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: 10220909
• 负责人: Terence Marques Williams
• 金额: $ 44.57万
• 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/10220909
• 关键词: 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; Disease; 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; 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; Play; Prognosis; RAS inhibition; Radiation; Radiation-Sensitizing Agents; Radiosensitization; Ras/Raf; Recurrence; Resistance; Role; Safety; Signal Pathway; Signal Transduction; Solid Neoplasm; TP53 gene; Testing; Tissue Sample; Toxic effect; Treatment Failure; Up-Regulation; Ursidae Family; anaplastic thyroid cancer; cancer cell; cancer therapy; chemotherapy; combinatorial; disorder control; genotoxicity; improved; improved outcome; in vivo; inhibitor/antagonist; 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.

甲状腺未分化癌（ATC）仍然是预后最差的实体瘤之一。标准治疗包括最大安全切除、外照射放射治疗 (EBRT) 和细胞毒性化疗。尽管如此，疾病复发率仍然很高。对于 ATC 患者来说，局部/区域复发尤其困难，导致气道和/或食管受损，从而导致死亡率和转移扩散。因此需要新的疗法来改善疾病控制并延长生存期。最近，ATC 的基因组分析发现了 RAS-RAF-MEK-ERK 通路（特别是 BRAF 和 RAS）的高频突变，以及其他 DNA 损伤和细胞周期检查点控制基因，包括 TP53。我们的临床前数据支持激活的 BRAFV600E 突变通过非同源末端连接修复 (NHEJ) DNA 修复途径促进对 EBRT 和基因毒性疗法的耐药性。此外，用小分子抑制剂靶向抑制 BRAFV600E 会导致 BRAF 突变体 (BRAFm) ATC 对 EBRT 敏感。此外，用 MEK-1/2 抑制剂处理 BRAF 突变细胞也会导致放射增敏。由于 BRAF 野生型 (BRAFwt) ATC 约占病例的 60-70%，因此制定针对 BRAFwt ATC 放射增敏的针对性策略也至关重要。因此，我们发现 TP53 突变体 ATC 可被 ATR 和 Wee1 激酶抑制剂有效地放射增敏，突出显示这些肿瘤对 G2/M 细胞周期检查点的依赖性。最后，我们将探讨辐射增敏 RAS 突变体 ATC 的方法，ATC 的另一种常见 BRAFwt 分子亚型。在本提案中，我们将尝试多种策略来推进 BRAFm 和 BRAFwt ATC 患者的治疗。在目标 1 中，我们将进行 I 期试验，以确定与 BRAFm ATC 的 EBRT 同时使用的达拉非尼（BRAF 抑制剂）和曲美替尼（MEK-1/2 抑制剂）的最大耐受剂量，并确定反应和治疗的生物标志物。导致耐药性的分子途径。在目标 2 中，我们将进行机制研究，以更好地了解 BRAFm 如何导致加速 DNA 修复，测试针对 DNA 修复成分的新治疗策略，并结合 EBRT 和其他 BRAFm ATC 基因毒性疗法开发和优化针对 DNA 修复的新策略。在目标 3 中，我们将尝试开发治疗 BRAF 野生型 ATC 的新策略，通过在体外和体内测试针对 TP53 和 RAS 缺陷或突变的 ATC 的不同靶向策略，以支持这些组合的未来临床测试。总之，这些研究将增进我们对 BRAF 突变如何赋予放射抗性的理解，并确定新的肿瘤选择性组合方法来治疗 BRAF 突变体和 BRAF 野生型 ATC 患者。