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Targeting Ferroptosis in BRAF (V600E) Mutant Anaplastic Thyroid Cancer

靶向 BRAF (V600E) 突变型甲状腺未分化癌中的铁死亡

基本信息

批准号：
10721967
负责人：
Electron Kebebew
金额：
$ 22.37万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10721967
关键词：
Advanced Malignant Neoplasm Apoptosis BRAF gene Cancer cell line Cell Death Cells Cessation of life Clinic Combined Modality Therapy Data Development Diagnosis Future Gatekeeping Goals Growth Human In Vitro Incidence Iron Knowledge Lipids MAP Kinase Gene MAPK Signaling Pathway Pathway Malignant Neoplasms Malignant neoplasm of thyroid Mesenchymal Mission Mitogen-Activated Protein Kinase Inhibitor Mitogen-Activated Protein Kinases Mutate Mutation Oncoproteins Outcome Pathway interactions Patient-Focused Outcomes Patients Peroxidases Persons Public Health Refractory Research Resistance Safety Science Signal Induction Signal Pathway Testing Therapeutic Time Toxic effect Translations Treatment Efficacy Treatment Protocols United States National Institutes of Health acquired treatment resistance anaplastic thyroid cancer anticancer activity cancer cell cancer therapy cell type combinatorial disability efficacy evaluation evidence base improved in vivo inhibitor innovation melanoma mortality mutant novel novel therapeutic intervention pre-clinical preclinical safety response standard care therapeutic effectiveness translational framework treatment strategy

项目摘要

PROJECT SUMMARY/ABSTRACT BRAFV600E mutations are common in anaplastic thyroid cancer (ATC, 50-75% positive), which is refractory to standard treatment and has high mortality rates. Monotherapy with BRAF inhibitors is ineffective in patients with BRAFV600E-mutant ATC. Although, combination therapy using a BRAF inhibitor, and a mitogen-activated protein kinase (MEK) inhibitor is more effective than BRAF inhibitor monotherapy, acquired resistance is common because BRAF and MEK act on the same downstream target and largely the same pathway. A feature of resistance to BRAF inhibition or combined BRAF and MEK inhibition is increased sensitivity to agents that induce ferroptosis (a distinct mechanism of programmed cell death dependent on iron). Moreover, it has been shown that treatment-resistant (including BRAF inhibitor-resistant) cancer cells (persister cells) are associated with a mesenchymal state that is dependent on GPX4 (a gatekeeper and suppressor of ferroptosis) and show increased sensitivity to ferroptosis induction. Our unpublished preliminary data show that ferroptosis induction is more pronounced in BRAFV600E-mutant than wild type ATC cells and that combination BRAF inhibition and ferroptosis induction has synergistic activity in causing cell death in BRAFV600E-mutant ATC cells. The long-term goal is the development of novel science-based treatment strategies for ATC that improve patient outcomes. The overall objective in this application is to determine the safety and preclinical therapeutic efficacy of combined BRAF inhibitor and ferroptosis induction treatment in BRAFV600E-mutant ATC. The central hypothesis in this proposal is that combination therapy with BRAF inhibitor and ferroptosis induction will have synergistic/additive anti-cancer activity in BRAFV600E-mutant ATC. The rationale for this project is that determination of the safety and preclinical therapeutic efficacy of ferroptosis induction with BRAF inhibition is likely to offer a strong scientific basis for translation of this novel combinatorial treatment strategy to the clinic. The central hypothesis will be tested by pursuing two specific aims: 1) Evaluate the safety and anticancer activity of targeting ferroptosis in combination with BRAF inhibition in BRAFV600E-mutant ATC in vitro and in vivo; and 2) Evaluate the efficacy of combined ferroptosis induction and BRAF inhibition compared to combination BRAF and MEK inhibition. The research proposed in this application is innovative, in the applicant’s opinion, as it represents a significant departure from the current strategy of targeting BRAF only or a single signaling pathway in BRAFV600E-mutant ATC to the concept that combined treatment with a BRAF inhibitor and ferroptosis induction will result in more robust and synergistic/additive anticancer activity. The proposed research is significant because it is expected to provide a strong scientific justification for future studies that could provide a new mechanism-based treatment regimen for BRAFV600E-mutant ATCs that could result in durable response. Ultimately, such knowledge has the potential of offering new opportunities for the development of novel therapeutic strategy for BRAFV600E-mutant ATC.

项目总结/文摘