Clinical Cancer Research最新文献

{"title":"Challenges to innovation arising from current companion diagnostics regulations and suggestions for improvements","authors":"Kelly S. Oliner, Michelle Shiller, Peter Schmid, Marianne J. Ratcliffe, Aaron J. Schetter, Ming-Sound Tsao","doi":"10.1158/1078-0432.ccr-24-2729","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2729","url":null,"abstract":"A companion diagnostic is a diagnostic test that provides information essential for the safe and effective use of a corresponding therapeutic product. To obtain marketing approval, the companion diagnostic must demonstrate acceptable analytical and clinical performance. Companion diagnostic regulations are intended to protect patients by ensuring quality and consistency of treatment-guiding biomarker testing in clinical trials and clinical practice. However, current regulations have had unintended negative consequences relating to innovation, implementation and accessibility of precision medicine, increasing complexity and cost burden as well as inhibiting development of novel diagnostics and biomarker-targeted therapeutics. We propose a range of practical solutions to these challenges, advocating that regulators, pharmaceutical companies, molecular pathologist groups and diagnostics companies work together to increase flexibility and promote diagnostic innovation, whilst maintaining high quality diagnostic testing to ensure all patients get the most appropriate treatments.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"15 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887555","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":"Longitudinal glioma monitoring via cerebrospinal fluid cell-free DNA","authors":"Cecile Riviere-Cazaux, Xiaoxi Dong, Wei Mo, Rahul Kumar, Chao Dai, Lucas P. Carlstrom, Amanda Munoz-Casabella, Keyvan Ghadimi, Cody L. Nesvick, Katherine M. Andersen, Matthew D. Hoplin, Nicholas Canaday, Ignacio Jusue-Torres, Noor Malik, Jian L. Campian, Michael W. Ruff, Joon H. Uhm, Jeanette E. Eckel-Passow, Timothy J. Kaufmann, David M. Routman, Sani H. Kizilbash, Ugur Sener, Arthur E. Warrington, Robert B. Jenkins, Pan Du, Shidong Jia, Terry C. Burns","doi":"10.1158/1078-0432.ccr-24-1814","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1814","url":null,"abstract":"PURPOSE: Current methods for glioma response assessment are limited. This study aimed to assess the technical and clinical feasibility of molecular profiling using longitudinal intracranial CSF from patients with gliomas. EXPERIMENTAL DESIGN: Adults with gliomas underwent longitudinal intracranial CSF collection via Ommaya reservoirs or ventriculoperitoneal shunts. cfDNA was extracted and analyzed using PredicineCARE for cancer variant profiling and/or PredicineSCORE for low-pass whole genome sequencing (LP-WGS). RESULTS: Five patients (2 females, 3 males; median age: 40 years, range 32-64 years) underwent longitudinal intracranial CSF collection via Ommaya reservoirs (n=4) or ventriculoperitoneal shunts (n=1). In total, forty-seven CSF samples were obtained (median volume: 4.00 mL; 0.5-5 mL). Forty-one samples (87.2%) yielded sufficient cfDNA for testing. Patient-specific tumor-associated variant allelic frequencies (VAFs), and thus tumor fraction, decreased in pre-versus-post chemoradiation samples, including through pseudoprogression. These also increased with radiographic progression in three patients, although identifying the time of definitive disease progression from MRIs was a significant limitation. In two patients with isocitrate dehydrogenase (IDH) mutant gliomas, decreasing IDH1 VAF after resection and chemoradiation correlated with decreased CSF D-2-hydroxyglutarate (D-2-HG) levels (0.64x and 0.62x, respectively, for the first patient, and 0.01x and 0.07x for the other patient), although D-2-HG and IDH1 VAF were not concordant in one patient thereafter. Moreover, CNB decreased below the limit of quantification during treatment and increased above the limit at progression. CONCLUSION: Longitudinal intracranial CSF cfDNA can feasibly be obtained in patients with gliomas during their disease course. Numerous questions and challenges should be answered before deploying this technique.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"80 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879641","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":"Prospective Trial of Biomarker-Guided Surveillance for HPV-positive Oropharynx Cancer Using Plasma Tumor Tissue Modified Viral HPV DNA","authors":"Eleni M. Rettig, Jonathan D. Schoenfeld, Julianna Miller, Bethany Sargent, Evan Carey, Danielle N. Margalit, Kartik Sehgal, Rosh K.V. Sethi, Ravindra Uppaluri, Roy B. Tishler, Laura A. Goguen, Donald J. Annino, Edward S. Sim, Vickie Y. Jo, Kristine S. Wong, Jeffrey P. Guenette, Robert I. Haddad, Glenn J. Hanna","doi":"10.1158/1078-0432.ccr-24-3053","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3053","url":null,"abstract":"Background: Observational studies suggest circulating tumor HPV DNA may facilitate early detection of recurrent HPV-positive oropharynx cancer (OPC). We prospectively investigated whether biomarker-guided surveillance detects recurrence sooner than standard-of-care. Patients and Methods: We enrolled patients evaluated for HPV-positive OPC at a single center 11/2020-4/2023 undergoing curative-intent treatment in a single-arm cohort study. Pretreatment plasma and/or tumor tissue were tested for tumor tissue modified viral HPV DNA (‘TTMV’) from HPV subtypes 16/18/31/33/35 using a ddPCR-based commercial assay. Post-treatment plasma TTMV was assessed periodically. Detectable/indeterminate tests prompted imaging. Primary outcome was proportion of recurrences first detected by TTMV. Results: Median follow-up was 23 months, with median 6 post-treatment TTMV tests for 155 subjects. Fifteen subjects (9%) recurred. Among these, 6 (40%, 95%CI=16%-68%) were ‘early true-positives’, for whom TTMV detection predated and prompted the imaging and clinical workup that diagnosed recurrence (median lead-time=132 days; range=47-280). Another 5 subjects (33%) were ‘confirmatory true-positives’, for whom detectable TTMV confirmed suspicious standard-of-care imaging findings. Finally, 4 subjects (27%) with recurrence had undetectable TTMV at diagnosis (‘false-negatives’). False-negatives had low or undetectable pretreatment TTMV, and 2/4 had non-HPV16 genotypes. Finally, 3 subjects had prolonged detectable TTMV without disease (‘false-positives’); all had immunologic comorbidities. Overall, sensitivity of TTMV for recurrence was 73% (95%CI=45-92%). Among 117 subjects with HPV16 and detectable pretreatment TTMV, sensitivity was higher (91%, 95%CI=59-100%) Conclusions: TTMV-guided surveillance facilitates early detection of many HPV-positive OPC recurrences, with highest sensitivity for HPV16 and detectable pretreatment TTMV. Clinical implementation should be carefully informed by the limitations described herein.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"34 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879640","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":"FDA Approval Summary: Nadofaragene firadenovec-vncg for bacillus Calmette-Guérin-unresponsive non-muscle invasive bladder cancer.","authors":"Laronna Colbert, Yuxia Jia, Anurag Sharma, Jiang Hu, Zhenzhen Xu, Daniel L Suzman, Asha Das, Peter Bross, Paul G Kluetz, Lola A Fashoyin-Aje","doi":"10.1158/1078-0432.CCR-24-2812","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2812","url":null,"abstract":"<p><p>On December 16, 2022, the FDA approved the adenoviral vector-based gene therapy nadofaragene firadenovec-vncg (brand name Adstiladrin) for the treatment of adult patients with high-risk bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS). The product represents the first approved adenoviral vector-based gene therapy and the first approved gene therapy for bladder cancer. Determination of efficacy was based on results from Study rAd-IFN-CS-003 (Study CS-003), a single-arm trial in 98 evaluable patients with BCG-unresponsive NMIBC with CIS who received intravesical instillations of the gene therapy product (75 mL of nadofaragene firadenovec at 3 × 1011 viral particles per mL) once every 3 months. The major efficacy outcome measures were complete response (CR) at any time and duration of response (DoR). Fifty subjects experienced CR 3 months after initial treatment (CR=51%; 95% CI: 40.7; 61.3%), of whom 46% remained in response for ≥12 months. The median DoR was 9.7 months (range: 3 to 52+). Common adverse reactions included instillation site discharge, fatigue, bladder spasm, micturition urgency, hematuria, chills, pyrexia, and dysuria. The approval of nadofaragene firadenovec provides a new therapy option for patients with BCG-unresponsive NMIBC with CIS who are ineligible for cystectomy.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863530","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":"Smoking carcinogen induced inflammation promotes lung carcinogenesis via IRAK4 activation.","authors":"Ritesh K Aggarwal, Simone Sidoli, Jingli Wang, Srabani Sahu, Rahul Sanawar, Varun Gupta, Srinivas Aluri, Vineeth Sukrithan, Charan T R Vegivinti, Phaedon D Zavras, Divij Verma, Shanisha Gordon-Mitchell, Beamon Agarwal, Tanya Verma, Daniel T Starczynowski, Ulrich G Steidl, Aditi Shastri, Balazs Halmos, Lindsay M LaFave, Haiying Cheng, Amit Verma, Yiyu Zou","doi":"10.1158/1078-0432.CCR-24-2182","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2182","url":null,"abstract":"<p><strong>Purpose: </strong>Even though smoking is associated with lung cancer, the exact molecular pathways that link carcinogens with inflammation and oncogenic transformation are not well elucidated. Two major carcinogens in cigarette smoke, Nicotine-derived nitrosamine ketone, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo(α)pyrene (BaP) have not been tested in models that mimic inhaled exposure for prolonged periods of time.</p><p><strong>Experimental design: </strong>ICR mice were treated with intratracheal delivery of NNK and BaP (NB) for 18 months. Tissue microarrays from human lung cancers were evaluated for IRAK4 expression. Functional effects of IRAK4 inhibition were evaluated in cell lines and in xenografts.</p><p><strong>Results: </strong>Smoking-associated carcinogen treated mice developed epithelial dysplasia followed by lung cancers at increased rates relative to controls. Histology revealed myeloid inflammation in murine lung tissues. Lung macrophages showed elevated levels of pro-inflammatory IL-1b when exposed to cigarette smoking condensate. A key downstream mediator of IL-1β signaling, Interleukin 1 receptor associated kinase-4 (IRAK4), was overexpressed in murine lung tissues exposed to carcinogens. Majority of human lung cancer samples also exhibited overactivated IRAK4 expression. IRAK4 localized in microtubules in lung cancer cell lines. Using mass spectrometry on isolated microtubules, we observed that IRAK4 inhibition was associated with decreased phosphorylation of tubular motility proteins including MYH9. Inhibition of IRAK4 resulted in decreased invasion in lung cancer cell lines and reduced growth of lung cancer xenografts.</p><p><strong>Conclusions: </strong>These data demonstrate that smoking associated carcinogens can be linked to oncogenic transformation via inflammatory IRAK4 activation.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863531","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":"Comparison of Shared Class I HLA-bound Non-canonical Neoepitopes between Normal and Neoplastic Tissues of Pancreatic Adenocarcinoma.","authors":"Tengyi Zhang, Betul Celiker, Yingkuan Shao, Jessica Gai, C Mark Hill, Chunyu Wang, Lei Zheng","doi":"10.1158/1078-0432.CCR-24-2251","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2251","url":null,"abstract":"<p><strong>Purpose: </strong>Developing T cell or vaccine therapies for pancreatic ductal adenocarcinoma (PDAC) has been challenging due to a lack of knowledge regarding immunodominant, cancer-specific antigens, as a scarcity of genomic mutation-associated neoepitopes characterizes PDAC and there are limited availability of effective approaches to discover them.</p><p><strong>Experimental design: </strong>We utilized an advanced mass spectrometry approach to compare the immunopeptidome of PDAC tissues and matched normal tissues from the same patients.</p><p><strong>Results: </strong>We identified HLA class I-binding variant peptides derived from canonical proteins, which had single amino-acid substitutions not attributed to genetic mutations or RNA editing. These amino-acid substitutions appeared to result from translational errors. The variant peptides were predominantly enriched in tumor tissues, with some peptides shared across patients. Importantly, several of these variant peptides were more immunogenic than their wild-type counterparts.</p><p><strong>Conclusions: </strong>The shared non-canonical neoepitopes identified in this study offer promising candidates for vaccine and T cell therapy development, potentially providing new avenues for immunotherapy in PDAC.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853225","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":"Histologic and immunologic factors associated with response to immune checkpoint inhibitors in advanced sarcoma.","authors":"Alex Q Lee, Clara Hao, Minggui Pan, Kristen N Ganjoo, Nam Q Bui","doi":"10.1158/1078-0432.CCR-24-3485","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-3485","url":null,"abstract":"<p><strong>Purpose: </strong>To characterize factors associated with response to immune checkpoint inhibitors (ICIs) in advanced sarcoma.</p><p><strong>Experimental design: </strong>This is a retrospective study with a cohort of 216 patients with advanced sarcoma treated with ICIs between 2016-2023 at Stanford Health Care. Overall survival (OS), progression free survival (PFS), objective response rates per RECIST criteria (ORR), and reason for ICI discontinuation were analyzed across histologic subtypes, ICI regimens, tumor mutational burden (TMB), and PD-L1 expression.</p><p><strong>Results: </strong>The overall ORR in the cohort was 16.7%. The histologic subtypes with the highest ORR were Kaposi sarcoma (KS, 66.7%), alveolar soft part sarcoma (ASPS, 50%), angiosarcoma (AS, 33.3%), myxofibrosarcoma (MFS, 28.6%), and undifferentiated pleomorphic sarcoma (UPS, 27.8%). The subtypes with the lowest ORR were osteosarcoma (0%), synovial sarcoma (SS, 0%), and liposarcoma (LPS, 3.7%). The subtypes with the highest median PFS were KS (median not reached, NR), ASPS (NR), MFS (27.4 months), and UPS (11.3 months). The ORR for sarcomas with PD-L1 ≥ 1% was 27.8% (p=0.02), while the ORR for sarcomas with TMB ≥ 10 mutations per megabase of DNA (mut/MB) was 28.6% (p=0.20).</p><p><strong>Conclusions: </strong>ORR and PFS were highly variable across sarcoma histologic subtype. In this large analysis, KS, ASPS, AS, MFS, and UPS demonstrated the highest ORR and longest PFS while osteosarcoma, SS, and LPS had the lowest ORR and shortest PFS. PD-L1 expression was also associated with increased ORR. Our findings provide further insight into understanding the sarcoma histologic and immunologic factors that correspond with response to ICIs.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853226","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":"Circulating tumor DNA dynamics and clinical outcome in metastatic colorectal cancer patients undergoing front-line chemotherapy","authors":"Michele Ghidini, Jens C. Hahne, Chiara Senti, Timon Heide, Paula Z. Proszek, Ridwan Shaikh, Paul Carter, Michael Hubank, Francesco Trevisani, Ornella Garrone, Maria Rosa Cappelletti, Daniele Generali, Monica Cattaneo, Nicoletta Gnocchi, Gianvito Donati, Angela Gobbi, Giulia Grizzi, Andrea Lampis, Raghad Elghadi, Giulia Tanzi, Gianluca Tomasello, Margherita Ratti, David J. Pinato, Matteo Fassan, Georgios Vlachogiannis, Andrea Sottoriva, Rodolfo Passalacqua, Nicola Valeri","doi":"10.1158/1078-0432.ccr-24-0924","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-0924","url":null,"abstract":"Purpose: we tested whether ctDNA changes may be used to assess early response and clinical outcome in metastatic colorectal cancer (mCRC) patients undergoing front-line systemic anti-cancer therapy (SACT). Experimental Design: 862 plasma samples were collected 4-weekly from baseline (BL) until disease progression in mCRC patients receiving front line SACT. ctDNA normalization was defined as ≥99% clearance after 1 month of therapy (Mo1) in the 3 variants with the highest allele frequency in BL ctDNA. Results: 83 paired samples from 75 patients were available for analysis. 12 pairs (14.4%) showed no variants in either BL or Mo1. In the remaining 71 comparisons (65 patients), 37 (52.1%) showed ctDNA normalization at Mo1. Patients that cleared ctDNA had significantly longer overall (45.6 months) and progression-free survival (13.9 months) compared to non-normalized patients [OS= 22.6 months (Log-rank p = 0.01) and PFS= 10.7 months (Log-rank p = 0.036) respectively]. In addition, higher response rate was observed in patients with ctDNA clearance (72.9%) compared to non-normalized cases (38.2%). Longitudinal sequencing of at least four timepoints in pts with a PFS&amp;gt;10 months showed emerging variants in 47.8% of cases; in all these patients the trajectory of these new “outlier” variants appeared in stark contrast with the clinical-radiological course of disease and the trend in other mutations. Conclusions: ctDNA clearance represents an early indicator of benefit from SACT in mCRC patients; serial tracking of multiple variants is warranted to improve specificity and to avoid misleading information due to the emergence of mutations of unknown clinical significance.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"47 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841429","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":"Genotype-Directed Synthetic Cytotoxicity of ATR Inhibition with Radiotherapy.","authors":"Victor Ng, Sonali Sinha, Ardijana Novaj, Jennifer Ma, Niamh McDermott, Xin Pei, Ana Leda F Longhini, Helen Grimsley, Rui Gardner, Ezra Rosen, Simon N Powell, Fresia Pareja, Diana Mandelker, Atif Khan, Jeremy Setton, Anne Roulston, Stephen Morris, Maria Koehler, Nancy Lee, Jorge Reis-Filho, Nadeem Riaz","doi":"10.1158/1078-0432.CCR-24-0154","DOIUrl":"10.1158/1078-0432.CCR-24-0154","url":null,"abstract":"<p><strong>Purpose: </strong>The importance of the DNA damage response in mediating effects of radiotherapy (RT) has galvanized efforts to target this pathway with radiosensitizers. Yet early clinical trials of this approach have failed to yield a benefit in unselected populations. We hypothesized that ataxia-telangiectasia mutated (Atm)-null tumors would demonstrate genotype-specific synergy between RT and an inhibitor of the DNA damage response protein ataxia-telangiectasia and Rad3-related (ATR) kinase.</p><p><strong>Experimental design: </strong>We investigated the synergistic potential of the ATR inhibitor (ATRi) RP-3500 and RT in two Atm-null and isogenic murine models, both in vitro and in vivo. Staining of γ-H2AX foci, characterization of the immune response via flow cytometry, and tumor rechallenge experiments were performed to elucidate the mechanism of interaction. To examine genotype specificity, we tested the interaction of ATRi and RT in a Brca1-null model. Finally, patients with advanced cancer with ATM alterations were enrolled in a phase I/II clinical trial to validate preclinical findings.</p><p><strong>Results: </strong>Synergy between RP-3500 and RT was confirmed in Atm-null lines in vitro, characterized by an accumulation of DNA double-strand breaks. In vivo, Atm-null tumor models had higher rates of durable control with RT and ATRi than controls. In contrast, there was no synergy in tumors lacking Brca1. Analysis of the immunologic response indicated that efficacy is largely mediated by cell-intrinsic mechanisms. Lastly, early results from our clinical trial showed complete responses in patients.</p><p><strong>Conclusions: </strong>Genotype-directed radiosensitization with ATRi and RT can unleash significant therapeutic benefit and could represent a novel approach to develop more effective combinatorial synthetic cytotoxic RT-based treatments. See related commentary by Schrank and Colbert, p. 5505.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"5643-5656"},"PeriodicalIF":10.0,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141896872","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":"Correction: The Retinoblastoma Tumor Suppressor Modulates DNA Repair and Radioresponsiveness.","authors":"Chellappagounder Thangavel, Ettickan Boopathi, Steve Ciment, Yi Liu, Raymond O'Neill, Ankur Sharma, Steve B McMahon, Hestia Mellert, Sankar Addya, Adam Ertel, Ruth Birbe, Paolo Fortina, Adam P Dicker, Karen E Knudsen, Robert B Den","doi":"10.1158/1078-0432.CCR-24-3735","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-3735","url":null,"abstract":"","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"30 24","pages":"5695"},"PeriodicalIF":10.0,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827359","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}