Developing BRAF mutant and BRAF wild-type selective strategies for radiosensitization in Anaplastic Thyroid Cancer

开发用于未变性甲状腺癌放射增敏的 BRAF 突变体和 BRAF 野生型选择性策略

• 批准号: 10380904
• 负责人: Terence Marques Williams
• 金额: $ 45.89万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10380904
• 关键词: Acceleration; Apoptosis; BRAF gene; Biological Markers; Biological Response Modifier Therapy; Blood specimen; Cell Cycle Checkpoint; Cell Survival; Cells; Cessation of life; Chemoresistance; Clinical; Cytotoxic Chemotherapy; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Gene; DNA Repair Pathway; DNA-dependent protein kinase; Data; Dependence; Double Strand Break Repair; Drug Kinetics; Esophagus; Excision; External Beam Radiation Therapy; FDA approved; Fostering; Frequencies; Future; G2/M Checkpoint Pathway; Genes; Genomics; Immunocompetent; Impairment; In Vitro; Institution; MAP2K1 gene; MEK inhibition; MEKs; Malignant Neoplasms; Malignant neoplasm of thyroid; Maximum Tolerated Dose; Mediating; Molecular; Morbidity - disease rate; Mutate; Mutation; Nonhomologous DNA End Joining; Nuclear; Oncogenes; Oncogenic; Operative Surgical Procedures; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Phosphotransferases; Play; Prognosis; RAS inhibition; Radiation; Radiosensitization; Ras/Raf; Recurrence; Recurrent disease; Regional Disease; Resistance; Role; Safety; Signal Pathway; Signal Transduction; Solid Neoplasm; TP53 gene; Testing; Tissue Sample; Toxic effect; Treatment Failure; Up-Regulation; anaplastic thyroid cancer; biomarker identification; cancer cell; cell type; chemotherapy; combinatorial; disorder control; genotoxicity; improved; improved outcome; in vivo; inhibitor; kinase inhibitor; molecular subtypes; mortality; mouse model; mutant; neoplastic cell; novel; novel strategies; novel therapeutic intervention; novel therapeutics; phase I trial; phase II trial; pre-clinical; radiation resistance; repaired; research clinical testing; response; response biomarker; sensor; small molecule inhibitor; standard of care; therapeutic target; therapy resistant; tumor; uptake

Anaplastic thyroid cancer (ATC) remains one of the solid tumors that is associated with the poorest prognosis. Standard therapy includes maximal safe resection, external beam radiation therapy (EBRT), and cytotoxic chemotherapy. Despite this, there are high rates of disease recurrence. Local/regional recurrence is particularly difficult for patients with ATC, resulting in airway and/or esophageal compromise which contributes to mortality and metastatic dissemination. Novel therapies are thus needed to improve disease control and lengthen survival. Recently, genomic profiling of ATC has uncovered high frequency mutations in the RAS-RAF-MEK-ERK pathway (particularly BRAF and RAS), as well as other DNA damage and cell cycle checkpoint control genes, including TP53. Our preclinical data supports that an activating BRAFV600E mutation promotes resistance to EBRT and genotoxic therapies, through the non-homologous end-joining repair (NHEJ) DNA repair pathway. In addition, targeted inhibition of BRAFV600E with a small molecule inhibitor results in sensitization to EBRT in BRAF mutant (BRAFm) ATC. Furthermore, treatment of BRAF mutant cells with a MEK-1/2 inhibitor also results in radiosensitization. Since BRAF wild-type (BRAFwt) ATC accounts for ~ 60-70% of cases, developing targeted strategies for radiosensitization in BRAFwt ATC is also critical. As such, we find that TP53 mutant ATC is effectively radiosensitized by ATR and Wee1 kinase inhibitors, highlighting the dependency of these tumors on the G2/M cell cycle checkpoint. Finally, we will explore radiation sensitization approaches for RAS mutant ATC, another common BRAFwt molecular subtype of ATC. In this proposal, we will attempt multiple strategies to advance therapy for patients with BRAFm and BRAFwt ATC. In Aim 1, we will perform a phase I trial to determine the maximally-tolerated doses of dabrafenib (BRAF inhibitor) and trametinib (MEK-1/2 inhibitor) to be used concurrently with EBRT for BRAFm ATC, and identify biomarkers of response and molecular pathways leading to resistance. In Aim 2, we will perform mechanistic studies to better understand how BRAFm leads to accelerated DNA repair, test novel therapeutic strategies targeting components of DNA repair, and develop and optimize novel strategies targeting DNA repair in combination with EBRT and other genotoxic therapies for BRAFm ATC. In Aim 3, we will attempt to develop novel strategies for treating BRAF wild-type ATC, by testing different targeted strategies for TP53 and RAS deficient or mutated ATC in vitro and in vivo to support future clinical testing of these combinations. Together, these studies will improve our understanding of how BRAF mutations impart radio-resistance, and identify new tumor-selective combinatorial approaches for treating patients with BRAF mutant and BRAF wild-type ATC.

型甲状腺癌（ATC）仍然是与最差预后相关的实体瘤之一。标准疗法包括最大安全切除，外束辐射疗法（EBRT）和细胞毒性化学疗法。尽管如此，疾病复发率很高。对于患有ATC的患者而言，局部/区域复发特别困难，导致气道和/或食管妥协，这有助于死亡率和转移性传播。因此，需要新的疗法来改善疾病控制并延长生存率。最近，ATC的基因组分析发现了RAS-RAF-MEK-ERK途径（尤其是BRAF和RAS）中的高频突变，以及其他DNA损伤和细胞周期检查点控制点基因，包括TP53。我们的临床前数据支持激活的BRAFV600E突变通过非同理端连接修复（NHEJ）DNA修复途径促进对EBRT和遗传毒性疗法的抗性。另外，用小分子抑制剂对BRAFV600E的靶向抑制会导致BRAF突变体（BRAFM）ATC的EBRT敏化。此外，用MEK-1/2抑制剂对BRAF突变细胞的处理也会导致放射敏化。由于BRAF野生型（BRAFWT）ATC占病例的约60-70％，因此在BRAFWT ATC中制定有针对性的放射敏化策略也至关重要。因此，我们发现TP53突变体ATC被ATR和WEE1激酶抑制剂有效地放射敏感，突出了这些肿瘤对G2/M细胞周期检查点的依赖性。最后，我们将探索辐射敏化 RAS突变体ATC的方法，ATC的另一种常见BRAFWT分子亚型。在此提案中，我们将尝试多种策略来推进BRAFM和BRAFWT ATC患者的治疗。在AIM 1中，我们将执行I期试验，以确定最大耐受性的Dabrafenib（BRAF抑制剂）和Trametinib（MEK-1/2抑制剂）与EBRT一起用于BRAFM ATC，并鉴定出反应和分子途径的生物标志物。在AIM 2中，我们将进行机械研究，以更好地了解BRAFM如何导致DNA修复加速，测试针对DNA修复组件的新型治疗策略，并制定和优化针对DNA修复的新型策略，以EBRT和其他遗传毒性疗法为BRAFM ATC结合使用。在AIM 3中，我们将尝试通过测试TP53的不同目标策略和RAS缺乏或体外突变的RAS来支持其他针对性的策略来制定新的策略，以支持这些组合的未来临床测试。总之，这些研究将提高我们对BRAF突变如何赋予放射性的理解，并确定用于治疗BRAF突变体和BRAF野生型ATC患者的新肿瘤选择性组合方法。

项目成果

BRAFV600E Inhibitor Radiosensitizes Thyroid Cancer-Response.

BRAFV600E 抑制剂可提高甲状腺癌的放射敏感性。

• DOI: 10.1158/1078-0432.ccr-19-2705
• 发表时间: 2019
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Williams,TerenceM

BRAF mutation correlates with worse local-regional control following radiation therapy in patients with stage III melanoma.

• DOI: 10.1186/s13014-021-01903-5
• 发表时间: 2021-09-18
• 期刊: Radiation oncology (London, England)
• 作者: Wolfe AR;Chablani P;Siedow MR;Miller ED;Walston S;Kendra KL;Wuthrick E;Williams TM
• 通讯作者: Williams TM

Narrative review of emerging roles for AKT-mTOR signaling in cancer radioimmunotherapy.

• DOI: 10.21037/atm-21-4544
• 发表时间: 2021-10
• 期刊: Annals of translational medicine
• 作者: Shen C;He Y;Chen Q;Feng H;Williams TM;Lu Y;He Z
• 通讯作者: He Z