Hedgehog pathway inhibition as a therapeutic target in acute myeloid leukemia

Introduction: The Hedgehog (HH) pathway constitutes a collection of signaling molecules which critically influence embryogenesis. In adults, however, the HH pathway remains integral to the proliferation, maintenance, and apoptosis of adult stem cells including hematopoietic stem cells.

Areas covered: We discuss the current understanding of the HH pathway as it relates to normal hematopoiesis, the pathology of acute myeloid leukemia (AML), the rationale for and data from combination therapies including HH pathway inhibitors, and ultimately the prospects that might offer promise in targeting this pathway in AML.

Expert opinion: Efforts to target the HH pathway have been focused on impeding this disposition and restoring chemosensitivity to conventional myeloid neoplasm therapies. The year 2018 saw the first approval of a HH pathway inhibitor (glasdegib) for AML, though for an older population and in combination with an uncommonly-used therapy. Several other clinical trials with agents targeting modulators of HH signaling in AML and MDS are underway. Further study and understanding of the interplay between the numerous aspects of HH signaling and how it relates to the augmented survival of AML will provide a more reliable substrate for therapeutic strategies in patients with this poor-risk disease.     

胃癌组织中Sonic Hedgehog和VEGF表达及临床意义的研究

目的:探讨胃腺癌中Sonic Hedge-hog(Shh)和VEGF的表达及临床意义。方法:应用免疫组化法检测45例胃癌组织及15例癌旁胃黏膜组织中Shh和VEGF的表达。结果:Shh在胃癌组织中阳性表达率为66.7%,在中、低分化胃癌中的表达高于高分化胃癌中的表达,与组织分化程度相关,P<0.01,在癌旁胃黏膜组织中Shh表达为阴性或弱阳性(15.3%);VEGF在胃癌组织中的阳性表达率(71.1%)显著高于癌旁胃黏膜组织中的阳性表达率(26.7%),P<0.01,与肿瘤分化程度、淋巴结转移呈正相关,P<0.05。Shh和VEGF在胃癌组织中的表达存在相关性(0.01相似文献   

肿瘤干细胞的调控机制研究进展

肿瘤干细胞是一群未分化、具有自我更新、多系分化潜能的细胞.现有的研究表明肿瘤干细胞的自我更新、分化、转移、致瘤性受到Wnt、Notch、Hedgehog、CXCR4-SDF-1轴、PTEN等多种信号传导通路的调控.而肿瘤干细胞与间充质干细胞分别构成肿瘤的上皮部分与间质部分,它们之间可能也存在着相互调控.深入研究肿瘤干细胞的调控机制,对于开发以肿瘤干细胞为靶点的新型靶向治疗药物,最终根除肿瘤具有重要意义.     

GLI1-induced mammary gland tumours are transplantable and maintain major molecular features

Increased expression of GLI1, the main Hedgehog signalling pathway effector, is related to unfavourable prognosis and progressive disease of certain breast cancer subtypes. We used conditional transgenic mice induced to overexpress GLI1 in the mammary epithelium either alone or in combination with deletion of one Trp53 allele to address the role of elevated GLI1 expression in breast tumour initiation and progression. Induced GLI1 expression facilitates mammary gland tumour formation and this was further increased upon heterozygous deletion of Trp53. The GLI1-induced primary tumours were of different murine molecular subtypes, including Normal-like^Ex, Class8^Ex, Claudin-Low^Ex and Erbb2-like^Ex. The gene expression profiles of some of the tumours correlated well with the PAM50 subtypes for human breast cancer. Whole-exome sequencing revealed somatic mutation profiles with only little overlap between the primary tumours. Orthotopically serially transplanted GLI1-induced tumours maintained the main morphological characteristics of the primary tumours for ≥10 generations. Independent of Trp53 status and molecular subtype, the serially transplanted GLI1-induced tumours were able to grow both in the absence of transgenic GLI1 expression and in the presence of the GLI1 inhibitor GANT61. These data suggest that elevated GLI1 expression has a determinant role in tumour initiation; however, additional genetic events are required for tumour progression.     

Forsaken Pharmaceutical: Glasdegib in Acute Myeloid Leukemia and Myeloid Diseases

Advancements in the understanding of the pathogenesis of acute myeloid leukemia (AML) have led to the introduction and approval of a number of novel drugs in AML. Glasdegib, an oral hedgehog pathway inhibitor, was approved in 2018 in combination with low-dose cytarabine for the treatment of newly diagnosed AML in patients unfit for intensive chemotherapy. In this review, we discuss the preclinical rationale for glasdegib, important clinical trials that led to glasdegib’s approval, and future trials of glasdegib in AML and other myeloid diseases. Notably, 2 large randomized, placebo-controlled phase 3 trials (AML BRIGHT 1019) are currently recruiting patients with newly diagnosed AML to evaluate glasdegib in combination with intensive chemotherapy or azacitidine, depending on the patient’s ability to tolerate induction chemotherapy. While glasdegib and low-dose cytarabine have been eclipsed by venetoclax and hypomethylating agent combinations for newly diagnosed AML in the United States, we discuss other areas where glasdegib may still have an opportunity to improve outcomes in this devastating disease.     

Hedgehog信号通路与肿瘤的关系研究进展

Hedgehog（Hh）信号通路在胚胎时期的细胞分化、组织发育及器官形成中扮演重要角色。近年来,Hh信号通路与肿瘤的关系日益受到人们的重视。多项研究结果显示Hh信号通路在多种肿瘤组织与细胞系中异常激活,并与肿瘤的增殖分化、细胞凋亡、血管新生、侵袭转移等密切相关。阻断肿瘤细胞中Hh信号传导通路将为人类肿瘤的治疗提供一个新的有效手段。     

顺铂联合米托蒽醌调节脑胶质瘤U87细胞Sonic Hedgehog信号通路的研究

目的：观察米托蒽醌（Mitoxantrone,MXT）联合顺铂（Cisplatin,CDDP）对脑胶质瘤U87细胞杀伤活性及对Sonic Hedgehog信号通路的影响。方法：应用MTT法检测不同浓度米托蒽醌、顺铂以及两药物联合对U87细胞成活率的影响。显微镜观察细胞的形态变化DiOC6荧光染料对细胞线粒体染色检测其膜电位变化来反映细胞凋亡。RT-PCR法检测顺铂、米托蒽醌及两药联合对U87细胞Gli1和Ptch基因表达的影响。结果：MTT结果显示顺铂、米托蒽醌均可以有效抑制U87细胞的增殖,当米托蒽醌和顺铂浓度≤0.625μg/ml时,两药联合对U87细胞增殖具有协同抑制作用;细胞形态变化及线粒体膜电位结果显示,单药处理可促进U87细胞凋亡,而联合用药可以协同促进U87细胞的凋亡;RT-PCR法检测显示顺铂对Gli1基因的表达有上调作用,而米托蒽醌、米托蒽醌联合顺铂能下调Ptch和Gli1基因的表达。结论：胶质瘤U87细胞在化疗药物米托蒽醌以及两药物联合作用下可影响Sonic Hedgehog信号通路,协同发挥其促凋亡作用,进而增强肿瘤细胞对化疗药物的敏感性。     

Hedgehog信号通路及其抑制物在抗肿瘤治疗中的研究进展

目的:Hedgehog信号通路不仅与胚胎的发育、组织的形成、成人组织再生及修复相关,同时已被证实与多种肿瘤细胞的形成、生长和转移具有相关性。当该信号通路异常激活时,会引起肿瘤的发生和发展。因此,对多种肿瘤中Hedgehog信号通路的了解,将有助于针对其特异性治疗药物的研发和应用。目前,第一个针对Hedgehog信号通路的小分子抑制剂GDC-0449已进入临床试验阶段,并显示了良好的临床疗效。本文就此途径与肿瘤的关系及在肿瘤治疗中的应用进行综述。     

Crosstalk between hedgehog and other signaling pathways as a basis for combination therapies in cancer

The hedgehog (Hh) pathway is aberrantly activated in a number of tumors. In medulloblastoma, basal cell carcinoma, and rhabdomyosarcoma, mutations in Hh pathway genes lead to ligand-independent pathway activation. In many other tumor types, ligand-dependent activation of Hh signaling is potentiated through crosstalk with other critical molecular signaling pathways. Among such pathways, RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, EGFR, and Notch are of particular interest because agents that selectively inhibit these pathways are available and can be readily combined with agents such as vismodegib, sonidegib (LDE225), and BMS-833923, which target smoothened—a key Hh pathway regulator. Numerous preclinical studies have revealed the ways in which Hh intersects with each of these pathways, and combination therapies have resulted in improved antitumor efficacy and survival in animal models. Hh also plays an important role in hematopoiesis and in the maintenance of BCR-ABL-driven leukemic stem cells. Thus, combined inhibition of the Hh pathway and BCR-ABL has emerged as a promising potential therapeutic strategy in chronic myeloid leukemia (CML). A number of clinical trials evaluating combinations of Hh inhibitors with other targeted agents are now underway in CML and a variety of solid tumors. This review highlights these trials and summarizes preclinical evidence of crosstalk between Hh and four other actionable pathways—RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, EGFR, and Notch—as well as the role of Hh in the maintenance of BCR-ABL-driven leukemic stem cells.