring a PIK3CA E545K mutation. To deliver the ASO systematically, we used an FDA-approved D-Lin-MC3-DMA lipid nanoparticle (LNP) formulation to load the ASO, showing that ASO capsulated efficiently (over 95%). Moreover, the dose of LNP-ASO in the nanomolar range could achieve the same potency as the micromolar level of free ASO in tissue culture cells. Experiments assessing the efficacy of the LNP-ASO in xenograft models are ongoing. To our knowledge, our study represents the first mutant-selective ASO against an oncogenic mutation, which may lead to the development of a mutant-selective ASO to treat patients whose tumors harbor a PIK3CA E545K mutation. Citation Format: Peng Ning, Yamu Li, Clemens Burda, Zhenghe Wang. Developing oncogenic mutant-selective antisense oligonucleotide to treat PIK3CA-mutated 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 4329.
Abstract 5343: Proximity labeling reveals role of 14-3-3 protein in CDK4/6 inhibitors resistance for hormone positive breast cancer
Authors: Wei-Ting Chung, Yi-Ru Tseng, Tsan-Jan Chen, Wenching Wang, Muh-Hwa Yang, Chun-Yu Liu, Yi-Fang Tsai, Chi-Cheng Huang, Ling-Ming Tseng, Ta-Chung Chao, Jiun-I Lai
Journal: Cancer Research (2025)

Abstract CDK4/6 inhibitors are currently standard of care for advanced hormone positive (HR+) breast cancer, and CDK6 overexpression induces resistance against CDK4/6 inhibitors. We incidentally discovered that overexpression of a CDK6 D224Y mutant mitigated this resistance. Mechanistic studies revealed that CDK6 overexpression resulted in suppressed apoptosis and increased G1/S progression after treatment with CDK4/6 inhibitors; these features were abolished when CDK6 D224Y was overexpressed. APEX2- based proximity labeling proteomics revealed CDK6 overexpression, but not CDK6 D224Y, induced proximity of the 14-3-3 protein YWHAB. Co-immunoprecipitation experiments confirmed YWHAB bound overexpressed wild type CDK6 but not CDK6 D224Y, and YWHAB knockdown decreased CDK6 protein in a proteosomal dependent manner, suggesting that YWHAB served as a chaperone role for CDK6 stablization. Knockdown of YWHAB reversed the resistance conferred by CDK6 amplification. Molecular modeling studies predicted that the aspartate-to-tyrosine mutation of CDK6 D224Y would result in destabilizing binding between CDK6 and YWHAB. Xenograft studies confirmed that CDK6 D224Y overexpression reversed the resistance conferred by CDK6 overexpression in vivo. Analysis of independent clinical cohorts revealed an association of 14-3-3 proteins with survival in HR (+) breast cancer. Both 14-3-3 beta (YWHAB) and zeta (YWHAZ) were associated with activation of G1/S pathway genes, suggesting a role for 14-3-3 proteins in CDK4/6 inhibitors treatment outcome. In a clinical cohort, high YWHAZ expression was associated with worse outcome to CDK4/6 inhibitors treatment. Transcriptomic studies revealed that high YWHAB/YWHAZ expression was associated with upregulated G1/S pathway signature, confirming a role of 14-3-3 proteins in CDK4/6-cyclinD-Rb-E2F axis. In summary, by studying CDK6 D224Y, we uncovered a role for the 14-3-3 protein YWHAB in CDK4/6 inhibitor resistance. Citation Format: Wei-Ting Chung, Yi-Ru Tseng, Tsan-Jan Chen, Wenching Wang, Muh-Hwa Yang, Chun-Yu Liu, Yi-Fang Tsai, Chi-Cheng Huang, Ling-Ming Tseng, Ta-Chung Chao, Jiun-I Lai. Proximity labeling reveals role of 14-3-3 protein in CDK4/6 inhibitors resistance for hormone positive 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 5343.
Abstract 6175: Sting pathway activation potentiates the antitumor efficacy of doxorubicin in soft-tissue sarcoma
Authors: Wonyoung Choi, Gi Yeon Lee, Sun-Young Kong
Journal: Cancer Research (2025)

Abstract Background: Systemic treatment for soft-tissue sarcoma (STS) primarily relies on cytotoxic chemotherapy. Doxorubicin remains the key agent for systemic treatment in STS, as effective targeted treatment is unavailable and immune checkpoint inhibitors have shown limited efficacy. This study investigated whether activation of the STING pathway could enhance the antitumor effect of doxorubicin in STS. Methods: STS cell lines were treated with doxorubicin to assess STING pathway activation, with Sting1 gene deletion used to validate its essential role. In a syngeneic mouse model of STS, the STING agonist ADU-S100 was administered intratumorally in combination with doxorubicin. Tumor-infiltrating CD45+ immune cells were magnetically sorted for RNA sequencing to identify differentially expressed genes and enriched pathways linked to STING activation. These immune-related genes were analyzed for their association with survival in the TCGA-SARC patient cohort. Results: Doxorubicin treatment in STS cell lines induced cytosolic DNA leakage, triggering STING pathway activation. Sting1 gene deletion in cells attenuated this doxorubicin-induced activation, but did not impact cell proliferation in vitro. In a syngeneic mouse model, doxorubicin suppressed tumor growth in vivo, an effect further enhanced by intratumoral co-administration of ADU-S100. RNA sequencing of CD45+ tumor-infiltrating immune cells revealed upregulation immune response pathways linked with STING signaling. In the TCGA-SARC cohort, patients with higher expression of genes upregulated in STING-activated tumors exhibited improved survival, while those with lower expression showed poorer overall survival. Conclusion: STING pathway activation by ADU-S100 enhances the antitumor efficacy of doxorubicin in STS, suggesting that combining doxorubicin with ADU-S100 may be a promising strategy for future clinical trials. Citation Format: Wonyoung Choi, Gi Yeon Lee, Sun-Young Kong. Sting pathway activation potentiates the antitumor efficacy of doxorubicin in soft-tissue sarcoma [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 6175.
Abstract 7196: Synergistic effect of sotorasib plus trametinib in patients with KRASG12C-mutated metastatic colorectal cancer
Authors: Silei Sui, Marwan Fakih, Yuan Li, Caiming Xu, Ajay Goel
Journal: Cancer Research (2025)

Abstract Background: KRAS is altered in approximately 40% of colorectal cancer (CRC), with the KRASG12C mutant (MUT) being particularly notable for its high prevalence in certain cancers that directly activates the MAPK pathway. Sotorasib, an irreversible, selective KRASG12C inhibitor, showed promising antitumor activity in KRASG12C-MUT colorectal cancer. However, despite recent FDA approval, the response rate of Sotorasib monotherapy in CRC remains below 10%. Herein, we aimed to investigate the synergistic efficacy for the combination of a MEK1 inhibitor (Trametinib) and Sotorasib in CRC. Methods: We conducted an integrative analysis of genomic and transcriptomic data, comparing pretreatment cases and those obtained following the development of resistance to Sotorasib. Dose-response curves were generated to determine the IC50 values of Sotorasib and Trametinib in CRC cell lines with distinct mutational profiles: SW837 (KRASG12C) and SW1463 (KRASG12C and MEK1 MUT). To further investigate the effects of the combination compared to the monotherapy of each drug, we performed a series of functional assays by focusing on perturbations within the MAPK/ERK/AKT signaling pathway. Results: Among the 27 patients analyzed, 10 were identified with putative resistance phenotype, of which 9 (37%) had acquired MEK1 mutations or amplifications. The Kaplan-Meier analysis for overall survival in CRC patients harboring wild-type and mutant MEK1. Functional analysis demonstrated a synergic effect of combined Sotorasib and Trametinib treatment in SW837 and SW1463 CRC cell lines. In MTT assays, the combination therapy significantly enhanced cytotoxicity compared to either monotherapy alone. Similarly, colony formation assay revealed a marked reduction in the proliferative capacity of CRC cells when treated with the combination therapy. Mechanistically, combination treatment with Sotorasib and Trametinib led to enhanced inhibition of the MAPK/ERK/AKT signaling pathway compared to monotherapy in SW837 and SW1463 cell lines. Furthermore, the introduction of activating mutations in MEK1 (MEK1K57T and MEK1K57N) demonstrated that combinatorial therapies of KRASG12C inhibitor and MEK1 inhibitors could effectively overcome the drug resistance acquired by these activating mutations. Conclusion: The combined treatment of Sotorasib and a MEK1 inhibitor, Trametinib, exhibit synergistic effects in drug-induced cytotoxicity and inhibition of MAPK pathways in colorectal cancer lines. Citation Format: Silei Sui, Marwan Fakih, Yuan Li, Caiming Xu, Ajay Goel. Synergistic effect of sotorasib plus trametinib in patients with KRASG12C-mutated metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7196.
Abstract 6626: Comprehensive, high sensitivity, high resolution, somatic variant detection in solid tumors with LinkPrep - an NGS assay
Authors: Cory C. Padilla, Ericca Stamper, Jonathan Torchia, Daniel Hwang, Mark Wadolkowski, Ek Danwanichakul, J. Zachary Sanborn, Lisa Munding
Journal: Cancer Research (2025)

Abstract The characterization of somatic variants, including structural variants (SVs), copy number variations (CNVs), and single-nucleotide variants (SNVs), is essential for understanding tumor biology. Current methodologies for somatic variant profiling are fragmented across several assays and requires ample sample material. We present LinkPrep™ assay, a novel linked-read NGS assay utilizing DNA proximity ligation, optimized for high sensitivity and high-resolution whole genome somatic variant detection. LinkPrep data enables unified profiling of SVs, CNVs, and SNVs/InDels from the same dataset, providing a streamlined approach to comprehensive genomic analysis. We applied the LinkPrep assay to a benchmark cohort consisting of cell lines (ductal carcinoma, HCC1187; myelogenous leukemia, K562) and clinically relevant tumor samples (ovarian serous adenocarcinoma, metastatic ovarian carcinoma, and nasal osteosarcoma). LinkPrep achieved high concordance with whole-genome sequencing (WGS) for CNVs (correlations &amp;gt;89% across all samples) while also detecting SVs with superior mean read support and robust F1 scores (cell lines). Moreover, LinkPrep demonstrated excellent overlap with WGS for SNVs and InDels, exceeding 92% across all samples, and identified critical oncogenic candidates. Notably, LinkPrep uncovered additional high-confidence SVs (including low SV VAF down to 1%) in clinical samples that were missed by WGS, highlighting its enhanced sensitivity for somatic variant detection in low tumor fraction samples. Furthermore, we demonstrate the ability to use LinkPrep data to refine SV breakpoints down to base pair resolution. The data underscore the utility of the LinkPrep assay in translational research, where precise and comprehensive variant detection is imperative. This study establishes the LinkPrep assay as a next-generation tool for the detection of somatic variants, offering a robust and scalable solution for cancer genomics. Citation Format: Cory C. Padilla, Ericca Stamper, Jonathan Torchia, Daniel Hwang, Mark Wadolkowski, Ek Danwanichakul, J. Zachary Sanborn, Lisa Munding. Comprehensive, high sensitivity, high resolution, somatic variant detection in solid tumors with LinkPrep - an NGS assay [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 6626.
Abstract 5460: C6P, a claudin 6 (CLDN6) directed ADC containing pyrolobenzodiazepine (PBD) for the treatment of advanced solid tumors
Authors: Xiaolan Yu, Shuting Wang, Lingfeng You, Zhibin Xu, Zhendong Xue, Yuchang Mao, Shuyu Cai, Jun Feng, Ting Zhang, Xin Ye, Min Hu, Feng He
Journal: Cancer Research (2025)

Claudin 6 (CLDN6), a member of the claudin family of tight junction proteins, is highly expressed in multiple solid tumors such as ovarian and endometrial cancers with limited expression in normal tissues. Here we developed an anti-CLDN6 ADC C6P comprising a Fc-silenced anti-CLDN6 monoclonal antibody, a cleavable linker and a modified PBD (compound A). C6P selectively bound to CLDN6 without cross-reactivity to other claudin family members such as CLDN 3/4/5/8/9. Additionally, it also bound to I143V-mutated CLDN6, a major single nucleotide polymorphism (SNP) in human population. The antibody demonstrated strong binding affinity to several ovarian cancer cell lines with different CLDN6 expression levels and showed good endocytosis. Compound A was an optimized mono-imine PBD dimer with less cytotoxicity than conventional bis-imine PBD dimers. High systemic clearance of this payload was also designed to minimize toxicities. To achieve homogeneous ADC, a glycan mediated site-specific conjugation was used to generate C6P. C6P showed CLDN6-dependent growth inhibition against various cell lines, without effect on CLDN6 negative cells. In PA-1 and OVCAR3 xenograft mouse models, C6P showed a dose-dependent anti-tumor effect and led to robust and sustained tumor regression. C6P demonstrated good stability and safety profiles, likely due to site-specific conjugation and the higher systemic clearance of compound A. Less than 1% payload release was observed in human plasma after a 21-days incubation. C6P was well-tolerated at a single dose of 0.5 mg/kg in cynomolgus monkeys and did not show hematology-related toxicity. The intact ADC/total antibody AUC ratio was above 95%, and the payload was undetectable in the plasma of cynomolgus monkeys after injection with C6P. Overall, the highly specific CLDN6-targeting antibody, the optimized PBD payload, site-specific conjugation and well-controlled DAR value collectively contributed to the potent anti-tumor efficacy, and good safety profile of C6P, supporting its future clinical research. Citation Format: Xiaolan Yu, Shuting Wang, Lingfeng You, Zhibin Xu, Zhendong Xue, Yuchang Mao, Shuyu Cai, Jun Feng, Ting Zhang, Xin Ye, Min Hu, Feng He. C6P, a claudin 6 (CLDN6) directed ADC containing pyrolobenzodiazepine (PBD) for the treatment of advanced solid 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 5460.
Abstract 5342: Inhibition of glutaminase elicits senolysis in therapy-induced senescent melanoma cells
Authors: Justin Kim, Bryce Brunetti, Ayanesh Kumar, Ankit Mangla, Kord Honda, Akihiro Yoshida
Journal: Cancer Research (2025)

Abstract The cyclin D1-Cyclin-Dependent Kinases 4 and 6 (CDK4/6) complex is crucial for the development of melanoma. We previously demonstrated that targeting CDK4/6 using small molecule inhibitors (CDK4/6i) suppresses BrafV600E melanoma growth in vitro and in vivo through induction of cellular senescence. However, clinical trials investigating CDK4/6i in melanoma have not yielded successful outcomes, underscoring the necessity to enhance the therapeutic efficacy of CDK4/6i. Accumulated research has shown that while senescence initially suppresses cell proliferation, a prolonged state of senescence eventually leads to tumor relapse by altering the tumor microenvironment, suggesting that removal of those senescent cells (in a process referred to as senolysis) is of clinical necessity to facilitate clinical response. We demonstrate that glutaminase 1 (GLS1) expression is specifically upregulated in CDK4/6i-induced senescent BrafV600E melanoma cells. Upregulated GLS1 expression renders BrafV600E melanoma senescent cells vulnerable to GLS1 inhibitor (GLS1i). Furthermore, we demonstrate that this senolytic approach targeting upregulated GLS1 expression is applicable even though those cells developed resistance to the BrafV600E inhibitor vemurafenib, a frequently encountered substantial clinical challenge to treating patients. Thus, this novel senolytic approach may revolutionize current CDK4/6i mediated melanoma treatment if melanoma cells undergo senescence prior to developing resistance to CDK4/6i. Given that we demonstrate that a low dose of vemurafenib induced senescence, which renders BrafV600E melanoma cells susceptible to GLS1i and recent accumulated research shows many cancer cells undergo senescence in response to chemotherapy, radiation, and immunotherapy, this senolytic therapy approach may prove applicable to a wide range of cancer types once senescence and GLS1 expression are induced. Citation Format: Justin Kim, Bryce Brunetti, Ayanesh Kumar, Ankit Mangla, Kord Honda, Akihiro Yoshida. Inhibition of glutaminase elicits senolysis in therapy-induced senescent melanoma 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 5342.
Abstract 7209: Status-agnostic therapy of breast cancer using antibodies targeting O-glycosylated proteins
Authors: Aaron C. Groen, Nisha Shrestha, Boris Klebanov, Byeongjun Yu, Beom Yong Lee, Yun-Hee Park, Chul-Woong Chung, Constantine Theodoropulos, Hans H. Wandall
Journal: Cancer Research (2025)

Abstract We have developed a novel antibody-drug conjugate (ADC), based on the mAb L100, that selectively targets a O-GalNAc-glycoprotein expressed in approximately 20% of all breast cancer. Unlike many ADC programs targeting Breast Cancer, L100 recognizes cancer-specific O-glycosylated versions of proteins do not present on normal tissues circumventing adverse events from on target off tumor binding to healthy tissues. The crystal structure of L100 provides insights into its binding specificity and affinity. L100 exhibits low nanomolar affinity (0.83nM) to the glycoprotein target and has also been developed as a companion diagnostic assay, further validating its potential as a therapeutic target. L100 is conjugated to the microtubule-disrupting agent MMAE and the topoisomerase inhibitor exatecan via a site-specific β-glucuronidase-cleavable linker. This linker is stable in plasma, but selectively releases the payload in tumor tissues, which exhibits a high expression pattern of beta-glucuronidase. In preclinical studies, the L100 ADC (LCB22A) demonstrated potent and selective cytotoxicity against various cancer cell lines (EC50=∼4.4 nM) and effectively eliminated tumors in breast cell-derived xenograft (CDX) and patient-derived xenografts (PDX) with MED = ∼2mpk. Importantly, L100-MMAE (LCB22A-MMAE) and L100-exatecan (LCB22A-exatecan) were well-tolerated in cynomolgus monkey toxicity studies, with no significant adverse events observed. Additionally, the ADC selectively killed target cells in a human mixed organotypic cancer model without affecting healthy cells, indicating excellent tolerability and safety. By specifically targeting cancer-specific O-glycans expressed only in cancer tissues and employing a tumor-selective payload release mechanism, L100 ADC (LCB22A) offers a promising and safe therapeutic option for treating breast cancer while avoiding the on-target off-tumor toxicity that plague other ADC therapies. Citation Format: Aaron C. Groen, Nisha Shrestha, Boris Klebanov, Byeongjun Yu, Beom Yong Lee, Yun-Hee Park, Chul-Woong Chung, Constantine Theodoropulos, Hans H. Wandall. Status-agnostic therapy of breast cancer using antibodies targeting O-glycosylated proteins [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 7209.