Inhibiting Basal Cell Carcinoma By Promoting Cellular Differentiation
通过促进细胞分化抑制基底细胞癌
基本信息
- 批准号:9178193
- 负责人:
- 金额:$ 16.86万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-07-01 至 2018-06-30
- 项目状态:已结题
- 来源:
- 关键词:Adverse effectsAffectAntineoplastic AgentsBasal cell carcinomaBiological AssayCell Culture SystemCell Culture TechniquesCell TherapyCellsComplementCoupledDNA Sequence AlterationDifferentiation TherapyDiseaseDisease remissionEffectivenessErinaceidaeFDA approvedFutureGeneticGenetic studyGoalsHair follicle structureHumanIn VitroLeadLesionMalignant Epithelial CellMalignant NeoplasmsMapsMediator of activation proteinModelingMusNatural regenerationNorth AmericaOutcomePathway interactionsPatientsPharmaceutical PreparationsPharmacotherapyPredispositionRecurrenceRecurrent tumorRelapseResidual TumorsRoleSeedsSiteSkinStagingStem cellsSystemTestingTherapeuticWithdrawalWithdrawing Treatmentsabstractingcancer cellcancer therapydosagedrug withdrawalgain of functionin vivoinhibitor/antagonistloss of functionmedulloblastomamouse modelneoplastic cellnotch proteinnovelnovel strategiesnovel therapeutic interventionpreventresearch studyresponsesmall molecule inhibitorsmoothened signaling pathwaytooltreatment durationtumortumor progression
项目摘要
Project Summary / Abstract
Basal cell carcinoma (BCC), the most common cancer in North America, is thought to be universally driven by
dysregulation of the Hedgehog (Hh) signaling pathway. Small molecule inhibitors of Hh, such as vismodegib,
have proven to be highly effective at regressing advanced BCCs; however, these drugs do not cure patients of
disease, as tumors typically recur at their original sites upon cessation of drug treatment. These observations
suggest that most BCCs contain at least a subset of persistent cells that can enter a dormant state upon Hh
blockade. To better understand how tumors respond to drug therapy, we have generated a mouse model of
BCC whereby deletion of Ptch1 is targeted to hair follicle stem cells. These mice develop nodular BCC-like
lesions that can be partially regressed by vismodegib, but recur upon subsequent drug withdrawal, similar to
human tumors. In Specific Aim 1 of this proposal, we will refine both in vivo and in vitro tumor regression
assays incorporating vismodegib treatment, and characterize residual tumor cells that persist during therapy.
In Specific Aim 2, we will perform genetic gain- and loss-of-function studies, coupled with lineage tracing, to
ascertain whether manipulating the Notch pathway, a major mediator of differentiation in the skin, can affect
vismodegib-induced tumor regression. Findings from these studies will help us better understand the cellular
pathways that underlie tumor response to anti-Hh blockade, and may lead to novel therapeutic approaches
whereby multiple tumor susceptibilities can be simultaneously targeted to prevent recurrence. Our Notch
experiments may also serve as a proof-of-principle study on the potential effectiveness of tumor differentiation
therapy.
项目概要/摘要
基底细胞癌 (BCC) 是北美最常见的癌症,普遍认为是由
Hedgehog (Hh) 信号通路失调。 Hh 的小分子抑制剂,例如 vismodegib,
已被证明在回归高级 BCC 方面非常有效;然而,这些药物并不能治愈患者
疾病,因为肿瘤通常在停止药物治疗后在其原始部位复发。这些观察
表明大多数 BCC 至少包含一个持久性细胞的子集,这些细胞可以在 Hh 时进入休眠状态
封锁。为了更好地了解肿瘤对药物治疗的反应,我们建立了一个小鼠模型
BCC,其中 Ptch1 的缺失靶向毛囊干细胞。这些小鼠出现结节性 BCC 样
vismodegib 可以部分消退病变,但随后停药后又复发,类似于
人类肿瘤。在该提案的具体目标 1 中,我们将完善体内和体外肿瘤消退
结合 vismodegib 治疗的测定,并表征治疗期间持续存在的残留肿瘤细胞。
在具体目标 2 中,我们将进行遗传功能获得和丧失研究,并结合谱系追踪,以
确定操纵Notch通路(皮肤分化的主要介质)是否会影响
vismodegib 诱导的肿瘤消退。这些研究的结果将帮助我们更好地了解细胞
肿瘤对抗 Hh 阻断反应的途径,并可能导致新的治疗方法
由此可以同时针对多种肿瘤易感性来预防复发。我们的缺口
实验还可以作为肿瘤分化潜在有效性的原理验证研究
治疗。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Sunny Y Wong其他文献
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{{ truncateString('Sunny Y Wong', 18)}}的其他基金
Exploring hair follicle-associated functions in normal and ichthyotic skin
探索正常和鱼鳞病皮肤的毛囊相关功能
- 批准号:
10415368 - 财政年份:2022
- 资助金额:
$ 16.86万 - 项目类别:
Developing Improved Models of Basal Cell Carcinoma to Evaluate Tumor-Drug Response
开发改进的基底细胞癌模型以评估肿瘤药物反应
- 批准号:
10518702 - 财政年份:2022
- 资助金额:
$ 16.86万 - 项目类别:
Exploring hair follicle-associated functions in normal and ichthyotic skin
探索正常和鱼鳞病皮肤的毛囊相关功能
- 批准号:
10630934 - 财政年份:2022
- 资助金额:
$ 16.86万 - 项目类别:
Regulation of sebaceous gland stem cells and their differentiated progeny in the skin
皮肤皮脂腺干细胞及其分化后代的调节
- 批准号:
10226584 - 财政年份:2020
- 资助金额:
$ 16.86万 - 项目类别:
Functional characterization of sebaceous gland stem cells and sebocytes in the skin
皮肤皮脂腺干细胞和皮脂腺细胞的功能表征
- 批准号:
10373597 - 财政年份:2014
- 资助金额:
$ 16.86万 - 项目类别:
The Hair Follicle Infundibulum: A Potential Mediator of Skin Barrier Function
毛囊漏斗部:皮肤屏障功能的潜在调节者
- 批准号:
9244732 - 财政年份:2014
- 资助金额:
$ 16.86万 - 项目类别:
Functional characterization of sebaceous gland stem cells and sebocytes in the skin
皮肤皮脂腺干细胞和皮脂腺细胞的功能表征
- 批准号:
10558590 - 财政年份:2014
- 资助金额:
$ 16.86万 - 项目类别:
The Hair Follicle Infundibulum: A Potential Mediator of Skin Barrier Function
毛囊漏斗部:皮肤屏障功能的潜在调节者
- 批准号:
8716299 - 财政年份:2014
- 资助金额:
$ 16.86万 - 项目类别:
The Hair Follicle Infundibulum: A Potential Mediator of Skin Barrier Function
毛囊漏斗部:皮肤屏障功能的潜在调节者
- 批准号:
8827249 - 财政年份:2014
- 资助金额:
$ 16.86万 - 项目类别:
Characterizing the Cells of Origin for Basal Cell Carcinoma
基底细胞癌起源细胞的特征
- 批准号:
8698712 - 财政年份:2012
- 资助金额:
$ 16.86万 - 项目类别:
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