Developing BRAF mutant and BRAF wild-type selective strategies for radiosensitization in Anaplastic Thyroid Cancer
Developing BRAF mutant and BRAF wild-type selective strategies for radiosensitization in Anaplastic Thyroid Cancer
批准号:
10332466
负责人:
MANISHA H SHAH
金额:
$22.67万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-08-01 至 2025-04-30
中文摘要
项目总结
英文摘要
PROJECT SUMMARY
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.
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Targeting RAF and VEGF Signaling in Thyroid Cancer
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批准号:7096658
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项目类别:
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资助金额:$19.83万
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财政年份:2005
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负责人:MANISHA H SHAH
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依托单位:
Targeting RAF and VEGF Signaling in Thyroid Cancer
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批准号:6938754
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项目类别:
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资助金额:$20.15万
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财政年份:2005
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负责人:MANISHA H SHAH
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依托单位:
BIOLOGIC MODIFIER THERAPIES IN AIDS MALIGNANCIES
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批准号:6930142
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项目类别:
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资助金额:$9.67万
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财政年份:1995
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负责人:MANISHA H SHAH
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依托单位:
BIOLOGIC MODIFIER THERAPIES IN AIDS MALIGNANCIES
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批准号:6522363
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项目类别:
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资助金额:$6.88万
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财政年份:1995
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负责人:MANISHA H SHAH
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依托单位:
国内基金
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