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,髓系肿瘤与
化疗和/或电离辐射是公众健康的重大问题。临床数据显示
与治疗相关的髓系肿瘤(t-MNS)患者的预后很差,有5年的
存活率为10%。T-MNS对标准癌症治疗的不良反应很大程度上是由于
肿瘤抑制基因P53的突变。已有研究表明,p5 3突变型t-mns
通过扩增携带预先存在的p53突变的罕见的肿瘤启动细胞。因此,
该项目的总体目标是通过抑制p53突变型t-MNS的发展
肿瘤起始细胞的扩增和/或在癌前阶段选择性地杀死肿瘤起始细胞
舞台。为了选择性地靶向p53突变细胞,我们将使用临床上使用的小分子药物APR-246
通过恢复野生型p53的构象和功能来重新激活突变的p53蛋白的试验。我们
假设APR-246治疗将阻止遗传毒性应激诱导的P53的扩张
突变的HSPC和选择性地杀死p53突变的HSPC,这些突变的HSPC在基因毒性治疗后已经扩张。
我们将使用我们开发的一种新的小鼠模型来验证这一假设,在该模型中,罕见的HSPC
表达p53R172H突变的两人在全身照射后经历细胞扩增
具体目标:目标1-评估APR-246治疗在全身照射中对
P53突变型HSPC的扩增及AIM 2--检测APR-246联合阿扎替丁的杀伤作用
P53突变型HSPC经全身照射后扩增。我们预计结果是
从这项概念验证R03拨款将生成可重现的数据,以支持对
利用APR-246或其他突变型p53激活剂将癌症患者t-MNS的风险降至最低
显示了肿瘤抑制基因P53的克隆性造血突变。
项目成果
期刊论文数量(0)
专著数量(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
p53对口腔粘膜炎的放射防护作用
- 批准号:
10775974 - 财政年份:2023
- 资助金额:
$ 8.05万 - 项目类别:
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:
10312803 - 财政年份:2021
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$ 8.05万 - 项目类别:
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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