A novel application of XPO1 inhibition for the treatment of myelofibrosis

Blood Neoplasia Pub Date : 2024-04-12 DOI:10.1016/j.bneo.2024.100010

Megan Metzger , Zachary M. Avigan , Pankit Vachhani , Julian Waksal , John Mascarenhas

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Abstract

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by constitutional symptoms, progressive cytopenias, and splenomegaly. Activating mutations in the JAK/STAT pathway and cytokine dysregulation driving bone marrow fibrosis and extramedullary hematopoiesis underlie the pathobiology of MF. Although multiple JAK inhibitors are currently approved and provide significant symptom improvement, these agents do not possess disease course modifying potential. Additionally, outcomes are poor for patients who fail JAK inhibitors, highlighting the need for novel mechanism-based therapies and innovative combination strategies. Selinexor, a novel Exportin 1 (XPO1) inhibitor that blocks nuclear export, increases nuclear localization and activity of p53 and other tumor suppressor pathways and decreases cytoplasmic activation of multiple proliferative and profibrotic pathways. Selinexor currently has approved indications in multiple myeloma and lymphoma, with broad potential applications in other malignancies, although it can be limited by toxicity in some settings. Selinexor has shown clinical activity and tolerability in MF, both as monotherapy and, particularly, in combination with ruxolitinib. The collective, early phase trial data support a phase 3 randomized, registration study of selinexor and ruxolitinib in patients with MF naïve to JAK inhibitor therapy. Further work is needed to elucidate the role of XPO1 inhibition as a potential disease-modifying strategy to improve outcomes in MF.

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XPO1抑制剂在骨髓纤维化治疗中的新应用

摘要骨髓纤维化（MF）是一种骨髓增生性肿瘤，其特征是全身症状、进行性细胞减少和脾脏肿大。JAK/STAT通路的激活突变和细胞因子失调是骨髓纤维化和髓外造血的驱动因素，也是骨髓纤维化的病理生物学基础。虽然目前已有多种 JAK 抑制剂获得批准，并能显著改善症状，但这些药物并不具备改变病程的潜力。此外，JAK 抑制剂失效的患者疗效不佳，这凸显了对基于机制的新型疗法和创新组合策略的需求。Selinexor 是一种新型 Exportin 1 (XPO1) 抑制剂，可阻断核输出，增加 p53 和其他肿瘤抑制通路的核定位和活性，并降低多种增殖和组织坏死通路的细胞质激活。Selinexor 目前已被批准用于多发性骨髓瘤和淋巴瘤，并有可能广泛应用于其他恶性肿瘤，但在某些情况下会受到毒性的限制。Selinexor 已在多发性骨髓瘤中显示出临床活性和耐受性，无论是作为单一疗法，还是与 Ruxolitinib 联用，都是如此。早期试验的综合数据支持对JAK抑制剂治疗无效的MF患者进行selinexor和ruxolitinib的3期随机注册研究。还需要开展更多的工作来阐明 XPO1 抑制作为一种潜在的疾病改变策略在改善 MF 预后中的作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Blood Neoplasia

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