Use of lingual organoids to screen for the impact of targeted cancer therapies on taste bud renewal

使用舌类器官筛选靶向癌症疗法对味蕾更新的影响

• 批准号: 9982260
• 负责人: Linda A Barlow
• 金额: $ 20.29万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982260
• 关键词: Adult; Affect; Animal Model; Antibodies; Antineoplastic Agents; Attention; BAY 54-9085; Biological; Biological Assay; Cancer Patient; Cell Death; Cell Differentiation process; Cell Survival; Cells; Clinical; Collection; Confocal Microscopy; Consumption; Data; Dental Hygiene; Diet Modification; Drug usage; Dysgeusia; Eating; Epithelial; Epithelial Cells; Epithelium; Functional disorder; Future; Goals; Growth; Harvest; Homeostasis; In Vitro; Intervention; Letters; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of kidney; Mediating; Metastatic Renal Cell Cancer; Methodology; Methods; Molecular; Monitor; Mus; Organoids; Outcome; Patients; Pharmaceutical Preparations; Phosphorylation; Prevalence; Process; Proteome; Proto-Oncogene Protein c-kit; Publishing; Quality of life; RNA; RNA Sequences; Receptor Cell; Receptor Protein-Tyrosine Kinases; Renal Cell Carcinoma; Reporter; Reporting; Role; Sodium Chloride; Sum; Surface; Symptoms; Taste Bud Cell; Taste Buds; Taste Perception; Technology; Testing; Therapeutic Uses; Time; Tongue; Toxic effect; Tyrosine Kinase Inhibitor; Vascular Endothelial Growth Factor Receptor-1; Work; automated image analysis; cancer cell; cancer therapy; cell type; cytotoxicity; detector; experience; in vivo; keratinocyte; mouse model; patient population; progenitor; regenerative; response; screening; self-renewal; sensory system; side effect; stem; stem cells; targeted cancer therapy; time use; tongue papilla; transcriptome; transcriptomics; tumor; tumor growth; tumor progression

PROJECT SUMMARY Taste buds are composed of a heterogeneous collection of taste receptor cells (TRCs) that are continually renewed. Likely because of this regenerative capacity, taste distortion or dysgeusia is a common side effect of many anti-cancer drugs used to treat a host of malignancies. Crucially, patients report loss of taste as an extremely disruptive aspect of cancer treatment, dramatically affecting their quality of life and clinical outcomes. Current interventions for taste loss are minimally effective and consist primarily of dietary modifications and attention to oral hygiene. Here, we submit a revised proposal in response to PA-16-258 Mechanisms of Cancer and Treatment-related Symptoms and Toxicities, with the explicit rationale that understanding how cancer drugs impact taste homeostasis will generate future approaches to ameliorate taste dysfunction for cancer patients. Although a host of cancer drugs cause dysgeusia, we focus on a specific patient population, those suffering from malignant renal cell carcinoma (mRCC), treated with a one or more of 6 specific tyrosine kinase inhibitors (TKIs) used to inhibit receptor tyrosine kinases (RTKs) critical to tumor growth, i.e., VEGFR1-3 and PDGFRb. Importantly, these drugs, sunitinib, pazopanib, axitinib, cabozantinib, lenvatinib, and sorafenib, cause significant and troubling taste distortion for patients. However, how these drugs perturb taste is completely unknown. Intriguingly, interrogating both our own and published RNA sequence data reveals that neither VEGFR1-3 nor PDGFRb are expressed in taste epithelium. However, these TKIs also inhibit numerous other unintended RTKs including PDGFRa, c-Kit and Ret, which are expressed in taste epithelium, whose functions in mRCC are less essential, and whose roles in taste bud homeostasis are little explored. Thus, it is entirely plausible that TKIs used to treat mRCC act on intended VEGFR1-3 and PDGFRb to slow tumor progression, while in taste epithelium unintended RTKs are inhibited causing dysgeusia, thus providing us with a potential future avenue to mitigate taste dysfunction without interfering with cancer therapy. To assess how these targeted TKIs impact taste cell renewal, rather than using time-consuming and expensive mouse models, we propose to use cutting edge lingual organoid technology to rapidly and inexpensively screen for the effect of these drugs on discrete aspects of taste cell renewal. Our explicit hypothesis is that: TKIs used to treat mRCC affect discrete aspects of taste bud cell renewal, and act on RTKs expressed in taste epithelium that are distinct from their anti-tumor targets. This will be tested in 3 aims: Do mRCC TKIs affect activity and/or survival of taste bud progenitor cells (Aim 1); and/or differentiation of all or distinct subsets of TRCs (Aim 2); and which RTKs are inhibited in taste epithelium by TKIs used to treat mRCC patients (Aim 3).

项目摘要 味蕾是由味觉感受器细胞（TRC）的异质集合组成的， 更新。可能是因为这种再生能力，味觉扭曲或味觉障碍是一种常见的副作用， 许多用于治疗恶性肿瘤的抗癌药物。至关重要的是，患者报告味觉丧失是一种 癌症治疗的破坏性方面，极大地影响了他们的生活质量和临床 结果。目前对味觉丧失的干预措施效果最低，主要包括饮食 修改和注意口腔卫生。在此，我们提交了一份修改后的提案，以回应PA-16-258 癌症的机制和治疗相关的症状和毒性，明确的理由是， 了解抗癌药物如何影响味觉稳态将产生未来改善味觉的方法 癌症患者的功能障碍。虽然许多抗癌药物会导致味觉障碍，但我们专注于一种特定的 患者群体，患有恶性肾细胞癌（mRCC）的那些，用以下一种或多种治疗： 6种特异性酪氨酸激酶抑制剂（TKI），用于抑制对肿瘤至关重要的受体酪氨酸激酶（RTK） 增长，即，VEGFR 1 -3和PDGFRb。重要的是，这些药物，舒尼替尼，帕唑帕尼，阿西替尼，卡博替尼， 乐伐替尼和索拉非尼对患者造成显著和令人不安的味觉扭曲。然而，这些 药物干扰味道是完全未知的。有趣的是，通过研究我们自己的和发表的RNA 序列数据揭示了VEGFR 1 -3和PDGFRb在味觉上皮中均不表达。然而，在这方面， 这些TKI还抑制许多其他非预期的RTK，包括PDGFRa、c-Kit和Ret， 在味觉上皮中表达，其在mRCC中的功能不太重要，并且其在味蕾中的作用 内稳态很少被探索。因此，用于治疗mRCC的TKI作用于预期的 VEGFR 1 -3和PDGFRb减缓肿瘤进展，而在味觉上皮中抑制非预期的RTK 从而为我们提供了一个潜在的未来途径，以减轻味觉功能障碍， 干扰癌症治疗为了评估这些靶向TKI如何影响味觉细胞更新， 使用耗时和昂贵的小鼠模型，我们建议使用尖端的舌类器官， 一种快速、廉价地筛选这些药物对味觉细胞各个方面影响的技术 退款我们明确的假设是：用于治疗mRCC的TKI影响味蕾细胞的离散方面， 更新，并作用于味觉上皮中表达的RTK，其不同于其抗肿瘤靶标。这将 在3个目标中进行测试：mRCC TKI是否影响味蕾祖细胞的活性和/或存活（目标1）;和/或 TRC的所有或不同子集的分化（目的2）;以及哪些RTK在味觉上皮中被抑制， TKI用于治疗mRCC患者（目的3）。