Inhibiting Basal Cell Carcinoma By Promoting Cellular Differentiation

通过促进细胞分化抑制基底细胞癌

• 批准号: 9178193
• 负责人: Sunny Y Wong
• 金额: $ 16.86万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/9178193
• 关键词: Adverse effects; Affect; Antineoplastic Agents; Basal cell carcinoma; Biological Assay; Cell Culture System; Cell Culture Techniques; Cell Therapy; Cells; Complement; Coupled; DNA Sequence Alteration; Differentiation Therapy; Disease; Disease remission; Effectiveness; Erinaceidae; FDA approved; Future; Genetic; Genetic study; Goals; Hair follicle structure; Human; In Vitro; Lead; Lesion; Malignant Epithelial Cell; Malignant Neoplasms; Maps; Mediator of activation protein; Modeling; Mus; Natural regeneration; North America; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Predisposition; Recurrence; Recurrent tumor; Relapse; Residual Tumors; Role; Seeds; Site; Skin; Staging; Stem cells; System; Testing; Therapeutic; Withdrawal; Withdrawing Treatments; abstracting; cancer cell; cancer therapy; dosage; drug withdrawal; gain of function; in vivo; inhibitor/antagonist; loss of function; medulloblastoma; mouse model; neoplastic cell; notch protein; novel; novel strategies; novel therapeutic intervention; prevent; research study; response; small molecule inhibitor; smoothened signaling pathway; tool; treatment duration; tumor; tumor progression

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.

项目摘要/摘要 基底细胞癌(BCC)是北美最常见的癌症，被认为是由 Hedgehog(HH)信号通路的失调。HH的小分子抑制剂，如vismodegib， 已被证明在消退晚期基底细胞癌方面非常有效；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位置复发。这些观察结果 表明大多数BCC至少包含可在HH后进入休眠状态的持久细胞的子集 封锁。为了更好地了解肿瘤对药物治疗的反应，我们制作了一个小鼠模型 Bcc，因此ptch1的缺失针对毛囊干细胞。这些小鼠发育成结节状的BCC样 可以通过vismodegib部分消退，但在随后停药时复发的皮损，类似于 人类肿瘤。在本提案的具体目标1中，我们将改进体内和体外的肿瘤消退。 包含vismodegib治疗的分析，并表征在治疗过程中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的研究，加上血统追踪，以 确定操纵Notch通路是否会影响皮肤分化的主要中介 Vismodegib诱导的肿瘤消退。这些研究的发现将有助于我们更好地理解细胞 肿瘤对抗HH阻断反应的基础通路，并可能导致新的治疗方法 从而可以同时针对多种肿瘤易感性来防止复发。我们的缺口 实验也可以作为对肿瘤分化的潜在有效性的原则验证研究 心理治疗。