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单细胞测序揭示多发性骨髓瘤复发患者的耐药途径及治疗靶点
作者:小柯机器人 发布时间:2021/2/23 13:09:01

通过单细胞测序鉴定多发性骨髓瘤(MM)复发患者的耐药途径和治疗靶点,这一成果由以色列魏兹曼研究所 Ido Amit小组经过不懈努力而取得。该研究成果于2021年2月22日发表在国际学术期刊《自然-医学》上。

在本研究中,研究人员进行了一项前瞻性、多中心、单向临床试验(NCT04065789),并结合纵向单细胞RNA测序(scRNA-seq)研究了MM耐药机制的分子动力学。对接受含硼替佐米诱导方案治疗后无反应或经历早期复发新确诊MM患者(41)的研究来评估daratumumab、carfilzomib、来那度胺和地塞米松联合治疗的安全性和有效性。主要临床终点是安全性和耐受性。次要终点包括总体缓解率、无进展生存期和总体生存期。治疗安全且耐受良好,获得了有效而持久的疗效。

在预先进行的探索性分析中,对41例原发性难治性和早期复发患者与11例健康受试者和15例新诊断MM患者的比较研究发现了新MM患者的耐药分子途径,包括低氧耐受性、蛋白折叠和线粒体呼吸作用,其适用于更广泛的临床人群(CoMMpass)。研究发现蛋白质折叠反应途径的核心酶肽基脯氨酰异构酶A(PPIA)是耐药性MM的潜在治疗新靶标。利用CRISPR–Cas9敲除PPIA或使用小分子抑制剂(环孢菌素)抑制PPIA可使MM肿瘤细胞对蛋白酶体抑制剂敏感。总之,该研究确定了在临床试验中整合scRNA-seq的路线图,确定了高耐药MM患者的特征,并发现PPIA是这类肿瘤的有效治疗靶点。

据了解,MM是一种肿瘤性浆细胞疾病,其特征是恶性浆细胞克隆增殖。尽管已经对该疾病进行了广泛的研究,但对耐药患者间的疾病异质性表征却很少。

附:英文原文

Title: Identification of resistance pathways and therapeutic targets in relapsed multiple myeloma patients through single-cell sequencing

Author: Yael C. Cohen, Mor Zada, Shuang-Yin Wang, Chamutal Bornstein, Eyal David, Adi Moshe, Baoguo Li, Shir Shlomi-Loubaton, Moshe E. Gatt, Chamutal Gur, Noa Lavi, Chezi Ganzel, Efrat Luttwak, Evgeni Chubar, Ory Rouvio, Iuliana Vaxman, Oren Pasvolsky, Mouna Ballan, Tamar Tadmor, Anatoly Nemets, Osnat Jarchowcky-Dolberg, Olga Shvetz, Meirav Laiba, Ofer Shpilberg, Najib Dally, Irit Avivi, Assaf Weiner, Ido Amit

Issue&Volume: 2021-02-22

Abstract: Multiple myeloma (MM) is a neoplastic plasma-cell disorder characterized by clonal proliferation of malignant plasma cells. Despite extensive research, disease heterogeneity within and between treatment-resistant patients is poorly characterized. In the present study, we conduct a prospective, multicenter, single-arm clinical trial (NCT04065789), combined with longitudinal single-cell RNA-sequencing (scRNA-seq) to study the molecular dynamics of MM resistance mechanisms. Newly diagnosed MM patients (41), who either failed to respond or experienced early relapse after a bortezomib-containing induction regimen, were enrolled to evaluate the safety and efficacy of a daratumumab, carfilzomib, lenalidomide and dexamethasone combination. The primary clinical endpoint was safety and tolerability. Secondary endpoints included overall response rate, progression-free survival and overall survival. Treatment was safe and well tolerated; deep and durable responses were achieved. In prespecified exploratory analyses, comparison of 41 primary refractory and early relapsed patients, with 11 healthy subjects and 15 newly diagnosed MM patients, revealed new MM molecular pathways of resistance, including hypoxia tolerance, protein folding and mitochondria respiration, which generalized to larger clinical cohorts (CoMMpass). We found peptidylprolyl isomerase A (PPIA), a central enzyme in the protein-folding response pathway, as a potential new target for resistant MM. CRISPR–Cas9 deletion of PPIA or inhibition of PPIA with a small molecule inhibitor (ciclosporin) significantly sensitizes MM tumor cells to proteasome inhibitors. Together, our study defines a roadmap for integrating scRNA-seq in clinical trials, identifies a signature of highly resistant MM patients and discovers PPIA as a potent therapeutic target for these tumors.

DOI: 10.1038/s41591-021-01232-w

Source: https://www.nature.com/articles/s41591-021-01232-w

期刊信息

Nature Medicine:《自然—医学》,创刊于1995年。隶属于施普林格·自然出版集团,最新IF:30.641
官方网址:https://www.nature.com/nm/
投稿链接:https://mts-nmed.nature.com/cgi-bin/main.plex