Cancer research最新文献

{"title":"Abstract CT010: Phase I dose-escalation and expansion study of JS107, a claudin 18.2 (CLDN18.2)-targeting antibody-drug conjugate (ADC), as monotherapy or in combination for patients (pts) with advanced solid tumors","authors":"Rui-Hua Xu, Dan-Yun Ruan, Rong-Bo Lin, Jian-Zhen Shan, Peng Nie, Ying-Hua Ji, Jing Wang, Yu Cao, Fu-Nan Liu, Jie-Er Ying, Li Liu, Tao Zhang, Hui-Ting Xu, Yan-Qiao Zhang, Wen-Can Song, Jin Xia, Wen-Feng Li, Zhi-Ye Zhang, Jian Shi, Ming-Xia Wang, Long Wu, Yan-Yan Lu, Xiao Zhang, Yan-Yan Hu, Yong-Dong Zhang","doi":"10.1158/1538-7445.am2025-ct010","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-ct010","url":null,"abstract":"Background: JS107 is a monomethyl auristatin E conjugated, CLDN18.2 specific ADC. JS107 exhibited potent anti-tumor activities in preclinical studies with a tolerable safety profile. Here we report the safety and efficacy results of JS107 monotherapy or in combination for pts with advanced solid tumors from the first-in-human phase 1 trial (NCT05502393). Methods: In Part A of the study, pts with advanced solid tumors refractory to standard therapies were treated with JS107 at 0.15-3.5 mg/kg Q3W during dose escalation and CLDN18.2+ pts were treated with JS107 at 2.0 and 3.0 mg/kg Q3W during dose expansion. In Part B of the study, pts with CLDN18.2+, HER2-negative, previously untreated, advanced gastric or gastroesophageal junction cancer (GC/GEJ) were treated with JS107 combined with toripalimab (240 mg Q3W) and XELOX (capecitabine and oxaliplatin), in dose escalation (JS107 at 2.0-3.0 mg/kg Q3W) and expansion (JS107 at 2.0 mg/kg Q3W) phases. The primary endpoint was safety. Secondary endpoints included efficacy and pharmacokinetics (PK). Results: As of January 7, 2025, 63 pts were enrolled in Part A (22 in dose escalation and 41 in dose expansion) and 27 enrolled in Part B (9 in dose escalation and 18 in dose expansion). The maximum tolerated dose was not reached for JS107 monotherapy and was 2.5 mg/kg for combination treatment. Grade 3 and above treatment-related adverse events (TRAEs) occurred in 47.6% pts in Part A and 40.7% pts in Part B. The most frequent grade 3 and above TRAE was neutropenia (22.2%) in Part A and thrombocytopenia (18.5%) in Part B. Among pts with CLDN18.2-high (defined as ≥20% of tumor cells with ≥2+ staining intensity) GC/GEJ who received JS107 monotherapy at 2.0-3.0 mg/kg (n=24), the objective response rate (ORR) was 34.8% (8/23, 95%CI 16.4-57.3) and median progression-free survival was 4.11 months (95%CI 3.15-9.63). Among efficacy evaluable pts with CLDN18.2-high GC/GEJ in Part B (n=14), the ORR was 78.6% (11/14, 95%CI 49.2-95.3). A positive association between CLDN18.2 expression level and efficacy was observed in Part A and Part B. PK analysis showed a dose-dependent ADC and total antibody exposure at doses of 0.15-3.5 mg/kg. JS107 elimination half-life was 4.41-6.96 days at doses of 2.0-3.5 mg/kg, with no obvious accumulation observed after multiple dosing. Conclusions: JS107 monotherapy or in combination with toripalimab and XELOX showed promising efficacy in pts with CLDN18.2-high advanced GC/GEJ with a manageable safety profile. The clinical benefit of CLDN18.2 ADC combination treatment was thus demonstrated for the first time. Further clinical development of JS107 in CLDN18.2+ advanced solid tumors is warranted. Citation Format: Rui-Hua Xu, Dan-Yun Ruan, Rong-Bo Lin, Jian-Zhen Shan, Peng Nie, Ying-Hua Ji, Jing Wang, Yu Cao, Fu-Nan Liu, Jie-Er Ying, Li Liu, Tao Zhang, Hui-Ting Xu, Yan-Qiao Zhang, Wen-Can Song, Jin Xia, Wen-Feng Li, Zhi-Ye Zhang, Jian Shi, Ming-Xia Wang, Long Wu, Yan-Yan Lu, Xiao Zhang, Yan-Yan Hu,","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"15 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract LB292: Endocrine therapy-resistant luminal A breast cancer cell lines are sensitive to the novel YES1/SRC tyrosine kinase inhibitor, NXP900","authors":"Iñigo Lanzagorta Calvillo, Enrique Poradosu, Neil Carragher, Asier Unciti-Broceta","doi":"10.1158/1538-7445.am2025-lb292","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb292","url":null,"abstract":"Background: The majority of patients with breast cancer present with tumors that are estrogen receptor positive (ER+), thus endocrine therapies have become the main treatment option for this type of cancer. However, endocrine resistance inevitably develops over time, resulting in an unmet clinical challenge to treat this breast cancer subtype. The novel YES1/SRC tyrosine kinase inhibitor NXP900, currently in phase 1 clinical trials, binds SRC in its ‘autoinhibited’ inactive conformation, thereby inhibiting the phosphorylation and the scaffolding properties of the kinase1. Recent findings using ER+ cell lines show increased sensitivity with NXP900 as opposed to other kinase inhibitors, such as dasatinib or bosutinib. The aim of the study was to investigate the therapeutic potential of NXP900 in combination with endocrine therapies, as well as the potential to treat ER+ cell lines with acquired endocrine resistance. Methods: ER+ cell lines were simultaneously treated with combinational dose-ratios of NXP900 and endocrine therapy, and viability determined using PrestoBlue assays. ER+ cell lines were cultured with endocrine therapy until resistance was acquired, approximately 1 year; periodical assays were undertaken during the course of the experiment to investigate mRNA abundance (RT-qPCR), drug sensitivity (cell viability), and growth (clonogenic assays) over time. Results: Statistical analysis using SynergyFinder+ demonstrated significantly stronger synergistic interactions in ER+ cell lines treated with endocrine therapy in combination with NXP900, rather than in combination with other kinase inhibitors. The longitudinal study of ER+ cell lines cultured with endocrine therapy showed continuous sensitivity to NXP900 treatment as endocrine resistance developed. Conclusions: Our results suggest that ER+ cell lines are more sensitive to endocrine therapy in combination with NXP900 rather than in combination with other kinase inhibitors. Additionally, our longitudinal data suggests that NXP900 is a strong therapeutic candidate to treat ER+ cell lines with acquired endocrine resistance. This study supports the potential translation of NXP900 into an adjuvant clinical setting, alongside endocrine therapies, to improve breast cancer treatment in patients with ER+ tumors. References 1. Temps C, Lietha D, Webb ER, et al. A Conformation Selective Mode of Inhibiting SRC Improves Drug Efficacy and Tolerability. Cancer Res. 2021;81(21):5438-5450. doi:10.1158/0008-5472.CAN-21-0613 Citation Format: Iñigo Lanzagorta Calvillo, Enrique Poradosu, Neil Carragher, Asier Unciti-Broceta. Endocrine therapy-resistant luminal A breast cancer cell lines are sensitive to the novel YES1/SRC tyrosine kinase inhibitor, NXP900 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2): nr LB292.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"41 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract LB131: The role of the proinflammatory cytokine IL-1β and its signaling cascade in glioblastoma pathogenesis and the therapeutic effect of IL-1RA and Tolcapone as anticancer agents","authors":"Jagadeesh Narasimhappagari, Ling Liu, Meenakshisundaram Balasubramaniam, Srinivas Srinivas Ayyadevara, Orwa Aboud, W Sue T Griffin","doi":"10.1158/1538-7445.am2025-lb131","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb131","url":null,"abstract":"Introduction: Interleukin-1 beta (IL-1β) is the major driving force in neuroinflammation. Here, we report on (i) the role of IL-1β in activating a signaling cascade that leads to proliferation and metastasis in glioblastoma cancer pathogenesis, and (ii) the potential of a therapeutic role for IL-1Receptor Antagonist (IL-1 RA) and Tolcapone against these untoward aspects of tumor pathogenesis. Materials and Methods: U87 glioblastoma cells were used to study the effect of IL-1β on proliferation and metastasis in vitro. RT-PCR was used to assess the gene expression levels of IL-1β-treated U87 cells for the TLR-MYD88-NF-κB signaling cascade in comparison to these levels in U87 cells treated with IL-1RA or Tolcapone. Western blotting analysis was used to assess the expression levels of signaling proteins involved in cancer proliferation and metastasis. Fluorescent Microscopy was used to identify the Glial fibrillary acidic protein (GFAP) expression in IL-1β-treated U87cells. Results: IL-1β increased the proliferation of U87 glioblastoma cells in vitro. IL-1β at 50ng/mL increased the proliferation at 48h (30 times (p≤0.05; t-test) which led to the formation of clones where rapidly dividing cancer cells aggregate together leading to the formation of organized GFAP-positive, clone-like structures with protruding spikes. RT-PCR results showed that IL-1β treatment at 50ng/mL significantly increased the expression of mRNA levels of TLR-MyD88-NF-κB-TNFα and IL-6 (p≤0.05; t-test) which are known to stimulate the over expression of growth factors including VEGF or EGF and cell adhesion molecules like Collagen, fibronectin and vimentin which help in tumor growth and metastasis. IL-1β also increased autophagy by upregulating cathepsin B, LAMP-2 and LC3B levels both at the mRNA and protein levels as well as increased expression of TLR2, MyD88, NF-κB, Calcineurin and IL-6 in IL-1β treated cells. In contrast, IL-1RA and Tolcapone inhibited the proliferation and the expression of these proteins, inhibiting autophagy by down regulating autophagy proteins and inducing apoptosis by upregulating the expression of apoptotic markers like caspase-8 and caspase-3. Further, IL-1β at 50ng/mL increased the expression of GFAP (1.5X; p≤0.05; t-test) at 48h. Conclusion: Our findings support our contention that neuroinflammation, read as elevated levels of IL-1β, increases the proliferation and metastasis of U87 glioblastoma, via the TLR-MyD88-NF-κB- TNFα and IL-6 signaling cascade. IL-1β increased the expression of GFAP in glioblastoma cells which may be correlated with its high metastatic and invasive nature. Our findings are consistent with our hypothesis (i) that IL-1β is responsible for increased proliferation and metastasis of U87 glioblastoma cells; and (ii) that IL-1β and its receptor can be targets of successful anticancer therapy such as shown here with the use of IL-1RA and/or Tolcapone as agents that as shown here may be useful in inhibiting these effects. Citation For","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"3 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract CT038: Phase 1 study of anti-CCR8 antibody CHS-114 with and without anti-PD-1 antibody toripalimab in patients with advanced solid tumors","authors":"Francis Worden, Cristina Rodriguez, Amita Patnaik, Justin Call, A. Dimitrios Colevas, Ammar Sukari, Trisha Wise-Draper, Nabil Saba, Koho Iizuka, Hong Tang, Varun N. Kapoor, Douglas Adkins","doi":"10.1158/1538-7445.am2025-ct038","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-ct038","url":null,"abstract":"Background: Selective depletion of intratumoral regulatory T cells (itTregs) is an attractive immunotherapy strategy. CHS-114 is a selective, cytolytic anti-CCR8 mAb designed to deplete immunosuppressive CCR8+ itTregs and remodel the tumor microenvironment (TME) to promote antitumor immunity. We present interim data from an ongoing phase 1 study focused on recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Methods: This multicenter ongoing phase 1 study (NCT05635643) enrolled adults whose disease progressed on or after standard therapies into 3 arms (Q3W IV cycles): Arm 1a (CHS-114 dose escalation from 5 to 1200 mg); Arm 1b (2 dose levels [DL1 or DL2] of pharmacologically active CHS-114); Arm 2 (CHS-114 DL1 or DL2 + toripalimab [tori] 240 mg). Arm 1a evaluated patients (pts) with solid tumors; Arms 1b and 2 evaluated pts with HNSCC, and Arm 1b required paired tissue biopsies. Primary objectives were to optimize the CHS-114 dose(s) for expansion and evaluate the safety of CHS-114 + tori. Secondary objectives were to evaluate the safety, PK and antitumor activity of CHS-114 ± tori and assess changes in Tregs and CD8 T cells in paired tumor biopsies and other immune biomarkers. Results: Two DLs were selected for dose optimization based on safety, peripheral CCR8+ Treg depletion, PK and biomarker data. As of October 20, 2024, 30 pts received CHS-114 (Arms 1a [n=20], 1b [n=3], 2 [n =7]). Rapid and sustained peripheral blood CCR8+ Treg depletion was observed at all DLs. No dose-limiting toxicities were reported. CHS-114 treatment-related adverse events (TRAEs) occurred in 40% of pts in Arms 1a, 67% in 1b, and 100% in 2. The most common TRAEs were: fatigue, sweats and nausea (33% each) in Arm 1b and fatigue, pain, infusion-related reaction (IRR), ALT and/or AST increased (29% each) in Arm 2; there were no serious TRAEs or TRAEs leading to death in Arms 1b or 2. The most common Grade ≥3 TEAEs were wound infection, anemia, swelling face, hyponatremia (33% each) in Arm 1b and wound infection, hypoxia, oropharyngeal fistula, IRR, ALT increased, blood alkaline phosphatase increased (14% each) in Arm 2. In on-treatment tumor biopsies, CCR8+ itTreg depletion with increased CD8+ T cells infiltration was observed, indicating favorable TME remodeling. Increased immune activation biomarkers were observed in blood. In Arm 2, one confirmed PR occurred with CHS-114 DL2 + tori (after the data cutoff date). Conclusions: CHS-114 with and without tori had an acceptable safety profile, depleted CCR8+ Tregs and increased CD8 T cells in the TME in pts, supporting further evaluation of CHS-114 in combination with other drugs including tori. Updated safety, efficacy, tumor biopsy and biomarker data will be presented. Citation Format: Francis Worden, Cristina Rodriguez, Amita Patnaik, Justin Call, A. Dimitrios Colevas, Ammar Sukari, Trisha Wise-Draper, Nabil Saba, Koho Iizuka, Hong Tang, Varun N. Kapoor, Douglas Adkins. Phase 1 study of anti-CCR8 antibody CHS-","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"28 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract LB290: Identifying novel mechanisms of resistance to KRAS-inhibitors in NSCLC","authors":"Samrat Kundu","doi":"10.1158/1538-7445.am2025-lb290","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb290","url":null,"abstract":"Mutations in the KRAS oncogene are commonly associated with pancreatic, colorectal, and lung malignancies. A frequently observed mutation involves the substitution of glycine at position 12 (e.g., G12C, G12D, G12V), which locks the protein in its active conformation, driving uncontrolled cell growth. KRAS was considered \"undruggable\" for decades due to its lack of accessible binding sites. Recent breakthroughs, however, have led to the development of covalent inhibitors such as Sotorasib (AMG510) and Adagrasib (MRTX849), which specifically target the KRAS G12C mutation and have received FDA approval following successful clinical trials. Research efforts are now focused on discovering inhibitors for other KRAS mutations, including the noncovalent KRAS-G12D inhibitor MRTX1133 and the pan-KRAS inhibitor BI3706674, offering new hope for KRAS-driven cancers. While these inhibitors have shown early success, resistance to treatment frequently arises, and the mechanisms behind this resistance remain unclear. To address this critical challenge, we are leveraging pre-clinical syngeneic mouse models and KRAS mutant allele-specific cell lines to investigate the molecular pathways responsible for resistance to allele-specific KRAS inhibitors. By generating a panel of acquired resistant cell lines from both murine syngeneic and human NSCLC models, we have begun to uncover the molecular drivers of resistance. Proteomic profiling using RPPA analysis has identified significant changes in protein expression, with the YAP/TEAD1 and the PDK1 pathways consistently upregulated in cells resistant to MRTX849 (G12Ci), MRTX1133 (G12Di) and the pan-RAS inhibitor BI3706674. Notably, resistant cells regained sensitivity to KRAS inhibitors when treated in combination with a TEAD inhibitor or PDK1 inhibitor in vitro. In vivo tumors from syngeneic mice implanted with resistant or sensitive cells and treated with KRAS inhibitors over 3-4 weeks exhibited increased nuclear localization of YAP1 and elevated expression of PDK1 in the drug-resistant tumors. Using genetic knockout and over-expression models, we could establish that both PDK1 and YAP1 are necessary and sufficient to impart resistance to MRTX1133 (G12Di). When we administered a combination treatment of MRTX1133 with a TEADi to mice bearing MRTX1133-resistant tumors, we also observed a partial reversal of MRTX1133 resistance. Currently, we are performing in vitro and in vivo studies to understand the role of PDK1 signaling in MRT1133 resistance. We are also trying to understand the molecular crosstalk between the PDK1 and YAP1/TEAD signaling pathways to functionally induce or maintain resistance to MRTX1133. Achieving the objectives of this research project will be instrumental in addressing the critical challenge of overcoming resistance to KRAS inhibitors and enhancing their effectiveness in clinical applications. Citation Format: Samrat Kundu. Identifying novel mechanisms of resistance to KRAS-inhibitors in NSCLC [abs","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"15 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract LB220: Microfluidic devices to decipher the role of the microenvironment in drug resistance","authors":"Mohammad Amir Mishan, Ali Rahnama, Ines Pulido Endrino, Laura Gunder, Malek Massad, Khaled Abdelhady, Agustin Lahoz, Ian Papautsky, Takeshi Shimamura","doi":"10.1158/1538-7445.am2025-lb220","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb220","url":null,"abstract":"Non-small cell lung carcinoma (NSCLC) is the leading cause of cancer-related deaths worldwide, with adenocarcinoma being the primary histological subtype. Third-generation EGFR tyrosine kinase inhibitor (TKI) osimertinib is the first-line treatment for NSCLC patients with tumors harboring EGFR kinase domain mutations, significantly improving patient survival. However, mechanisms of acquired drug resistance inevitably emerge and must be addressed. While the acquisition of secondary mutations in EGFR, such as C797S mutation, is a known resistance mechanism, non-genetic mechanisms of drug resistance, including vasoconstriction reducing the flow of the blood and the drug to the tumors, have also been observed and are highly significant. We have developed microfluidic devices that support the independent growth of tumor spheroids and patient-derived organoids (PDOs). These platforms feature U-shaped microwells that enable the sustained growth of spheroids for several weeks. This system has proven highly effective for viability assays using small samples including PDOs, suggesting its potential application in personalized medicine assays. More recently, these devices have been employed to evaluate the impact of tumor microenvironment (TME) components, such as endothelial and aortic smooth muscle cells, on drug sensitivity. Indirect co-culture of endothelial HUVEC cells and H6080 aortic smooth muscle cells with various EGFR mutant NSCLC cells promoted EGFR TKI resistance in the epithelial cells, increasing the IC50 by the factor of 10 in H1975 and HCC827. Pharmacodynamic analyses revealed that ERK phosphorylation levels in the presence of supernatants from endothelial and vascular cells, indicating a significant paracrine interaction between TME cells and tumor cells. Notably, this enhanced drug resistance was also observed in KRASG12C H358 mutant cells in response to adagrasib, a KRASG12C inhibitor.Interestingly, this microfluidic device can be optimized to measure relevant chemokines and cytokines secreted by cell lines and PDOs. Characterizing the content and concentrations of various metabolites is particularly important. For example, we have demonstrated that elevated levels of EDN1 promote vasoconstriction leading to drug resistance both in vitro and in vivo. The HCC827, HCC4006 and H1975 EGFR-mutant cell lines show a significant increase in EDN1 mRNA expression and decrease in VEGFA mRNA after 72h of osimertinib treatment. This transcriptional regulation of EDN1 and VEGF-A result in elevated level of EDN1 peptide and depleted VEGF-A in cell lines and EGFR-mutant PDOs including RLUN007. The resulting changes in the peptides promoted vasoconstriction in tumor-feeding vessels and reduced concentration of osimertinib in tumors. These findings underscore the need to develop tools that replicate and mimic the intricate interactions between tumor cells and the TME. Such advancements will enable the use of relevant and limited patient samples to implemen","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"7 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract LB187: YF087 is a potent and selective inhibitor of WRN, specifically targeting MSI-H cancer cells","authors":"Yaolin Wang, Rongfeng Liu, Yanxin Yu, Hong Yang, Jifang Weng, Yan Weng, Hong Mei, David Dai","doi":"10.1158/1538-7445.am2025-lb187","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb187","url":null,"abstract":"The impairment of DNA mismatch repair (MMR) function occurs in various cancers, including colorectal (15%), gastric (22%), endometrial (20-30%) and ovarian (10-15%) cancers. MMR-deficient (dMMR) cancers are characterized by a high mutational load and frequent insertion and/or deletion events in repetitive DNA sequences, a condition known as microsatellite instability-high (MSI-H). The Werner syndrome protein (WRN) is essential for the survival of cancer cells exhibiting microsatellite instability (MSI) and represents a synthetic lethal target for MSI-H/dMMR cancers. We have identified YF087, a highly selective, reversible and potent WRN inhibitor that has demonstrated robust activity in both in vitro anti-proliferation assays and in vivo cancer xenograft models. YF087 exhibited an IC50 of 8.1 nM in the WRN helicase enzymatic assay and an IC50 of 42 nM in the anti-proliferation assay in SW48 (MSI-H) colorectal cancer cell. YF087 exhibits excellent selectivity against another helicase BLM at the enzymatic level and is highly selective for MSI-H cells compared to microsatellite stable (MSS) cell in the anti-proliferation assay. YF087 is more effective than both WRN reversible inhibitor HRO761 and irreversible inhibitor RG6457 in the SW48 cellular anti-proliferation assay in the presence of 50% human serum. In the HCT116 colorectal cancer xenograft model, 5 mg/kg, 15 mg/kg and 45 mg/kg YF087 oral and daily treatment for 22 days induced regression rates of 32%, 43% and 57%, respectively. Tumors continue to regress after the treatment ends and remained tumor-free status for more than two months after dose termination at the 45 mg/kg dose. YF087 also exhibits superior in vivo anti-tumor efficacy in other MSI-H/dMMR cancer xenograft models upon oral and daily treatment and maintained longer tumor regression after termination of treatment vs HRO761 and RG6457. In patient derived MSI-H gastrointestinal cancer models resistant to anti-PD-1 therapy, treatment with YF087 resulted in tumor inhibition or regression. YF087 also possesses favorable preclinical ADME profiles suitable for clinical development. Based on these findings, YF087 is currently in IND-enabling studies to support phase 1 clinical trial in MSI-H/dMMR cancer patients. Citation Format: Yaolin Wang, Rongfeng Liu, Yanxin Yu, Hong Yang, Jifang Weng, Yan Weng, Hong Mei, David Dai. YF087 is a potent and selective inhibitor of WRN, specifically targeting MSI-H cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2): nr LB187.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"124 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract LB453: Elucidating the signaling mechanisms of Galpha13-mediated inflammation and tumor suppression in pancreatic cancer","authors":"Khadijeh Karbalaei, Anastasia E. Metropulos, Khulood Alzahrani, Apurba Majumder, Thao N. Pham, Hidayatullah G. Munshi, Mario A. Shields","doi":"10.1158/1538-7445.am2025-lb453","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb453","url":null,"abstract":"Host inflammation and tumor-driving genetic alterations significantly influence the immune microenvironment of pancreatic cancer. Indeed, chronic pancreatitis (CP) is a major risk factor for pancreatic ductal adenocarcinoma (PDAC), which is characterized by an early inflammatory response that evolves with tumor initiation and progression. Our previous work highlighted the role of the Pdk1/mTOR signaling axis in promoting pancreatic cancer development, particularly after genetic ablation of Gα13, a heterotrimeric G-protein frequently dysregulated in human tumors. To further investigate how Gα13 modulates the inflammatory response in both pancreatitis and pancreatic cancer, we employed mouse models to examine its role in inflammatory cytokines expression and mTOR signaling. We found that pancreas-specific loss of Gα13 exacerbated tissue injury, elevated pro-inflammatory cytokines, and increased macrophage recruitment in models of pancreatitis. Additionally, loss of Gα13 promoted mTOR signaling in these models, mirroring our earlier findings in pancreatic cancer. Interestingly, while mTOR inhibition alleviated tissue damage and suppressed inflammation in acute pancreatitis, it had no effect in the chronic phase. These findings align with our analysis of human tissue samples, where Gα13 expression was significantly reduced only in acute pancreatitis. Furthermore, in Gα13-deficient tumors, mTOR inhibition suppressed inflammatory cytokine expression and hindered tumor progression. Notably, targeting Pdk1 signaling resulted in a stronger anti-tumor response, with evidence for collagen remodeling and enhanced adaptive immune response. Overall, our findings uncover a novel, targetable pathway regulating both inflammation and tumor progression in pancreatic cancer, which could offer therapeutic opportunities depending on the G-protein status in patients. Citation Format: Khadijeh Karbalaei, Anastasia E. Metropulos, Khulood Alzahrani, Apurba Majumder, Thao N. Pham, Hidayatullah G. Munshi, Mario A. Shields. Elucidating the signaling mechanisms of Galpha13-mediated inflammation and tumor suppression in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2): nr LB453.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"17 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract LB410: Precision oral cancer screening and diagnostic solution using DNA methylation and machine learning to stratify high-risk lesions in saliva from patients of mixed ancestry","authors":"Ashley Ramos-Lopez, Amanda Garcia Negron, Guie Beeu Guerrero Hunt, Adhi Guerrero-Thillet, Carolina Zambrano Rabanal, Paola Quiñonez Mendez, Andrea Lopez-Marrero, Alvaro Gutierrez, Fernando Zamuner, Bruce J. Trock, Wayne Koch, Mariana Brait, David Sidransky, Rafael Guerrero-Preston","doi":"10.1158/1538-7445.am2025-lb410","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb410","url":null,"abstract":"Analysis of quantitative methylation specific PCR (qMSP) data for diagnosis and early detection of cancer has consisted of summarizing singleplex or multiplex DNA data in a cumulative methylation index, followed by threshold analyses. Recently, a novel clustering algorithm was used to examine digital PCR data, prior to downstream analysis. However, clustering of Real-Time qMSP data has not been used by laboratories developing DNA methylation biomarkers for the oral cancer screening and diagnostic space. We created a precision DNA methylation algorithm to quantify Differentially Methylated Promoters (DMPs) with Real-Time PCR instruments, combined with machine learning, for discovery and validation of head and neck squamous cell carcinoma (HNSCC) early detection, diagnosis, and prognostication targets. Analytic validation of PAX1, PAX5, ZIC4, PLCB1, and HHIP was performed to develop a qMSP protocol for clinical samples. The performance of the six singleplex reactions was tested in 307 oral cancer tissue and 55 normal uvulopalatopharyngoplasty (UPPP) samples from a mixed ancestry cohort (40% Black) obtained from the Johns Hopkins School of Medicine Head and Neck Cancer Tumor Bank. An R script for automated analysis of qMSP data was developed to import, process, and analyze multiple qMSP raw data files exported from Applied Biosystems SDS or DA2 software packages. The workflow includes data preprocessing; filtering by quality control metrics, such as CT and PCR efficiency; normalizing against a control gene (Bactin), and visualizing results through boxplots. A precision DNA methylation algorithm was then developed to perform unsupervised hierarchical clustering of singleplex qMSP observations for five genes, center the data, calculate the distance between all samples, determine the variance explained by each Principal Component (PC), set a cutoff DNA methylation value that maximizes performance for each gene and identify the best model fit. Logistic regression, Linear Discriminant Analysis, Loess, K nearest neighbor, and Random Forrest models, as well as an ensemble of all five models were then trained to model the relationship between test samples and PAX1, PAX5, ZIC4, PLCB1, HHIP DMPs. Model performance was compared based on accuracy and logistic regression was used for downstream analyses. The discriminatory ability of the five genes was evaluated using the Receiver Operator Characteristic (ROC) curve and Area Under the Curve (AUC) analyses. The best performance was obtained when using all five genes (PAX1, PAX5, ZIC4, PLCB1, HHIP): 94% Sensitivity, 96% Specificity, 97% Positive Predictive Value, 91% Negative Predictive Value, correctly classifying 95% with an AUC = 0.99. We also found HHIP fully discriminated between normal and tumor samples in a smaller subset of saliva samples (n=73). The normalized tissue-saliva Inter Quartile Range (IQR) ratio of HHIP DNA methylation was 98%. These results warrant to be validated in a larger cohort. RealTime ","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"15 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract LB169: Establishment of patient-derived organoid (PDO) from single cell-originated core-needle biopsied (CNB) samples of breast cancer","authors":"Wen-Hung Kuo, Jia-Yang Chen, Chia-Chun Liu, Mark D. Pegram, Yu-Min Lin, Chia-Yuan Chang, Ying-Chih Chang","doi":"10.1158/1538-7445.am2025-lb169","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb169","url":null,"abstract":"Breast cancer (BC) exhibits differential subtypes with morphological and genetic heterogeneity. Lack of adequate ex vivo model and relevant PDO bank limits following clinical and applications and anti-cancer developments. Three-dimensional cell cultures, such as tumor spheroids, offered a promising alternative tool to reduce animal testing and act as patient avatar for cancer research. However, current platforms, such as scaffold-free low-adherence attachment plates, face challenges with low efficiency of spheroid formation and suffocate in handling rare cell samples. To address this issue, we employed the R3CE platform (Rapid, Reproducible, Rare Cell 3D Expansion; AcroCyte Therapeutics) to facilitate PDO cultivation and establishment including CNB samples based on single cell-derived 3D culture. Paired total 23 normal, 22 tumor, and 14 lymph node CNB tissue samples from various subtypes of cancer patients were collected for PDO culture. Observations revealed varied morphologies in paired normal versus tumor PDOs after culture. The overall successful rate was 84% (93% exclude lymph node) with normal PDO achieving 100% (23/23) success and tumor PDO culture reaches 86% (19/22) successful rate. Lymph node cultures on PDO had a success rate of 57% (8/14) due to potential sentinel node evaluation during routine examination. The established PDOs were confirmed by IHC staining for ER, PR, or Her2 expression. The tumorigenicity of the tumor PDOs was also validated through in vivo xenograft formation with pathology verified histological appearance. Our results demonstrate a streamlined procedures on amplification and establishment, enhancing PDOs model development and further clinical applications. Citation Format: Wen-Hung Kuo, Jia-Yang Chen, Chia-Chun Liu, Mark D. Pegram, Yu-Min Lin, Chia-Yuan Chang, Ying-Chih Chang. Establishment of patient-derived organoid (PDO) from single cell-originated core-needle biopsied (CNB) samples of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2): nr LB169.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"29 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}