Minimizing the risk of therapy-related myeloid neoplasms by inhibiting genotoxic stress-induced expansion of leukemia-initiating cells with p53 mutations
通过抑制基因毒性应激诱导的 p53 突变白血病起始细胞的扩增,最大限度地降低治疗相关的骨髓肿瘤的风险
基本信息
- 批准号:10113420
- 负责人:
- 金额:$ 8.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-12-01 至 2022-11-30
- 项目状态:已结题
- 来源:
- 关键词:Acute Myelocytic LeukemiaAppearanceAzacitidineCancer PatientCancer SurvivorCell DeathCellsChemotherapy and/or radiationClinicalClinical DataClinical ResearchClinical TrialsClonal ExpansionDNADataDevelopmentDominant-Negative MutationDysmyelopoietic SyndromesExposure toFutureGenotoxic StressGoalsGrantHematopoiesisHematopoieticHematopoietic stem cellsHumanImpairmentInvestigationIonizing radiationMalignant - descriptorMalignant NeoplasmsModelingMolecularMolecular ConformationMutationMyeloproliferative diseaseOutcomePatient-Focused OutcomesPatientsPharmaceutical PreparationsPhase I/II Clinical TrialPopulationPrimary NeoplasmProteinsPublic HealthRadiation therapyRefractory NeoplasmReporterReproducibilityResearchRiskSamplingTP53 geneTestingTumor ExpansionWhole-Body Irradiationcancer therapyclinically relevantdeep sequencingdriver mutationeffective therapyexperimental studyfitnessgenotoxicityhigh riskleukemia initiating cellmouse modelmutantnovelnovel strategiesnovel therapeutic interventionpre-clinicalpremalignantpreventrare cancerresponserisk minimizationsmall moleculetherapy developmenttumor
项目摘要
ABSTRACT
Due to an ever-increasing number of cancer survivors, myeloid neoplasms associated with
chemotherapy and/or ionizing radiation are a significant concern for public health. Clinical data indicate
that the outcome for patients with therapy-related myeloid neoplasms (t-MNs) is poor, with a 5-year
survival of 10%. The unfavorable response of t-MNs to standard cancer therapies is largely due to
mutations in the tumor suppressor p53. It has been demonstrated that p53 mutant t-MNs are developed
through the expansion of rare tumor-initiating cells harboring pre-existing p53 mutations. Therefore, the
overall goal of this project is to prevent the development of p53 mutant t-MNs by inhibiting the
expansion of tumor-initiating cells and/or by selectively killing tumor-initiating cells at the premalignant
stage. To selectively target p53 mutant cells, we will use APR-246, a small molecule drug in clinical
trials that reactivates mutant p53 protein by restoring wild-type p53 conformation and function. We
hypothesize that treatment with APR-246 will prevent the genotoxic stress-induced expansion of p53
mutant HSPCs and selectively kill p53 mutant HSPCs that have expanded after genotoxic therapies.
We will test this hypothesis using a novel mouse model that we have developed in which rare HSPCs
expressing a p53R172H mutation undergo cell expansion after exposure to total-body irradiation in two
specific aims: Aim 1 – Evaluate the impact of APR-246 treatment during total-body irradiation on the
expansion of p53 mutant HSPCs and Aim 2 – Examine the effect of APR-246 plus azacitidine on killing
p53 mutant HSPCs that have expanded after total-body irradiation. We anticipate that the outcomes
from this proof-of-concept R03 grant will generate reproducible data that support further investigation of
utilizing APR-246 or other mutant p53 activators to minimize the risk of t-MNs in cancer patients who
show clonal hematopoiesis of mutations in the tumor suppressor p53.
摘要
由于癌症幸存者的数量不断增加,与癌症相关的骨髓肿瘤
化疗和/或电离辐射是公众健康的重要关注点。临床数据表明
治疗相关性髓系肿瘤(t-MN)患者的结局较差,5年
生存率10%。t-MN对标准癌症治疗的不利反应主要是由于
肿瘤抑制基因p53的突变已经证明,p53突变型t-MN是由
通过扩增携带预先存在的p53突变的罕见肿瘤起始细胞。因此
该项目的总体目标是通过抑制p53突变t-MN的发生来防止p53突变t-MN的发生。
肿瘤起始细胞的扩增和/或通过选择性杀死癌前病变的肿瘤起始细胞
阶段为了选择性地靶向p53突变细胞,我们将使用小分子药物APR-246,
通过恢复野生型p53构象和功能来重新激活突变型p53蛋白的试验。我们
假设用APR-246治疗将防止遗传毒性应激诱导p53扩增
突变型HSPC和选择性杀死在遗传毒性治疗后扩增的p53突变型HSPC。
我们将使用我们开发的一种新的小鼠模型来测试这一假设,在这种模型中,罕见的HSPC
表达p53 R172 H突变的小鼠在暴露于全身照射后经历细胞扩增,
具体目的:目的1 -评价全身照射期间APR-246治疗对
p53突变体HSPC的扩增和目的2 -检查APR-246加阿扎胞苷对杀伤的作用
p53突变型HSPC在全身照射后扩增。我们预计,
从这个概念验证R 03赠款将产生可重复的数据,支持进一步调查,
利用APR-246或其它突变型p53激活剂使患有t-MN的癌症患者的风险最小化,
显示肿瘤抑制基因p53突变的克隆造血。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)
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Chang-Lung Lee其他文献
Chang-Lung Lee的其他文献
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{{ truncateString('Chang-Lung Lee', 18)}}的其他基金
Radioprotective effect of p53 against oral mucositis
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- 批准号:
10775974 - 财政年份:2023
- 资助金额:
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Inhibition of CaMKK2 sensitizes rectal cancers to radiation therapy
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10312803 - 财政年份:2021
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Inhibition of CaMKK2 sensitizes rectal cancers to radiation therapy
CaMKK2 的抑制使直肠癌对放射治疗敏感
- 批准号:
10112586 - 财政年份:2021
- 资助金额:
$ 8.05万 - 项目类别:
Minimizing the risk of therapy-related myeloid neoplasms by inhibiting genotoxic stress-induced expansion of leukemia-initiating cells with p53 mutations
通过抑制基因毒性应激诱导的 p53 突变白血病起始细胞的扩增,最大限度地降低治疗相关的骨髓肿瘤的风险
- 批准号:
10310505 - 财政年份:2020
- 资助金额:
$ 8.05万 - 项目类别:
Dissecting mechanism(s) by which ionizing radiation promotes clonal expansion of premalignant cells in the thymus
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- 批准号:
9353350 - 财政年份:2016
- 资助金额:
$ 8.05万 - 项目类别:
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