Graduate School of Health, Discipline of Pharmacy, University of Technology Sydney, Ultimo, NSW, 2007, Australia.
Institute of Haematology, Royal Prince Alfred Hospital, Camperdown, NSW, 2050, Australia.
Blood Cancer J. 2020 Mar 13;10(3):37. doi: 10.1038/s41408-020-0304-7.
Multiple myeloma is an incurable cancer of bone marrow plasma cells, with a 5-year survival rate of 43%. Its incidence has increased by 126% since 1990. Treatment typically involves high-dose combination chemotherapy, but therapeutic response and patient survival are unpredictable and highly variable-attributed largely to the development of multidrug resistance (MDR). MDR is the simultaneous cross-resistance to a range of unrelated chemotherapeutic agents and is associated with poor prognosis and survival. Currently, no clinical procedures allow for a direct, continuous monitoring of MDR. We identified circulating large extracellular vesicles (specifically microparticles (MPs)) that can be used to monitor disease burden, disease progression and development of MDR in myeloma. These MPs differ phenotypically in the expression of four protein biomarkers: a plasma-cell marker (CD138), the MDR protein, P-glycoprotein (P-gp), the stem-cell marker (CD34); and phosphatidylserine (PS), an MP marker and mediator of cancer spread. Elevated levels of P-gp and PS MPs correlate with disease progression and treatment unresponsiveness. Furthermore, P-gp, PS and CD34 are predominantly expressed in CD138 MPs in advanced disease. In particular, a dual-positive (CD138P-gpCD34) population is elevated in aggressive/unresponsive disease. Our test provides a personalised liquid biopsy with potential to address the unmet clinical need of monitoring MDR and treatment failure in myeloma.
多发性骨髓瘤是一种不可治愈的骨髓浆细胞瘤癌症，其 5 年生存率为 43%。自 1990 年以来，其发病率增加了 126%。其治疗通常涉及大剂量联合化疗，但治疗反应和患者生存情况不可预测且高度多变，这主要归因于多药耐药性（MDR）的发展。MDR 是对一系列不相关的化疗药物的同时交叉耐药性，与预后不良和生存相关。目前，没有临床程序可以直接、连续地监测 MDR。我们鉴定出循环的大型细胞外囊泡（特别是微颗粒（MPs）），可用于监测骨髓瘤的疾病负担、疾病进展和 MDR 的发展。这些 MPs 在四种蛋白生物标志物的表达上表现出不同的表型：浆细胞标志物（CD138）、MDR 蛋白、P 糖蛋白（P-gp）、干细胞标志物（CD34）；和磷脂酰丝氨酸（PS），一种 MP 标志物和癌症扩散的介质。P-gp 和 PS MPs 的水平升高与疾病进展和治疗无反应相关。此外，P-gp、PS 和 CD34 主要在晚期疾病的 CD138 MPs 中表达。特别是，在侵袭性/无反应性疾病中，双阳性（CD138P-gpCD34）群体升高。我们的测试提供了一种个性化的液体活检，有可能满足监测骨髓瘤 MDR 和治疗失败的未满足的临床需求。
