Dermatology, Children's Health Ireland at Crumlin, Dublin 12, Ireland.
Department of Biomedical Sciences and Human Oncology (DIMO), Division of Medical Genetics, University of Bari "Aldo Moro", 70124, Bari, Italy.
Orphanet J Rare Dis. 2021 Feb 27;16(1):109. doi: 10.1186/s13023-021-01745-0.
PIK3CA-related overgrowth spectrum (PROS) refers to a group of rare disorders, caused by somatic activating mutations in PIK3CA, resulting in abnormal PI3K-AKT-mTOR pathway signalling. Significant associated morbidity is frequently observed, and approved treatments are lacking. Miransertib (ARQ 092) is a novel, orally available, selective pan-AKT inhibitor with proven in vitro efficacy. Following recent results of the use of AKT inhibitors in Proteus syndrome (PS) and AKT-mutant cancers, we investigated its therapeutic use in two patients with severe PROS who had exhausted conventional treatment methods.
Two patients, one with CLOVES variant (P1) and one with facial infiltrating lipomatosis and hemimegalencephaly (P2), were commenced on miransertib treatment on a compassionate use basis. In patient one, intra-abdominal and paraspinal overgrowth had resulted in respiratory compromise, obstructive uropathy, dysfunctional seating and lying postures, and chronic pain. In patient two, hemifacial overgrowth and hemimegalencephaly had caused difficulties with articulation and oral function, and refractory epilepsy. Miransertib treatment was continued for a median duration of 22 months (range 22-28). In patient one, alleviation of respiratory compromise was observed and functionally, seating and lying postures improved. Serial volumetric MRI analysis revealed 15% reduction in calculated volumes of fatty overgrowth between treatment commencement and end. In patient two, reduction in seizure burden and improved parent-reported quality of life measures were reported. Treatment was discontinued in both patients due to lack of sustained response, and poor compliance in year two of treatment (P2). No significant toxicities were reported.
We report the first paediatric case series of the use of miransertib in two children with PROS. Objective clinical response was observed in patient one, and improvement in key qualitative outcomes was reported in patient two. Treatment was well tolerated with no significant toxicities reported. This case series highlights the potential therapeutic utility of miransertib in selected paediatric patients with severe PROS, and further demonstrates the potential for re-purposing targeted therapies for the treatment of rare diseases. An open label, Phase 1/2 study of miransertib in children with PROS and PS is underway to more accurately assess the efficacy of miransertib in the treatment of PROS disorder (NCT03094832).
PIK3CA 相关过度生长谱（PROS）是一组罕见疾病，由 PIK3CA 的体细胞激活突变引起，导致异常的 PI3K-AKT-mTOR 信号通路。常观察到显著相关的发病率，且缺乏批准的治疗方法。Miransertib（ARQ 092）是一种新型、口服、选择性全 AKT 抑制剂，具有体外疗效。鉴于最近 AKT 抑制剂在 Proteus 综合征（PS）和 AKT 突变型癌症中的应用结果，我们研究了其在两名已用尽常规治疗方法的严重 PROS 患者中的治疗用途。
两名患者，一名患有 CLOVES 变异型（P1），另一名患有面部浸润性脂肪瘤病和大脑半球肥大（P2），开始根据同情使用原则接受 miransertib 治疗。在患者 1 中，腹腔内和脊柱旁过度生长导致呼吸窘迫、阻塞性尿路、功能失调的坐姿和卧位，以及慢性疼痛。在患者 2 中，面部偏侧过度生长和大脑半球肥大导致发音和口腔功能困难，以及难治性癫痫。miransertib 治疗的中位持续时间为 22 个月（范围为 22-28）。在患者 1 中，观察到呼吸窘迫缓解，坐姿和卧位改善。系列容积 MRI 分析显示，治疗开始和结束时计算出的脂肪过度生长体积减少了 15%。在患者 2 中，报道了癫痫发作负担减少和父母报告的生活质量改善。由于缺乏持续反应和治疗第二年的依从性差（P2），两名患者均停止了治疗。未报告明显的毒性。
我们报告了首例儿童使用 miransertib 治疗 PROS 的病例系列。患者 1 观察到客观的临床反应，患者 2 报告了关键定性结局的改善。治疗耐受性良好，未报告明显毒性。该病例系列强调了 miransertib 在选定的严重 PROS 儿科患者中的潜在治疗效用，并进一步证明了重新利用靶向治疗治疗罕见疾病的潜力。一项开放标签、1/2 期研究正在对 PROS 和 PS 患儿进行 miransertib 治疗，以更准确地评估 miransertib 治疗 PROS 障碍的疗效（NCT03094832）。
