دورية أكاديمية
Sequential Targeting of Retinoblastoma and DNA Synthesis Pathways Is a Therapeutic Strategy for Sarcomas That Can Be Monitored in Real Time.
| العنوان: | Sequential Targeting of Retinoblastoma and DNA Synthesis Pathways Is a Therapeutic Strategy for Sarcomas That Can Be Monitored in Real Time. |
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| المؤلفون: | Nguyen TDT; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Wang Y; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Bui TN; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Lazcano R; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Ingram DR; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Yi M; Departments of Breast Surgical Oncology and Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas., Vakulabharanam V; University of Houston, Houston, Texas., Luo L; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Pina MA; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Karakas C; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Li M; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas., Kettner NM; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Somaiah N; Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Hougton PJ; Greehey Children's Cancer Research Institute and Molecular Medicine, The University of Texas Health Science Center, San Antonio, Texas., Mawlawi O; Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas., Lazar AJ; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Hunt KK; Departments of Breast Surgical Oncology and Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas., Keyomarsi K; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. |
| المصدر: | Cancer research [Cancer Res] 2023 Mar 15; Vol. 83 (6), pp. 939-955. |
| نوع المنشور: | Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 2984705R Publication Model: Print Cited Medium: Internet ISSN: 1538-7445 (Electronic) Linking ISSN: 00085472 NLM ISO Abbreviation: Cancer Res Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Baltimore, Md. : American Association for Cancer Research Original Publication: Chicago [etc.] |
| مواضيع طبية MeSH: | Antineoplastic Agents*/pharmacology , Retinal Neoplasms* , Retinoblastoma*/drug therapy , Sarcoma*/metabolism, Humans ; Cyclin-Dependent Kinase 4 ; Cyclin-Dependent Kinase 6 ; DNA ; Retinoblastoma Protein/genetics |
| مستخلص: | Treatment strategies with a strong scientific rationale based on specific biomarkers are needed to improve outcomes in patients with advanced sarcomas. Suppression of cell-cycle progression through reactivation of the tumor suppressor retinoblastoma (Rb) using CDK4/6 inhibitors is a potential avenue for novel targeted therapies in sarcomas that harbor intact Rb signaling. Here, we evaluated combination treatment strategies (sequential and concomitant) with the CDK4/6 inhibitor abemacicib to identify optimal combination strategies. Expression of Rb was examined in 1,043 sarcoma tumor specimens, and 50% were found to be Rb-positive. Using in vitro and in vivo models, an effective two-step sequential combination strategy was developed. Abemaciclib was used first to prime Rb-positive sarcoma cells to reversibly arrest in G1 phase. Upon drug removal, cells synchronously traversed to S phase, where a second treatment with S-phase targeted agents (gemcitabine or Wee1 kinase inhibitor) mediated a synergistic response by inducing DNA damage. The response to treatment could be noninvasively monitored using real-time positron emission tomography imaging and serum thymidine kinase activity. Collectively, these results show that a novel, sequential treatment strategy with a CDK4/6 inhibitor followed by a DNA-damaging agent was effective, resulting in synergistic tumor cell killing. This approach can be readily translated into a clinical trial with noninvasive functional imaging and serum biomarkers as indicators of response and cell cycling. Significance: An innovative sequential therapeutic strategy targeting Rb, followed by treatment with agents that perturb DNA synthesis pathways, results in synergistic killing of Rb-positive sarcomas that can be noninvasively monitored. (©2023 American Association for Cancer Research.) |
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| معلومات مُعتمدة: | P30 CA016672 United States CA NCI NIH HHS; R01 CA223772 United States CA NCI NIH HHS; R01 CA255960 United States CA NCI NIH HHS |
| المشرفين على المادة: | 0 (Antineoplastic Agents) EC 2.7.11.22 (Cyclin-Dependent Kinase 4) EC 2.7.11.22 (Cyclin-Dependent Kinase 6) 9007-49-2 (DNA) 0 (Retinoblastoma Protein) |
| تواريخ الأحداث: | Date Created: 20230105 Date Completed: 20230317 Latest Revision: 20240914 |
| رمز التحديث: | 20240914 |
| مُعرف محوري في PubMed: | PMC10023441 |
| DOI: | 10.1158/0008-5472.CAN-22-2258 |
| PMID: | 36603130 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1538-7445 |
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| DOI: | 10.1158/0008-5472.CAN-22-2258 |