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 味蕾由不断的味觉受体细胞（TRC）组成 更新。可能是由于这种再生能力，口味失真或d症症是常见的副作用 许多用于治疗许多恶性肿瘤的抗癌药物。至关重要的是，患者报告口味丧失 癌症治疗的极具破坏性方面，极大地影响其生活质量和临床 结果。目前的味觉丧失干预措施至少有效，主要由饮食组成 修改和对口腔卫生的关注。在这里，我们提交了一项修订的建议，以回应PA-16-258 癌症的机制和与治疗相关的症状和毒性，并具有明确的理由 了解癌症药物如何影响味道稳态会产生未来的方法以改善味道 癌症患者功能障碍。尽管许多癌症药物会引起肿瘤症，但我们专注于特定的 患者群体是患有恶性肾细胞癌（MRCC）的患者，接受了一个或多个治疗 6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VEGFR1-3和PDGFRB。重要的是，这些药物，舒尼替尼，pazopanib，axitinib，cabozantinib， Lenvatinib和Sorafenib会对患者造成严重且令人不安的味觉失真。但是，这些是如何的 药物扰动味道是完全未知的。有趣的是，询问我们自己的和出版的RNA 序列数据表明，VEGFR1-3和PDGFRB均未在味觉上皮中表达。然而， 这些TKI还抑制了许多其他意外的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，并且在味蕾中的作用 稳态几乎没有探索。因此，TKI用来治疗MRCC ACT ACT的预期是完全合理的 VEGFR1-3和PDGFRB降低了肿瘤的进展，而在味道上皮意外RTK中则受到抑制 引起肿瘤障碍，从而为我们提供潜在的未来途径，以减轻味道功能障碍 干扰癌症治疗。评估这些目标TKI如何影响味觉细胞的更新，而不是 我们建议使用耗时且昂贵的鼠标型号 快速且廉价地筛选这些药物对味觉细胞离散方面的影响的技术 更新。我们明确的假设是：用于治疗MRCC的TKI会影响味蕾细胞的离散方面 更新，并对在味觉上皮表达的RTK上作用于其抗肿瘤靶标不同。这会 在3个目标中进行测试：MRCC TKI会影响味蕾祖细胞细胞的活性和/或存活（AIM 1）；和/或 分化TRC的所有或不同子集（AIM 2）；以及哪些RTK在味觉上皮中被抑制 TKI用于治疗MRCC患者（AIM 3）。