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，被认为是普遍驱动的 刺猬（HH）信号通路的失调。 HH的小分子抑制剂，例如Vismodegib， 事实证明，在回归先进的BCC方面非常有效；但是，这些药物无法治愈 疾病，因为停止药物治疗后，肿瘤通常会在其原始部位复发。这些观察 表明大多数BCC至少包含一个可以在HH上进入休眠状态的持续细胞的子集 封锁。为了更好地了解肿瘤对药物治疗的反应，我们产生了一个小鼠模型 BCC的删除PTCH1针对毛囊干细胞。这些小鼠会形成结节性BCC状 可以通过vismodegib部分回归的病变，但在随后的药物戒断后重复出现，类似于 人类肿瘤。在本提案的特定目的1中，我们将在体内和体外肿瘤回归中完善 纳入vismodegib治疗的测定，并表征在治疗过程中持续存在的残留肿瘤细胞。 在特定的目标2中，我们将进行遗传增益和功能丧失研究，并与谱系追踪相结合，与 确定操纵Notch途径是皮肤分化的主要中介者是否会影响 Vismodegib诱导的肿瘤回归。这些研究的发现将有助于我们更好地了解细胞 肿瘤对抗HH封锁的反应的途径可能导致新型治疗方法 可以同时靶向多个肿瘤敏感性以防止复发。我们的缺口 实验也可以作为有关肿瘤分化潜在有效性的原则研究证明 治疗。