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

项目总结 味蕾由一组不同种类的味觉感受器细胞(TrCs)组成，这些细胞不断地 续订了。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 许多抗癌药物曾被用来治疗多种恶性肿瘤。至关重要的是，患者报告味觉丧失是一种 极具破坏性的癌症治疗，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效果微乎其微，主要包括饮食 修改和注意口腔卫生。在此，我们提交一份针对PA-16-258的订正提案 癌症的机制和治疗相关的症状和毒性，其明确的理论基础是 了解抗癌药物如何影响味道动态平衡将产生未来改善味道的方法 癌症患者的功能障碍。虽然许多抗癌药物会导致排便障碍，但我们关注的是一种特定的 患者群体，那些患有恶性肾细胞癌(MRCC)的人，接受一种或多种 6种特异性酪氨酸激酶抑制剂(TKI)用于抑制与肿瘤有关的受体酪氨酸激酶(RTK) 生长，即VEGFR1-3和PDGFRb。重要的是，这些药物，舒尼替尼，帕佐帕尼，阿西替尼，卡波赞替尼， Lenvatinib和索拉非尼对患者造成严重和令人不安的味觉扭曲。然而，这些是如何 药物扰乱的味道是完全未知的。耐人寻味的是，询问我们自己和发表的RNA 序列分析表明，VEGFR1-3和PDGFRb在味觉上皮细胞中均不表达。然而， 这些TKI还抑制许多其他非预期RTK，包括PDGFRA、c-Kit和Ret，这些RTK是 在味觉上皮细胞中表达，其在肾小管细胞癌中的功能不是很重要，而在味蕾中的作用 对动态平衡的研究很少。因此，用于治疗肾细胞癌的TKI完全有可能作用于预期的 VEGFR1-3和PDGFRb延缓肿瘤进展，而在味觉上皮中，意外的RTK被抑制 导致味觉障碍，从而为我们提供了一个潜在的未来途径来缓解味觉功能障碍，而不是 干扰癌症治疗。评估这些靶向TKI如何影响味觉细胞更新，而不是 使用耗时和昂贵的小鼠模型，我们建议使用尖端的舌质器官 快速廉价地筛选这些药物对味觉细胞不同方面的影响的技术 更新。我们明确的假设是：用于治疗肾癌的TKI影响味蕾细胞的不同方面 更新，并作用于不同于其抗肿瘤靶点的味觉上皮中表达的RTK。这将是 进行三个目标的测试：mRCC TKI是否影响味蕾前体细胞的活动和/或存活(目标1)；和/或 所有或不同的TRCs亚群的分化(目标2)；以及在味觉上皮中哪些RTK被抑制 TKIs用于治疗肾细胞癌患者(目标3)。

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).