Clinical Cancer Research最新文献

{"title":"Targeting c-MET for Endoscopic Detection of Dysplastic Lesions Within Barrett’s Esophagus Using EMI-137 Fluorescence Imaging","authors":"Yi-Jhih Huang, Jonas Rieder, Kel Vin. Tan, Anna Tenditnaya, Borivoj Vojnovic, Dimitris Gorpas, Michael Quante, Katherine A. Vallis","doi":"10.1158/1078-0432.ccr-24-1522","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1522","url":null,"abstract":"Purpose: Esophageal cancer (EC) carries a poor prognosis with 5-year overall survival of less than 20%. Barrett’s esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). The aim of this study was to investigate the ability of EMI-137, a mesenchymal-epithelial transition factor (c-MET)-targeting optical imaging tracer, to detect dysplasia in BE. Experimental Design: c-MET expression in human esophageal tissue was investigated using Gene Expression Omnibus (GEO) datasets, tissue microarrays and BE biopsies. EMI-137 was tested in a dual xenograft mouse model bearing OE33 (c-MET high expression) and FLO-1 (c-MET low expression) tumors. Fluorescence molecular endoscopy (FME) was performed in a mouse model of Barrett’s-like metaplasia and dysplasia (L2-IL1β). Tumors and organs-of-interest were evaluated through ex vivo fluorescence imaging. Results:MET mRNA expression analyses and c-MET immunostaining confirmed upregulation of c-MET in BE and EAC compared to normal epithelium. There was strong accumulation of EMI-137 in OE33 xenografts 3 h post injection decreasing by more than 50% on co-injection of a 10-fold molar excess of unlabeled EMI-137. The target-to background ratio (TBR) at 3 h p.i. for OE33 and FLO-1 tumors was 10.08 and 1.42, respectively. FME of L2-IL1β mice showed uptake of EMI-137 in dysplastic lesions within BE with a TBR of 1.9 in vivo, and greater than 2 in ex vivo fluorescence imaging. Conclusions: EMI-137 accumulates in dysplastic lesions within BE and in c-MET positive EAC. EMI-137 imaging has potential as a screening and surveillance tool for patients with BE and as a means to detecting dysplasia and EAC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"36 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597279","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":"BRAF deletion in adult patients with Langerhans cell histiocytosis correlates with multisystem disease and poor outcome","authors":"Min Lang, Long Chang, Hao Cai, He Lin, Zheng-zheng Liu, Ming-hui Duan, Dao-bin Zhou, Xin-xin Cao","doi":"10.1158/1078-0432.ccr-24-1802","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1802","url":null,"abstract":"Background: Langerhans cell histiocytosis (LCH) is a rare and highly heterogeneous histiocytosis. There are currently few studies examining the correlation between molecular profiling and clinical phenotype or outcome in adult patients with LCH. The objective of this study was to characterize the genomic landscape of adult LCH and correlate molecular findings with clinical features and patient outcomes. Methods: This study included 254 patients aged ≥18 years with biopsy-proven LCH from January 2000 to December 2023. All patients underwent next-generation sequencing (NGS) or fluorescence quantitative PCR (qPCR) for the BRAFV600E mutation. Patient demographics, disease characteristics and treatments were collected through electronic medical records. Patient outcomes were collected through clinical and telephone follow-up. Results: Overall, 254 patients were enrolled. MAPK/PI3K pathway alterations were observed in 77.6%（n=197）of the patients. BRAFV600E mutation was the most common (30.7%, n=78), followed by BRAFindel (18.1%, n=46) andMAP2K1 mutations (12.6%, n=32). The proportion of BRAFindel was much higher in patients with MS involvement than single system disease (24.5% vs 6.6%, p＜0.001). In overall patients, BRAFindel was associated with inferior overall survival (3-year OS 89.6% vs 99.0%, p=0.014) and progression-free survival (3-year PFS 50.0% vs 78.6%, p＜0.001). In MS LCH patients, BRAFindel was associated to worse PFS (3-year PFS 47.8% vs 76.0%, p=0.001). Conclusions: This large study provides molecular and clinical pathologic characterization of adult LCH. BRAFindel was highly correlated with MS LCH, and was associated to worse outcome.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"45 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597280","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":"Pilot Trial of Perampanel on Peritumoral Hyperexcitability in Newly Diagnosed High-grade Glioma.","authors":"Steven Tobochnik, Michael S Regan, Maria K C Dorotan, Dustine Reich, Emily Lapinskas, Md Amin Hossain, Sylwia Stopka, David M Meredith, Sandro Santagata, Melissa M Murphy, Omar Arnaout, Wenya Linda Bi, E Antonio Chiocca, Alexandra J Golby, Michael A Mooney, Timothy R Smith, Keith L Ligon, Patrick Y Wen, Nathalie Y R Agar, Jong Woo Lee","doi":"10.1158/1078-0432.CCR-24-1849","DOIUrl":"10.1158/1078-0432.CCR-24-1849","url":null,"abstract":"<p><strong>Purpose: </strong>Glutamatergic neuron-glioma synaptogenesis and peritumoral hyperexcitability promote glioma growth in a positive feedback loop. The objective of this study was to evaluate the feasibility and estimated effect sizes of the targeted AMPA receptor antagonist perampanel on peritumoral hyperexcitability.</p><p><strong>Experimental design: </strong>An open-label trial was performed comparing perampanel with standard of care (SOC) in patients undergoing resection of newly diagnosed radiologic high-grade glioma. Perampanel was administered as a preoperative loading dose followed by maintenance therapy until progressive disease or up to 12 months. SOC treatment involved levetiracetam for 7 days or as clinically indicated. The primary outcome of hyperexcitability was defined by intraoperative electrocorticography high-frequency oscillation (HFO) rates. Seizure freedom and overall survival were estimated by the Kaplan-Meier method. Tissue concentrations of perampanel, levetiracetam, and correlative biomarkers were measured by mass spectrometry.</p><p><strong>Results: </strong>HFO rates were similar between patients treated with perampanel and levetiracetam. The trial was terminated early after a planned interim analysis, and outcomes assessed in 11 patients (seven perampanel treated; four treated with SOC). Over a median 281 days of postenrollment follow-up, 27% of patients had seizures, including 14% maintained on perampanel and 50% treated with SOC. Overall survival in perampanel-treated patients was similar to that in a glioblastoma reference cohort. Glutamate concentrations in surface biopsies were positively correlated with HFO rates in adjacent electrode contacts and were not significantly associated with treatment assignment or drug concentrations.</p><p><strong>Conclusions: </strong>Glioma peritumoral glutamate concentrations correlated with high-gamma oscillation rates. Targeting glutamatergic activity with perampanel achieved similar electrocorticographic hyperexcitability levels as in levetiracetam-treated patients.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"OF1-OF9"},"PeriodicalIF":10.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582102","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":"YAP regulates HER3 signaling-driven adaptive resistance to RET inhibitors in RET-aberrant cancer.","authors":"Yuki Katayama, Tadaaki Yamada, Keiko Tanimura, Hayato Kawachi, Masaki Ishida, Yohei Matsui, Soichi Hirai, Ryota Nakamura, Kenji Morimoto, Naoki Furuya, Sachiko Arai, Yasuhiro Goto, Yoshihiko Sakata, Kazumi Nishino, Michiko Tsuchiya, Akihiro Tamiya, Go Saito, Satoshi Muto, Takayuki Takeda, Koji Date, Yasuhito Fujisaka, Satoshi Watanabe, Daichi Fujimoto, Hisanori Uehara, Mano Horinaka, Toshiyuki Sakai, Seiji Yano, Shinsaku Tokuda, Koichi Takayama","doi":"10.1158/1078-0432.CCR-24-1762","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-1762","url":null,"abstract":"<p><strong>Purpose: </strong>Rearranged during transfection (RET) aberrations represent a targetable oncogene in several tumor types, with RET inhibitors displaying marked efficacy. However, some patients with RET-aberrant cancer are insensitive to RET tyrosine kinase inhibitors (TKIs). Recently, drug-tolerant mechanisms have attracted attention as targets for initial therapies to overcome drug resistance. The underlying mechanisms of drug-tolerant cell emergence treated with RET-TKIs derived from RET-aberrant cancer cells remain unknown. This study investigated the role of YAP-mediated HER3 signaling in the underlying mechanisms of adaptive resistance to RET-TKIs in RET-aberrant cancer cells.</p><p><strong>Experimental design: </strong>Four RET-aberrant cancer cell lines were used to assess sensitivity to the RET-TKIs selpercatinib and pralsetinib and to elucidate molecular mechanisms underlying adaptive resistance using RNA sequencing, phospho-RTK antibody arrays, chromatin immunoprecipitation assay, and luciferase reporter assays. Clinical specimens from patients with RET-fusion-positive lung cancer were analyzed for pre-treatment YAP expression and correlated with treatment outcomes.</p><p><strong>Results: </strong>In high YAP-expressing RET-aberrant cancer cells, YAP-mediated HER3 signaling activation maintained cell survival and induced the emergence of cells tolerant to the RET-TKIs selpercatinib and pralsetinib. The pan-ErBB inhibitor afatinib and YAP/TEAD inhibitors verteporfin and K-975 sensitized YAP-expressing RET-aberrant cancer cells to the RET-TKIs selpercatinib and pralsetinib. Pre-treatment YAP expression in clinical specimens obtained from patients with RET-fusion-positive lung cancer was associated with poor RET-TKI treatment outcomes.</p><p><strong>Conclusion: </strong>The YAP-HER3 axis is crucial for the survival and adaptive resistance of high YAP-expressing RET-aberrant cancer cells treated with RET-TKIs. Combining YAP/HER3 inhibition with RET-TKIs represents a highly potent strategy for initial treatment.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567627","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":"Intestinal subtype as a biomarker of response to neoadjuvant immunochemotherapy in locally advanced gastric adenocarcinoma: insights from a prospective phase II trial.","authors":"Lei Wang, Mengting Sun, Jinyang Li, Linghong Wan, Yuting Tan, Shuoran Tian, Yongying Hou, Linyu Wu, Ziyi Peng, Xiao Hu, Qihua Zhang, Zening Huang, Mengyi Han, Shiyin Peng, Yuwei Pan, Yuanfeng Ren, Mengsi Zhang, Dongfeng Chen, Qin Liu, Xianfeng Li, Zhong-Yi Qin, Junyv Xiang, Mengxia Li, Jianwu Zhu, Qiyue Chen, Huiyan Luo, Shunan Wang, Tao Wang, Fan Li, Xiu-Wu Bian, Bin Wang","doi":"10.1158/1078-0432.CCR-24-2436","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2436","url":null,"abstract":"<p><strong>Purpose: </strong>Neoadjuvant immunochemotherapy (NAIC) markedly induces pathologic regression in locally advanced gastric adenocarcinoma (GAC). However, specific biomarkers are still lacking to effectively identify the beneficiary patients for NAIC.</p><p><strong>Patients and methods: </strong>A prospective, single-arm, phase II study was conducted to treat locally advanced GAC with NAIC (NCT05515796). Correlation between clinicopathological characteristics and neoadjuvant efficacy was investigated. Bulk RNA-seq data from 104 samples (from 75 patients in two independent cohorts) and scRNA-seq data from 105 treatment-naïve GACs were comprehensively analyzed to decipher the association of epithelial and microenvironmental characteristics and clinical responses.</p><p><strong>Results: </strong>The pre-specified primary endpoints were achieved: pathological complete regression (pathCR) rate was 30%, major pathological regression (MPR) rate was 43%, while the regimen was well tolerated. Analysis of baseline clinical-pathological parameters revealed the intestinal subtype of Lauren's classification as a key feature stratifying patients with increased sensitivity to NAIC. Mechanistically, an increased pool of DNA damage repair (DDR)-active cancer cells and enrichment of CLEC9A+ dendritic cells (DCs) in the tumor microenvironment were associated with enhanced responsiveness of the intestinal subtype GAC to NAIC. More importantly, an intestinal-subtype specific signature model was constructed by the machine learning algorithm NaiveBayes via integrating the transcriptomic features of both DDR-active cancer cells and CLEC9A+ DCs, which accurately predicted the efficacy of NAIC in multiple independent GAC cohorts.</p><p><strong>Conclusions: </strong>Intestinal subtype is a histological biomarker of enhanced sensitivity of GAC to NAIC. The Intestinal-subtype specific signature model is applicable to guide NAIC for patients with locally advanced GAC.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567610","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":"Unearthing a prostate cancer cfDNA signature that \"stems\" from AR alterations.","authors":"Rashad Nawfal, Razane El Hajj Chehade, Jacob E Berchuck","doi":"10.1158/1078-0432.CCR-24-2849","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2849","url":null,"abstract":"<p><p>Androgen receptor (AR) alterations portend a poor prognosis in patients with advanced prostate cancer. A recent study identified a stemness signature enriched in cell-free DNA from AR-altered patients, associated with worse outcomes. These findings highlight the potential of epigenomic liquid biopsy tools to discover novel clinically relevant tumor molecular subtypes.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567613","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 Atezolizumab, Pertuzumab, and High-Dose Trastuzumab for Central Nervous System Metastases in Patients with HER2-Positive Breast Cancer.","authors":"Antonio Giordano, Priya U Kumthekar, Qingchun Jin, Busem Binboga Kurt, Siyang Ren, Tianyu Li, Jose Pablo Leone, Elizabeth A Mittendorf, Alyssa M Pereslete, Laura Sharp, Raechel Davis, Molly DiLullo, Nabihah Tayob, Erica L Mayer, Eric P Winer, Sara M Tolaney, Nancy U Lin","doi":"10.1158/1078-0432.CCR-24-1161","DOIUrl":"10.1158/1078-0432.CCR-24-1161","url":null,"abstract":"<p><strong>Purpose: </strong>Patients with HER2-positive breast cancer brain metastases have few effective systemic therapy options. In a prior study, pertuzumab with high-dose trastuzumab demonstrated a high clinical benefit rate (CBR) in the central nervous system (CNS) in patients with brain metastases. The current trial evaluated whether the addition of atezolizumab to this regimen would produce further improvements in CNS response.</p><p><strong>Patients and methods: </strong>This was a single-arm, multicenter, phase II trial of atezolizumab, pertuzumab, and high-dose trastuzumab for patients with HER2-positive breast cancer brain metastases. Participants received atezolizumab 1,200 mg i.v. every 3 weeks, pertuzumab (loading dosage 840 mg i.v., then 420 mg i.v. every 3 weeks), and high-dose trastuzumab (6 mg/kg i.v. weekly for 24 weeks, then 6 mg/kg i.v. every 3 weeks). The primary endpoint was CNS overall response rate per Response Assessment in Neuro-Oncology Brain Metastases criteria. Key secondary endpoints included CBR, overall survival, and safety and tolerability of the combination.</p><p><strong>Results: </strong>Among 19 enrolled participants, two had a confirmed intracranial partial response for a CNS overall response rate of 10.5% (90% confidence interval, 1.9%-29.6%). The study did not meet the prespecified efficacy threshold and was terminated early. The CBR was 42.1% at 18 weeks and 31.6% at 24 weeks. Seven patients (36.8%) required a dose delay or hold, and the most frequent any-grade adverse events were diarrhea (26.3%) and fatigue (26.3%).</p><p><strong>Conclusions: </strong>The addition of atezolizumab to pertuzumab plus high-dose trastuzumab does not result in improved CNS responses in patients with HER2-positive breast cancer brain metastases.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"4856-4865"},"PeriodicalIF":10.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11528201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142125003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Histopathologic Correlation Study Evaluating Glymphatic Function in Brain Tumors by Multiparametric MRI.","authors":"Min Gao, Zhengliang Liu, Hongjing Zang, Xiong Wu, Yizhong Yan, Hai Lin, Jianmin Yuan, Tianming Liu, Yu Zhou, Jun Liu","doi":"10.1158/1078-0432.CCR-24-0150","DOIUrl":"10.1158/1078-0432.CCR-24-0150","url":null,"abstract":"<p><strong>Purpose: </strong>This study aimed to elucidate the impact of brain tumors on cerebral edema and glymphatic drainage by leveraging advanced MRI techniques to explore the relationships among tumor characteristics, glymphatic function, and aquaporin-4 (AQP4) expression levels.</p><p><strong>Experimental design: </strong>In a prospective cohort from March 2022 to April 2023, patients with glioblastoma, brain metastases, and aggressive meningiomas, alongside age- and sex-matched healthy controls, underwent 3.0T MRI, including diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index and multiparametric MRI for quantitative brain mapping. Tumor and peritumor tissues were analyzed for AQP4 expression levels via immunofluorescence. Correlations among MRI parameters, glymphatic function (DTI-ALPS index), and AQP4 expression levels were statistically assessed.</p><p><strong>Results: </strong>Among 84 patients (mean age: 55 ± 12 years; 38 males) and 59 controls (mean age: 54 ± 8 years; 23 males), patients with brain tumor exhibited significantly reduced glymphatic function (DTI-ALPS index: 2.315 vs. 2.879; P = 0.001) and increased cerebrospinal fluid volume (201.376 cm³ vs. 115.957 cm³; P = 0.001). A negative correlation was observed between tumor volume and the DTI-ALPS index (r: -0.715, P < 0.001), whereas AQP4 expression levels correlated positively with peritumoral brain edema volume (r: 0.989, P < 0.001) and negatively with proton density in peritumoral brain edema areas (ρ: -0.506, P < 0.001).</p><p><strong>Conclusions: </strong>Our findings highlight the interplay among tumor-induced compression, glymphatic dysfunction, and altered fluid dynamics, demonstrating the utility of DTI-ALPS and multiparametric MRI in understanding the pathophysiology of tumor-related cerebral edema. These insights provide a radiological foundation for further neuro-oncological investigations into the glymphatic system. See related commentary by Surov and Borggrefe, p. 4813.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"4876-4886"},"PeriodicalIF":10.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11528195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141283160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Update on Pediatric Cancer Surveillance Recommendations for Patients with Neurofibromatosis Type 1, Noonan Syndrome, CBL Syndrome, Costello Syndrome, and Related RASopathies.","authors":"Melissa R Perrino, Anirban Das, Sarah R Scollon, Sarah G Mitchell, Mary-Louise C Greer, Marielle E Yohe, Jordan R Hansford, Jennifer M Kalish, Kris Ann P Schultz, Suzanne P MacFarland, Wendy K Kohlmann, Philip J Lupo, Kara N Maxwell, Stefan M Pfister, Rosanna Weksberg, Orli Michaeli, Marjolijn C J Jongmans, Gail E Tomlinson, Jack Brzezinski, Uri Tabori, Gina M Ney, Karen W Gripp, Andrea M Gross, Brigitte C Widemann, Douglas R Stewart, Emma R Woodward, Christian P Kratz","doi":"10.1158/1078-0432.CCR-24-1611","DOIUrl":"10.1158/1078-0432.CCR-24-1611","url":null,"abstract":"<p><p>Neurofibromatosis type 1 (NF1), Noonan syndrome, and related syndromes, grouped as RASopathies, result from dysregulation of the RAS-MAPK pathway and demonstrate varied multisystemic clinical phenotypes. Together, RASopathies are among the more prevalent genetic cancer predisposition syndromes and require nuanced clinical management. When compared with the general population, children with RASopathies are at significantly increased risk of benign and malignant neoplasms. In the past decade, clinical trials have shown that targeted therapies can improve outcomes for low-grade and benign neoplastic lesions but have their own challenges, highlighting the multidisciplinary care needed for such individuals, specifically those with NF1. This perspective, which originated from the 2023 American Association for Cancer Research Childhood Cancer Predisposition Workshop, serves to update pediatric oncologists, neurologists, geneticists, counselors, and other health care professionals on revised diagnostic criteria, review previously published surveillance guidelines, and harmonize updated surveillance recommendations for patients with NF1 or RASopathies.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"4834-4843"},"PeriodicalIF":12.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11530332/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142079415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic Screen in a Preclinical Model of Sarcoma Development Defines Drivers and Therapeutic Vulnerabilities.","authors":"Jack Freeland, Maria Muñoz, Edmond O'Donnell, Justin Langerman, Morgan Darrow, Jessica Bergonio, Julissa Suarez-Navarro, Steven Thorpe, Robert Canter, Robert Lor Randall, Kathrin Plath, Kermit L Carraway, Owen N Witte, Thomas G Graeber, Janai R Carr-Ascher","doi":"10.1158/1078-0432.CCR-24-1238","DOIUrl":"10.1158/1078-0432.CCR-24-1238","url":null,"abstract":"<p><strong>Purpose: </strong>High-grade complex karyotype sarcomas are a heterogeneous group of tumors with a uniformly poor prognosis. Within complex karyotype sarcomas, there are innumerable genetic changes but identifying those that are clinically relevant has been challenging.</p><p><strong>Experimental design: </strong>To address this, we utilized a pooled genetic screening approach, informed by The Cancer Genome Atlas (TCGA) data, to identify key drivers and modifiers of sarcoma development that were validated in vivo.</p><p><strong>Results: </strong>YAP1 and wild-type KRAS were validated as drivers and transformed human mesenchymal stem cells into two distinct sarcoma subtypes, undifferentiated pleomorphic sarcoma and myxofibrosarcoma, respectively. A subset of tumors driven by CDK4 and PIK3CA reflected leiomyosarcoma and osteosarcoma demonstrating the plasticity of this approach and the potential to investigate sarcoma subtype heterogeneity. All generated tumors histologically reflected human sarcomas and had increased aneuploidy as compared to simple karyotype sarcomas. Comparing differential gene expression of TCGA samples to model data identified increased oxidative phosphorylation signaling in YAP1 tumors. Treatment of a panel of soft tissue sarcomas with a combination of YAP1 and oxidative phosphorylation inhibitors led to significantly decreased viability.</p><p><strong>Conclusions: </strong>Transcriptional co-analysis of TCGA patient samples to YAP1 and KRAS model tumors supports that these sarcoma subtypes lie along a spectrum of disease and adds guidance for further transcriptome-based refinement of sarcoma subtyping. This approach can be used to begin to understand pathways and mechanisms driving human sarcoma development, the relationship between sarcoma subtypes, and to identify and validate new therapeutic vulnerabilities for this aggressive and heterogeneous disease.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"4957-4973"},"PeriodicalIF":10.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11530313/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}