Pre-clinical testing of low intensity ultrasound as novel strategy to prevent paclitaxel-induced hair follicle damage in a humanized mouse model of chemotherapy-induced alopecia

低强度超声的临床前测试作为预防化疗引起的脱发人源化小鼠模型中紫杉醇引起的毛囊损伤的新策略

• 批准号: 10722518
• 负责人: Ralf Paus
• 金额: $ 39.47万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-23 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10722518
• 关键词: Acute; Address; Adverse effects; Alopecia; Animal Model; Anxiety; Apoptosis; Biology; Biopsy; Brain; Cancer Patient; Cancer Survivor; Cell Death; Cells; Chronic; Clinic; Clinical; Clinical Medicine; Clinical Trials; Cultured Cells; DNA Damage; Data; Diagnostic; Distress; Dose; Dose Limiting; Drug usage; Ensure; Epithelium; Event; Exposure to; Eyebrow structure; Eyelash; Face; Growth; Hair; Hair follicle structure; Human; Immunocompromised Host; Injections; Intervention; Keratin; Lead; Life; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Medical; Medical Technology; Meningeal; Mental Depression; Microtubule Bundle; Microtubule Stabilization; Microtubules; Mitosis; Mitotic; Modeling; Morbidity - disease rate; Mus; Natural Killer Cells; Natural regeneration; Nerve; Oncology; Organ Culture Techniques; Outcome; Paclitaxel; Patients; Pattern; Pharmaceutical Preparations; Preclinical Testing; Prevention; Prevention strategy; Preventive; Preventive therapy; Process; Proliferating; Quality of life; Risk; Risk Reduction; Safety; Scalp structure; Skin; Study models; Technology; Testing; Therapeutic; Time; Toxic effect; Translating; Transplantation; Ultrasonic Therapy; Vascularization; Xenograft procedure; cancer therapy; cell injury; chemotherapy; clinical practice; cytotoxic; design; docetaxel; dosage; epithelial stem cell; humanized mouse; improved; in vivo; innovation; keratinocyte; medication compliance; mouse model; novel; novel strategies; novel therapeutic intervention; pre-clinical; preclinical study; prevent; psychologic; reinnervation; repaired; response; simulation; skin xenograft; stem cells; taxane; ultrasound

PROJECT SUMMARY Taxanes like paclitaxel (PTX) are highly effective anti-microtubule agents frequently used in cancer therapy, but they also cause major dose-limiting skin toxicity. The most dreaded of these is hair loss, which can even be permanent. PTX-induced alopecia (PIA) severely impacts patients’ quality of life, and may lead to refusal of life-saving chemotherapy. While scalp hair loss may be reduced by scalp cooling, this technology is not yet widely available, cannot be applied to eyebrows, eyelashes and facial hair, and is of unpredictable benefit. Therefore, prevention of this acute and chronic cancer-related morbidity will not only reduce distress, anxiety, and depression associated with PIA, but likely also improve medication adherence. To this end, our project aims to generate proof-of-principle for the innovative strategy to protect hair follicles (HFs) from alopecia by applying low intensity ultrasound (LIUS), a much-used and widely available medical technology with an excellent safety profile. We have demonstrated that PTX stabilizes microtubules in highly proliferative hair matrix keratinocytes, thus inducing their apoptosis and causing hair loss. In addition, PTX also induces major HF stem cell damage, which can obliterate the HF’s capacity to regenerate. We have also discovered that a brief exposure to LIUS can effectively neutralize the cytotoxic effects of PTX on cultured cells by disrupting PTX-induced rigid microtubule bundles and thus prevent cell death. Most importantly, we have generated preliminary evidence that LIUS also protects organ-cultured human scalp HFs and their epithelial stem cells ex vivo as well as mouse HFs in vivo from PTX toxicity. Finally, we have established a humanized mouse model for studying PIA by treating human scalp skin xenografts on SCID/beige mice with PTX. This enables us, for the first time, to study candidate PTX-protective interventions under in vivo conditions that optimally mimic the clinical reality of human PIA. As a critical step towards introducing this PIA prevention strategy into the clinic, we propose to test preclinically whether LIUS is also PIA-protective in vivo, using our humanized PIA mouse model. Specifically, we will determine how LIUS impacts on the microtubule network, function, and survival of human hair matrix keratinocytes and HF stem cells under acute and repetitive PTX therapy. These studies will reveal whether LIUS provides protection against acute and chronic damage by PTX to human HFs in vivo. The expected results will guide the subsequent design of a clinical trial that probes the efficacy of LIUS in clinical PIA prevention during ovarian cancer management. If successful, this innovative, drug-free, easily translatable and widely available, economical, and very well-tolerated PIA prevention strategy will greatly improve the quality of life of numerous taxane-treated cancer patients by liberating them from a major skin toxicity of oncological therapy and will thus improve medication adherence.

项目总结 紫杉烷类药物如紫杉醇(Ptx)是一种高效的抗微管药物，常用于癌症。 治疗，但它们也会造成重大的剂量限制皮肤毒性。其中最可怕的是脱发，这可能 甚至是永久的。PTX诱导的脱发(PIA)严重影响患者的生活质量，并可能导致 拒绝接受挽救生命的化疗。虽然通过头皮降温可以减少头皮脱发，但这项技术 尚未广泛使用，不能用于眉毛、睫毛和面部毛发，并且是不可预测的 利益。因此，预防这种与癌症相关的急慢性发病率不仅会减少痛苦， 与PIA相关的焦虑和抑郁，但也可能改善服药依从性。 为此，我们的项目旨在为保护头发的创新战略生成原则证明 应用低强度超声波(LIUS)从脱发中分离毛囊(HFs)，这是一种广泛使用和广泛使用的方法 具有极佳安全性的医疗技术。我们已经证明了PTX可以稳定微管。 高度增殖的头发基质角质形成细胞，从而诱导其凋亡，导致脱发。此外, PTX还会导致主要的心力衰竭干细胞损伤，这可能会破坏心力衰竭的再生能力。我们有 还发现，短暂暴露于Lius可以有效地中和PTX对培养的细胞的毒性作用 通过破坏PTX诱导的刚性微管束，从而防止细胞死亡。最重要的是，我们 已经产生了初步证据表明Lius也保护器官培养的人类头皮HFs和他们的 上皮干细胞体外以及小鼠体内HFs免受PTX毒性。最后，我们建立了一个 人源化小鼠治疗SCID/Beige小鼠头皮移植研究PIA的研究 PTX。这使得我们第一次能够在体内研究候选的PTX保护性干预措施 最佳模拟人类PIA临床现实的条件。 作为将这种PIA预防策略引入临床的关键一步，我们建议测试 使用我们人源化的PIA小鼠模型，研究临床前LIUS在体内是否也具有PIA保护作用。具体来说， 我们将确定LIUS如何影响人类头发基质的微管网络、功能和存活。 角质形成细胞和HF干细胞在急性和重复的PTX治疗下。这些研究将揭示 LIUS对体内PTX对人HFs的急性和慢性损伤具有保护作用。预期中的 这些结果将指导后续临床试验的设计，以探索LUS在临床PIA中的疗效 卵巢癌治疗中的预防。如果成功，这种创新、不含药物、易于翻译和 广泛可用的、经济的和非常耐受的PIA预防策略将极大地提高 通过将大量接受紫杉烷治疗的癌症患者从肿瘤学的主要皮肤毒性中解放出来，延长他们的生命 治疗，从而将提高服药依从性。