Clinical Cancer Research最新文献

{"title":"Update on Cancer and Central Nervous System Tumor Surveillance in Pediatric NF2-, SMARCB1-, and LZTR1-Related Schwannomatosis.","authors":"Melissa R Perrino, Marjolijn C J Jongmans, Gail E Tomlinson, Mary-Louise C Greer, Sarah R Scollon, Sarah G Mitchell, Jordan R Hansford, Kris Ann P Schultz, Wendy K Kohlmann, Jennifer M Kalish, Suzanne P MacFarland, Anirban Das, Kara N Maxwell, Stefan M Pfister, Rosanna Weksberg, Orli Michaeli, Uri Tabori, Gina M Ney, Philip J Lupo, Jack J Brzezinski, Douglas R Stewart, Emma R Woodward, Christian P Kratz","doi":"10.1158/1078-0432.CCR-24-3278","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-3278","url":null,"abstract":"<p><p>Schwannomatoses (SWN) are distinct cancer predisposition syndromes caused by germline pathogenic variants in the genes NF2, SMARCB1, or LZTR1. There is significant clinical overlap between these syndromes with the hallmark of increased risk for cranial, spinal and peripheral schwannomas. Neurofibromatosis type 2 was recently renamed as NF2-related SWN and is the most common SWN syndrome with increased risk for bilateral vestibular schwannomas, intradermal schwannomas, meningiomas and less commonly ependymoma. SMARCB1-related SWN is a familial SWN-syndrome associated with peripheral and spinal schwannomas and an increased risk for meningiomas and malignant peripheral nerve sheath tumors, even in the absence of radiation. These individuals do not develop bilateral vestibular schwannomas. Finally, patients with LZTR1-related SWN typically present with peripheral schwannomas, and unilateral vestibular schwannomas have been reported. The following perspective is intended to highlight the clinical presentation and international tumor surveillance recommendations across these SWN-syndromes.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143398180","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":"AZD8701, an Antisense Oligonucleotide Targeting FOXP3 mRNA, as Monotherapy and in Combination with Durvalumab: Phase I trial in Patients with Advanced Solid Tumors.","authors":"Lillian L Siu, Sophie Postel-Vinay, Rafael Villanueva-Vázquez, Guillermo de Velasco, Eduardo Castanon Alvarez, Christos E Kyriakopoulos, Melissa Johnson, Kaïssa Ouali, Stephen McMorn, Helen K Angell, Felicia Ng, Shashank Saran, Mahdiye Bayat, Teresa Collins, Archana Roy, Arthur W Lambert, Song Cho, Neil Miller, Michele Petruzzelli, John Stone, Christophe Massard","doi":"10.1158/1078-0432.CCR-24-1818","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-1818","url":null,"abstract":"<p><strong>Purpose: </strong>AZD8701 uses next-generation antisense oligonucleotide (ASO) technology to selectively reduce human forkhead box P3 (FOXP3) expression in regulatory T cells, reversing their immunosuppressive function. FOXP3 ASOs alone or with programmed cell death protein (ligand) 1 (PD-[L]1) inhibition attenuated tumor growth in mice. We report a phase I study of AZD8701 alone or combined with durvalumab in patients with advanced solid tumors.</p><p><strong>Methods: </strong>Eligible patients had solid tumors and had received prior standard-of-care treatment including anti-PD-(L)1 therapy. Patient cohorts were treated with AZD8701 intravenously (IV) weekly at escalating doses, either alone (60-960 mg) or combined (240-720 mg) with durvalumab 1,500 mg IV every 4 weeks. The primary objective was safety and tolerability, with the aim of determining the maximum tolerated dose.</p><p><strong>Results: </strong>Forty-five patients received AZD8701 monotherapy and 18 received AZD8701 with durvalumab. One dose-limiting toxicity (increased alanine aminotransferase [ALT]) occurred with AZD8701 960 mg. The most common adverse events (AEs) related to AZD8701 monotherapy were fatigue (22.2%), asthenia, pyrexia, and increased ALT (20%, each); the safety profile was similar when combined with durvalumab. With AZD8701 monotherapy, 24.4% and 15.6% of patients had stable disease for ≥16 and ≥24 weeks, respectively; one patient treated with AZD8701 720 mg and durvalumab had a partial response. FOXP3mRNA changes were heterogeneous (8/13 patients showed reduction), with no clear dose relationship. ASO accumulated in the tumor epithelium and stroma.</p><p><strong>Conclusions: </strong>This study demonstrates the clinical feasibility of ASO therapy, with generally manageable AEs, FOXP3 knockdown, and ASO delivery to the tumor.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397966","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":"Characterization of plasma cell-free DNA variants as of tumor- or clonal hematopoiesis-origin in 16,812 advanced cancer patients.","authors":"Daniel Magee, Valeriy Domenyuk, Jim Abraham, Nieves Perdigones Borderias, Jeff Swensen, Praveena Solipuram, Adanma Ayanambakkam, Raja Mehdi, Jagathi Challagalla, Elisabeth Heath, Megan Landsverk, Magdalena Jurkiewicz, Brian Shimkus, Ian Pinto, Daniel Patterson, David Hsiehchen, Supriya Koya, Bradley Somer, Michel Velez, Anthony F Shields, Jennifer Cultrera, Jennifer R Ribeiro, Robert Hahn-Lowry, George W Sledge, Matthew Oberley, Milan Radovich, David Spetzler","doi":"10.1158/1078-0432.CCR-24-3335","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-3335","url":null,"abstract":"<p><strong>Purpose: </strong>Plasma-based liquid biopsy tests can detect tumor-specific genetic alterations and offer many advantages that complement tissue-based Comprehensive Genomic Profiling (CGP). However, age-related clonal hematopoiesis (CH) mutations can confound liquid biopsy results and potentially lead to incorrect therapy choice.</p><p><strong>Experimental design: </strong>We assessed the landscape of 16,812 liquid profiles across 49 cancer types using the Caris Assure assay, a whole exome and whole transcriptome NGS workflow that independently sequences both plasma-derived cell-free total nucleic acids (cfTNA) as well as the white blood cell DNA and RNA from the buffy coat. The variant source was identified algorithmically by comparing plasma and buffy coat variant frequency and read quality metrics.</p><p><strong>Results: </strong>42.3% of 16,812 patients presented at least one CH variant among reportable clinical genes. We found 39% of BRCA2 variants to be of CH origin, as well as 37.9% of CHEK2, 27.4% of BRCA1, 20.1% of ATM, 7.3% NRAS, 5.8% BRAF, 2.1% EGFR, 2.1% KRAS, and 18.5% TP53. For patients aged 65-69, the median proportion of CH variant classification was 20%, whereas it was 33% for patients aged 70-74, 33% for ages 75-79, and 50% for ages 80+. We found high rates of CH detected in what would be otherwise druggable targets in many cancer types typically treated with PARP inhibitors, including breast, female genital tract, ovarian, pancreatic, prostate, and endometrial cancers.</p><p><strong>Conclusion: </strong>This large study highlights the need for thorough CH classification during liquid biopsy to appropriately recommend therapies, especially PARP inhibitors.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390445","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":"Can longitudinal biomarkers guide treatment decisions? Time will tell.","authors":"Mark Y Jeng, Adam J Schoenfeld","doi":"10.1158/1078-0432.CCR-24-4297","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-4297","url":null,"abstract":"<p><p>Defining patterns of acquired resistance has important prognostic and therapeutic implications in patients with lung cancer. Longitudinal biomarker analysis has enhanced our understanding of tumor biology and treatment response. However, the role of temporally informed biomarkers in guiding clinical decisions, such as local therapy intervention, remains unproven.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390407","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":"Results of the phase I/II study and preliminary B cell gene signature of combined inhibition of glutamine metabolism and EGFR in colorectal cancer.","authors":"Kristen K Ciombor, Seong-Woo Bae, Jennifer G Whisenant, Gregory D Ayers, Quanhu Sheng, Todd E Peterson, Gary T Smith, Kangyu Lin, Saikat Chowdhury, Preeti Kanikarla Marie, Alexey Sorokin, Allison S Cohen, Laura W Goff, Dana B Cardin, John Paul Shen, Scott Kopetz, Cathy Eng, Yu Shyr, Jordan Berlin, H Charles Manning","doi":"10.1158/1078-0432.CCR-24-3133","DOIUrl":"10.1158/1078-0432.CCR-24-3133","url":null,"abstract":"<p><strong>Purpose: </strong>EGFR-targeting monoclonal antibodies are essential for managing RAS WT metastatic colorectal cancer (mCRC), but their limited efficacy necessitates exploring immunological and metabolic factors influencing response. This study evaluated glutamine metabolism targeting with EGFR inhibition to identify response biomarkers in patients with prior anti-EGFR treatment progression.</p><p><strong>Experimental design: </strong>We conducted a phase I/II trial in KRAS WT mCRC patients, combining panitumumab and CB-839, hypothesizing that dual inhibition of glutamine metabolism and MAPK signaling would enhance outcomes. As study correlatives, we investigated the B cell activation signature 'Bscore' and glutamine PET as potential treatment response biomarkers.</p><p><strong>Results: </strong>The combination of panitumumab and CB-839 was tolerable with manageable side effects, including Grade 4 hypomagnesemia in four patients, a known panitumumab-related event. Two patients achieved partial response (PR), and five had stable disease (SD), with a 41% disease control rate (DCR). Median progression-free survival (PFS) and overall survival (OS) were 1.84 and 8.87 months, respectively. A positive correlation between 'Bscore' and lesion size reduction suggested its association with clinical benefit (PR and SD). Lower 'Bscore' correlated with greater tumor avidity for glutamine by PET, indicating B cell activation sensitivity to glutamine depletion.</p><p><strong>Conclusions: </strong>The combination of CB-839 and panitumumab showed safety and promising preliminary responses, but the study closed early due to CB-839 development termination. The B cell activation signature 'Bscore' emerged as a potential biomarker for EGFR and glutaminase inhibition in mCRC, warranting further studies. These findings suggest opportunities to improve immune response and therapies in glutaminolysis-dependent tumors.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381731","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":"Anlotinib versus placebo as adjuvant therapy for localized high-grade soft tissue sarcomas: a phase 2, double-blinded, randomized controlled trial.","authors":"Chunmeng Wang, Xianglin Hu, Lingge Yang, Yu Xu, Biqiang Zheng, Jilong Yang, Zhichao Liao, Zhengwang Sun, Shengjian Zhang, Lin Yu, Yan Yan, Yong Chen, Tomohiro Fujiwara, Jianrong Zhang, Ilia N Buhtoiarov, Yangbai Sun, Wangjun Yan","doi":"10.1158/1078-0432.CCR-24-2531","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2531","url":null,"abstract":"<p><strong>Purpose: </strong>We aimed to investigate the efficacy and safety of anlotinib as adjuvant targeted therapy for completely resected localized high-grade soft tissue sarcomas (STS).</p><p><strong>Patients and methods: </strong>Patients with localized high-grade STS after complete resection were randomly assigned in a 1:1 ratio to receive either oral 12 mg anlotinib or placebo once daily on days 1-14 every 21 days as a cycle, with up to 6 cycles until disease relapse, unmanageable toxicity or death. The efficacy and safety were analyzed. This trial was the first trial exploring adjuvant targeted therapy for STS (NCT03951571).</p><p><strong>Results: </strong>Between June 2019 and November 2023, 88 patients were randomly assigned to receive anlotinib (n=44) or placebo (n=44). With a median follow-up of 30.95 months, the 1-year and 2-year disease-free survival (DFS) rates were 88% and 77% in the anlotinib group, compared to 64% and 58% in the placebo group. Compared to patients treated with surgery alone, patients receiving adjuvant anlotinib combined with surgery had a reduced risk of disease recurrence (HR 0.47 [95% CI 0.22~1.00, P=0.0445]). Based on the tumor histology, the reduced risk of disease recurrence with anlotinib versus placebo was observed in patients with myxofibrosarcoma (HR 0.54 [95% CI 0.17~1.65], P=0.2698) and undifferentiated pleomorphic sarcoma (HR 0.58 [95% CI 0.12~2.87], P=0.4971). Four patients discontinued anlotinib, including two for proteinuria/hematuria (2/44, 5%) and two for poor healing of surgical wound (2/44, 5%).</p><p><strong>Conclusions: </strong>Compared to surgery alone, adjuvant anlotinib following surgery reduces the incidence of disease relapse in localized high-grade STS, with acceptable toxicity.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363759","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":"Endothelial cell pY397-FAK expression predicts risk of breast cancer recurrences after radiotherapy in SweBCG91-RT cohort.","authors":"Rebecca J G Drake, Amalia H Landén, Erik Holmberg, Axel Stenmark Tullberg, Fredrika Killander, Emma Niméus, Alexander Jordan, Jennifer McGuinness, Per Karlsson, Kairbaan Hodivala-Dilke","doi":"10.1158/1078-0432.CCR-24-2939","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2939","url":null,"abstract":"<p><strong>Purpose: </strong>Identifying biomarkers of radiotherapy (RT) response is important for optimising the treatment of early breast cancer (BC). Here we tested the interaction between endothelial cell (EC) expression of phospho-Tyr397-FAK (pY397-FAK) and adjuvant-RT on clinical outcomes after breast-conserving surgery (BCS) within a randomised study. Preclinical data suggests an enhanced effect of RT with low EC_ pY397-FAK expression.</p><p><strong>Methods: </strong>We analysed tissue microarrays (TMAs) from the SweBCG91-RT (stage I-II, lymph node-negative) BC cohort, consisting of 1,178 patients randomly assigned to receive either BCS alone or BCS plus adjuvant-RT. TMA sections were immunostained for pY397-FAK, CD31, α-smooth-muscle-actin (αSMA) and pan-cytokeratin (panCK). HALO analysis scored mean pY397-FAK intensity in CD31+ ECs, panCK+ tumour epithelial cells (TCs) and αSMA+ mural/stromal cells per core. For 822 patients, multivariable Cox regression analysis was performed for the primary and secondary 5-year endpoints, locoregional recurrence (LRR) and 'all recurrence', respectively, as dependent variables, and RT and EC_pY397-FAK as independent variables.</p><p><strong>Results: </strong>EC_ pY397-FAK expression was not predictive for the primary endpoint, LRR (p=0.098), but the direction of the RT effect was in line with preclinical findings. For the secondary endpoint, all recurrence, there was a significant interaction (p=0.026) between EC_ pY397-FAK and RT. Without RT, higher EC_ pY397-FAK expression resulted in lower risk for all recurrence (HR 0.74 per SD, CI 95% 0.57-0.96, p=0.026).</p><p><strong>Conclusion: </strong>Within the first 5-years post-BCS, patients with low EC_pY397-FAK expression derive greater benefit from RT than patients with high EC_pY397-FAK expression. However, without RT low EC_pY397-FAK expression is associated with a higher risk of recurrence.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188427","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":"A phase II study of abemaciclib for patients with retinoblastoma-positive, triple-negative metastatic breast cancer.","authors":"Shom Goel, Bojana Jovanović, Xiangying Chu, Melissa Hughes, Timothy K Erick, Douglas Russo, Molly DiLullo, Eileen Wrabel, Rinath Jeselsohn, Nancy U Lin, Nabihah Tayob, Elizabeth Mittendorf, Stuart Schnitt, Sara M Tolaney","doi":"10.1158/1078-0432.CCR-24-2647","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2647","url":null,"abstract":"<p><strong>Background: </strong>Cyclin-dependent kinase (CDK) 4/6 inhibitors can significantly extend survival when given in combination with endocrine therapy in hormone receptor-positive metastatic breast cancer patients. However, their activity has been relatively underexplored in patients with metastatic triple-negative breast cancer (mTNBC).</p><p><strong>Methods: </strong>We conducted a single-arm phase II study of abemaciclib monotherapy in patients with retinoblastoma-positive (Rb+) mTNBC. Patients were treated with abemaciclib 200 mg orally twice daily until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR), disease control rate (DCR), and safety and tolerability.</p><p><strong>Results: </strong>A total of 27 patients were enrolled before the trial was closed early due to slow accrual. Patients had received a median of 2 lines of systemic therapy in the metastatic setting prior to enrollment. After a median follow-up of 28.5 months, the ORR was 0%, the CBR was 14.8%, and the DCR was 22.2%. The median PFS was 1.94 months (95% confidence interval (CI):1.84-11.47), and the median OS was 8.44 months (95% CI:4.57-15.57). Median PFS and OS did not differ significantly based on AR and PD-L1 status. Pre-treatment gene expression profiling of tumor tissue provided some hypothesis-generating insights into biological features associated with clinical benefit in this study. The most common treatment-related adverse events of grade 2 or higher were diarrhea (40.7%), neutropenia (40.7%), anemia (29.6%), and nausea (29.6%).</p><p><strong>Conclusions: </strong>Abemaciclib monotherapy did not show clinical activity in patients with pretreated Rb+ metastatic TNBC.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188422","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":"The Mode of Action and Clinical Outcomes of Sacituzumab Govitecan in Solid Tumors","authors":"Sara M. Tolaney, Thomas M. Cardillo, Chih-Chien Chou, Carrie Dornan, Mary Faris","doi":"10.1158/1078-0432.ccr-24-1525","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1525","url":null,"abstract":"Sacituzumab govitecan (SG), a Trop-2-directed antibody-drug conjugate, is currently approved to treat metastatic triple-negative breast cancer and HR+/HER2– breast cancer, and is under clinical investigation for a range of other tumor types. This review describes its mode of action, development, and clinical outcomes. SG is composed of SN-38 (a topoisomerase I inhibitor derived from irinotecan) covalently linked to an anti-Trop-2 monoclonal antibody (sacituzumab; hRS7) via a hydrolysable CL2A linker. SN-38 was chosen due to its potent antitumor activity; CL2A occupies the most effective position on SN-38 for maintaining stability during transport, with pH-sensitive payload release in the tumor, and the antigen target (Trop-2) is highly expressed on many solid tumors. SG has an ~8:1 drug-to-antibody ratio and delivers therapeutic SN-38 concentration to Trop-2+ expressing tumor cells via rapid internalization and efficient payload release. Free SN-38 can subsequently enter the tumor microenvironment and kill adjacent tumor cells with or without Trop-2 expression (bystander effect). SN-38 induces DNA breakage and inhibits nucleic acid synthesis via a drug-induced topoisomerase 1:DNA complex that interferes with cell proliferation, causing apoptosis. Dose-finding studies support SG 10 mg/kg on days 1 and 8 of a 21-day cycle as the monotherapy dose for clinical use; this was determined by therapeutic index improvement based on efficacy and safety. Payload-linker dynamics and SG potency ensure continued tissue penetration. Neutropenia and diarrhea are the most common grade ≥ 3 treatment-emergent adverse events with SG, but they are manageable. Efficacy of SG has been demonstrated across a broad spectrum of solid tumors.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"10 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143125460","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":"Bcl-Xl Protects ASS1-Deficient Cancers From Arginine Starvation Induced Apoptosis.","authors":"Prashanta Kumar Panda, Ana Carolina Paschoalini Mafra, Alliny C S Bastos, Li Cao, Maria Serra Bonet, Caitlyn B Brashears, Ethan Yang Chen, Heather M Benedict-Hamilton, William Ehrhardt, John Bomalaski, Carina Dehner, Leonard C Rogers, Toshinao Oyama, Brian A Van Tine","doi":"10.1158/1078-0432.CCR-24-2548","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2548","url":null,"abstract":"<p><strong>Purpose: </strong>Argininosuccinate Synthetase 1 (ASS1) silencing in carcinomas and sarcomas leads to a dependence on extracellular arginine for survival. Arginine deprivation therapies, like PEGylated arginine deiminase (ADI-PEG20), have shown limited effectiveness, which may be due to underlying mechanisms that inhibit apoptosis.</p><p><strong>Experimental design: </strong>The effects of ADI-PEG20 on cell cycle regulation, apoptosis, and Bcl-xL-mediated survival pathways in ASS1-deficient cancer cells were determined. The mechanism of cell death protection was determined by assessing caspase and PARP cleavage, CDK2 activity, MCL1 expression, and the interactions between Bcl-xL, Bax, and Bak. In vitro synergy was determined, and in vivo efficacy was modeled.</p><p><strong>Results: </strong>Treatment with ADI-PEG20 led to reduced CDK2 activity and inhibited cell cycle progression but did not induce significant cell death. Bcl-xL was found to bind to Bax and Bak, preventing the initiation of apoptosis despite arginine starvation. Inhibition of Bcl-xL allowed proapoptotic Bax and Bak to initiate the intrinsic apoptosis pathway, leading to increased cell death. This was found to be synergistic in vitro and efficacious in combination in vivo.</p><p><strong>Conclusions: </strong>The study identifies Bcl-xL as a key factor limiting the efficacy of arginine starvation therapies. Combining Bcl-xL inhibitors with arginine deprivation strategies may overcome this resistance and enhance therapeutic outcomes. These findings provide a strong preclinical rationale for testing this combination approach in Phase 1 clinical trials for ASS1-deficient cancers.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078563","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}