Targeting the epichaperome as an effective precision medicine approach in a novel PML-SYK fusion acute myeloid leukemia.
Targeting the epichaperome as an effective precision medicine approach in a novel PML-SYK fusion acute myeloid leukemia.
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DOI：
10.1038/s41698-021-00183-2
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发表时间：
2021-05-26
影响因子：
7.9
通讯作者：
Guzman ML
中科院分区：
文献类型：
--
作者：
Sugita M;Wilkes DC;Bareja R;Eng KW;Nataraj S;Jimenez-Flores RA;Yan L;De Leon JP;Croyle JA;Kaner J;Merugu S;Sharma S;MacDonald TY;Noorzad Z;Panchal P;Pancirer D;Cheng S;Xiang JZ;Olson L;Van Besien K;Rickman DS;Mathew S;Tam W;Rubin MA;Beltran H;Sboner A;Hassane DC;Chiosis G;Elemento O;Roboz GJ;Mosquera JM;Guzman ML
Epichaperome 是一种新的癌症靶点，由促进细胞存活的 Chaperome 成员的超连接网络组成。分子伴侣构型改变的癌症可能对外分子伴侣抑制剂敏感。我们开发了一种基于流式细胞术的测定法，用于在单细胞水平上评估和监测表质体丰度，目的是前瞻性地识别可能对表质体抑制剂产生反应的患者，以测量治疗期间的靶标参与度和依赖性。作为原理证明，我们描述了一名患有未分类骨髓增生性肿瘤的患者，该肿瘤具有新型 PML-SYK 融合，尽管接受化疗和同种异体干细胞移植，但仍进展为急性髓系白血病。白血病被鉴定为具有高表质体丰度。我们同情地获得了一种正在研究的表质体抑制剂 PU-H71。 16 次给药后，患者实现了持久的完全缓解。这些令人鼓舞的结果表明，有必要对基线表质体水平丰富的患者进行表质体抑制剂的进一步研究。
The epichaperome is a new cancer target composed of hyperconnected networks of chaperome members that facilitate cell survival. Cancers with an altered chaperone configuration may be susceptible to epichaperome inhibitors. We developed a flow cytometry-based assay for evaluation and monitoring of epichaperome abundance at the single cell level, with the goal of prospectively identifying patients likely to respond to epichaperome inhibitors, to measure target engagement, and dependency during treatment. As proof of principle, we describe a patient with an unclassified myeloproliferative neoplasm harboring a novel PML-SYK fusion, who progressed to acute myeloid leukemia despite chemotherapy and allogeneic stem cell transplant. The leukemia was identified as having high epichaperome abundance. We obtained compassionate access to an investigational epichaperome inhibitor, PU-H71. After 16 doses, the patient achieved durable complete remission. These encouraging results suggest that further investigation of epichaperome inhibitors in patients with abundant baseline epichaperome levels is warranted.
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影响因子：
28.2
作者：
Pauli C;Hopkins BD;Prandi D;Shaw R;Fedrizzi T;Sboner A;Sailer V;Augello M;Puca L;Rosati R;McNary TJ;Churakova Y;Cheung C;Triscott J;Pisapia D;Rao R;Mosquera JM;Robinson B;Faltas BM;Emerling BE;Gadi VK;Bernard B;Elemento O;Beltran H;Demichelis F;Kemp CJ;Grandori C;Cantley LC;Rubin MA
通讯作者：
Rubin MA
影响因子：
5.8
作者：
Shugay, Mikhail;Ortiz de Mendibil, Inigo;Novo, Francisco J.
通讯作者：
Novo, Francisco J.
影响因子：
4.4
作者：
Maus, MV;Kovacs, B;June, CH
通讯作者：
June, CH
患者衍生的类器官为罕见的前列腺癌表型建模。
影响因子：
16.6
作者：
Puca L;Bareja R;Prandi D;Shaw R;Benelli M;Karthaus WR;Hess J;Sigouros M;Donoghue A;Kossai M;Gao D;Cyrta J;Sailer V;Vosoughi A;Pauli C;Churakova Y;Cheung C;Deonarine LD;McNary TJ;Rosati R;Tagawa ST;Nanus DM;Mosquera JM;Sawyers CL;Chen Y;Inghirami G;Rao RA;Grandori C;Elemento O;Sboner A;Demichelis F;Rubin MA;Beltran H
通讯作者：
Beltran H
影响因子：
30.8
作者：
Lappalainen I;Almeida-King J;Kumanduri V;Senf A;Spalding JD;Ur-Rehman S;Saunders G;Kandasamy J;Caccamo M;Leinonen R;Vaughan B;Laurent T;Rowland F;Marin-Garcia P;Barker J;Jokinen P;Torres AC;de Argila JR;Llobet OM;Medina I;Puy MS;Alberich M;de la Torre S;Navarro A;Paschall J;Flicek P
通讯作者：
Flicek P