請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/102137完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 郭頌鑫 | zh_TW |
| dc.contributor.advisor | Sung-Hsin Kuo | en |
| dc.contributor.author | 楊文綺 | zh_TW |
| dc.contributor.author | Wen-Chi Yang | en |
| dc.date.accessioned | 2026-03-13T16:43:45Z | - |
| dc.date.available | 2026-03-14 | - |
| dc.date.copyright | 2026-03-13 | - |
| dc.date.issued | 2025 | - |
| dc.date.submitted | 2025-09-10 | - |
| dc.identifier.citation | [1] Taiwan Cancer Registry Annual Report. 2018.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/102137 | - |
| dc.description.abstract | 本研究旨在透過結合臨床觀察與前臨床實驗，評估CDK4/6抑制劑、放射治療及免疫療法之治療策略，以期達成乳癌治療的最佳化，提供個人化治療的依據。
在臨床分析中，我們針對接受系統性治療並合併不同放射治療方式的早期乳癌患者進行預後評估。研究結果顯示，單純鎖骨上淋巴區域放射治療的成效與更廣泛的區域性淋巴結放射治療（含內乳淋巴結）相當。此外，針對病理分期為N3的患者，額外增加腋下淋巴結放射治療並未顯著提升治療成效，暗示對於此類高風險患者，加強系統性治療可能較擴大放療範圍更具療效。 在前臨床實驗部分，我們探討CDK4/6抑制劑合併RT於荷爾蒙受體陽性、人類表皮生長因子受體2 (HER2)陰性乳癌的治療效果。研究顯示CDK4/6抑制劑可透過抑制ERK及NF-κB/c-Myc訊息傳導路徑，以及干擾DNA雙股斷裂修復，明顯提升細胞對放射治療的敏感性。此外，本研究進一步以具免疫功能的三陰性乳癌小鼠模式（4T1及EMT6），評估CDK4/6抑制劑、放射治療與抗PD-L1免疫療法的三合一治療策略。結果證實此三合一療法能有效抑制腫瘤生長，增加血液中干擾素-γ（IFN-γ）濃度，並促進CD4+ T細胞、CD8+ T細胞及M1型巨噬細胞浸潤腫瘤組織，成功將腫瘤微環境轉變為較具免疫刺激性的狀態。 整體而言，本研究成果凸顯CDK4/6抑制劑合併放射治療對於提升各種亞型乳癌的治療成效，以及促進免疫療法療效的潛力。上述前臨床研究結果值得未來進一步推展至臨床驗證，以期提升乳癌患者的整體預後及存活率。 | zh_TW |
| dc.description.abstract | This study aimed to optimize breast cancer treatment by integrating clinical insights and preclinical evaluations of CDK4/6 inhibitor, radiotherapy (RT), and immunotherapy, supporting personalized therapeutic strategies.
Clinically, we analyzed outcomes in early-stage breast cancer patients receiving systemic therapy combined with various radiotherapy approaches. Supraclavicular radiotherapy (SCF-RT) alone showed comparable results to extensive regional nodal irradiation, including the internal mammary chain. Additionally, extending radiotherapy to axillary nodes did not improve outcomes for pathologically N3 patients, suggesting intensified systemic therapy might be more effective. Preclinically, we assessed CDK4/6 inhibitors combined with RT in HR-positive, HER2-negative breast cancer. CDK4/6 inhibitors increased radiosensitivity by suppressing ERK and NF-κB/c-Myc signaling and impairing DNA double-strand break repair. Furthermore, combining CDK4/6 inhibitors, RT, and anti-PD-L1 immunotherapy in immunocompetent triple-negative breast cancer (TNBC) mouse models effectively inhibited tumor growth, increased circulating IFN-γ levels, and enhanced immune cell infiltration, shifting the tumor microenvironment towards immunostimulation. Overall, this integrated approach highlights the promise of combining CDK4/6 inhibitors with RT to enhance therapeutic effects in breast cancer across various subtypes and improve the efficacy of immunotherapy. These promising preclinical results warrant further clinical investigation to potentially enhance treatment outcomes and patient survival. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2026-03-13T16:43:45Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2026-03-13T16:43:45Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 口委審定書 I
ACKNOWLEGEMENT II 中文摘要 III ABSTRACT IV CONTENT V LIST OF FIGURES VIII LIST OF TABLES XI CHAPTER 1. INTRODUCTION 1 1.1 INTRODUCTION OF BREAST CANCER 1 1.2 CHALLENGES IN THE TREATMENT OF LUMINAL-TYPE BREAST CANCER 3 1.3 THERAPEUTIC LIMITATION IN TRIPLE NEGATIVE BREAST CANCER 4 1.4 ROLE OF RADIOTHERAPY IN BREAST CANCER 5 1.5 ROLE CDK4/6 INHIBITORS IN BREAST CANCER 8 1.5.1 MECHANISM OF CDK4/6 INHIBITORS 8 1.5.2 ANTITUMOR EFFECT OF CDK4/6 INHIBITORS 8 1.5.3 CDK4/6 INHIBITORS IN IMMUNE MODULATION 10 1.6 FIND OUT THE BEST TREATMENT COCKTAIL IN BREAST CANCER 11 CHAPTER 2. ROLE OF RADIOTHERAPY FOR EARLY BREAST CANCER IN THE ERA OF MORDERN SYSTEMIC TREATMENT 14 2.1 INTRODUCTION 14 2.2 MATERIALS AND METHODS 15 2.2.1 PATIENTS 15 2.2.2 TECHNIQUE OF RADIOTHERAPY 16 2.2.3 RESPONSE EVALUATION AND STATISTICAL ANALYSIS 16 2.3 RESULTS 17 2.3.1 CLINICAL CHARACTERISTICS OF PATIENTS 17 2.3.2 CLINICAL OUTCOMES AND PROGNOTISC FACTORS 20 2.3.3 CLINICAL OUTCOMES FOR PATIENTS WHO RECEIVED ALRT 26 2.4 DISCUSSION 29 2.5 SUMMARY 33 CHAPTER 3. RADIOSENSITIZING EFFECTS OF CDK4/6 INHIBITORS IN HORMONE POSITIVE AND HER2-NEGATIVE BREAST CANCER 35 3.1 INTRODUCTION 35 3.2 MATERILS AND METHODS 36 3.2.1 BREAST CANCER CELL LINES AND CULTURE CONDITIONS 36 3.2.2 CDK4/6 INHIBITORS AND IONIZAING RADIATION 37 3.2.3 COLONOGENIC ASSAY 37 3.2.4 FLOW CYTOMETRY 37 3.2.5 CELL PROLIFERATION ASSAY 38 3.2.6 IMMUNOFLUORESCENCE STAINING 39 3.2.7 WESTERN BLOT ANALYSIS 39 3.2.8 NF-κB ACTIVITY ASSAY 40 3.2.9 IN VIVO MOUSE MODEL 40 3.2.10 IMMUNOHISTOCHEMISTRY STAINING 41 3.2.11 STATISTICAL ANALYSIS 41 3.3 RESULTS 44 3.3.1 CDK4/6 INHIBITORS SENSITIZE HR-POSITIVE, HER2-NEGATIVE BREAST CANCER CELL TO RADIOTHERAPY 44 3.3.2 IMPACT OF CDK4/6 INHIBITION COMBINED WITH RT ON CELL CYCLE PROGRESSION 49 3.3.3 IMPACT OF CDK4/6 INHIBITIOR AND RADIATION SEUQENCE ON CELL SURVIVAL 51 3.3.4 EFFECT OF CDK4/6 INHIBITORS COMBINED WITH RT ON DNA DOUBLE STRAND BREAKS AND REPAIR AND THE IMPACT ON CELLULAR APOPTOSIS 52 3.3.5 CDK4/6 INHIBITORS ATTENUATE ERK AND NF-κB/C-MYC PATHWAYS 58 3.3.6 SYNERGISTIC ANTITUMOR EFFECT OF CDK4/6 INHIBITORS AND RT IN VIVO 60 3.4 DISCUSSION 65 3.5 SUMMARY 70 CHAPTER 4. SYNERGISTIC ANTITUMOR EFFECTS OF CDK4/6 INHIBITORS, RADIOTHERAPY, AND ANTI-PD-L1 THERAPY IN TRIPLE-NEGATIVE BREAST CANCER VIA MICROENVIRONMENT REPROGRAMMING 72 4.1 INTRODUCTION 72 4.2 MATERILS AND METHODS 73 4.2.1 BREAST CANCER CELL LINES AND CULTURE CONDITIONS 74 4.2.2 DRUG AND IONIZAING IRRADIATION 74 4.2.3 CELL PROLIFERATION ASSAY 75 4.2.4 COLONOGENIC ASSAY 75 4.2.5 FLOW CYTOMETRY 76 4.2.6 WESTERN BLOT ANALYSIS 77 4.2.7 ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA) 78 4.2.8 IN VIVO MOUSE MODELS 79 4.2.9 IMMUNOHISTOCHEMISTRY STAINING 80 4.2.10 STATISTICAL ANALYSIS 82 4.3 RESULTS 82 4.3.1 EFFICACY AND RADIOSENSTIZATIZING POTENTIAL OF CDK4/6 INHIBITORS IN TNBC 82 4.3.2 RADIOTHERAPY MODULATES CELL SURFACE PD-L1 EXPRESSION IN TNBC CELLS 88 4.3.3 CDK4/6 INHIBITORS COMBINED WITH RT ENHANCES IN VIVO EFFICACY OF ANTI-PD-L1 91 4.3.4 COMBINED CDK4/6 INHIBITIOR, RT, AND ANTI-PD-L1 INCREASED CIRCULATING IFN-γ 94 4.3.5 TRIPLE COMBINATION THERAPY MODULATE TUMOR MICROENVIRONMENT 96 4.4 DISCUSSION 104 4.5 SUMMARY 111 CHAPTER 5. CONCLUSION 113 PUBLICATIONS ARISING FROM THIE DISSERTATION 117 REFERENCES 118 | - |
| dc.language.iso | en | - |
| dc.subject | 乳癌 | - |
| dc.subject | 放射治療 | - |
| dc.subject | 放射增敏作用 | - |
| dc.subject | CDK4/6抑制劑 | - |
| dc.subject | 免疫療法 | - |
| dc.subject | 腫瘤微環境 | - |
| dc.subject | Breast cancer | - |
| dc.subject | Radiotherapy | - |
| dc.subject | Radiosensitization | - |
| dc.subject | CDK4/6 inhibitor | - |
| dc.subject | Immunotherapy | - |
| dc.subject | Tumor microenvironment | - |
| dc.title | 利用CDK4/6抑制劑的協同細胞毒殺與腫瘤微環境調控最佳化乳癌放射治療成效 | zh_TW |
| dc.title | Optimizing Radiotherapy Efficacy in Breast Cancer: Synergistic Tumor Cell Killing and Tumor Microenvironment Reprogramming with CDK4/6 Inhibitors | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 114-1 | - |
| dc.description.degree | 博士 | - |
| dc.contributor.oralexamcommittee | 盧彥伸;劉峻宇;熊佩韋;李欣倫 | zh_TW |
| dc.contributor.oralexamcommittee | Yen-Shen Lu;Chun-Yu Liu;Pei-Wei Shueng;Hsin-Lun Lee | en |
| dc.subject.keyword | 乳癌,放射治療放射增敏作用CDK4/6抑制劑免疫療法腫瘤微環境 | zh_TW |
| dc.subject.keyword | Breast cancer,RadiotherapyRadiosensitizationCDK4/6 inhibitorImmunotherapyTumor microenvironment | en |
| dc.relation.page | 134 | - |
| dc.identifier.doi | 10.6342/NTU202504448 | - |
| dc.rights.note | 同意授權(全球公開) | - |
| dc.date.accepted | 2025-09-11 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 腫瘤醫學研究所 | - |
| dc.date.embargo-lift | 2026-03-14 | - |
| 顯示於系所單位： | 腫瘤醫學研究所 | |
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