Targeting cancer hallmark vulnerabilities in hematologic malignancies by interfering with Hedgehog/GLI signaling

刺猬 癌症研究 平滑 生物 癌症 刺猬信号通路 肿瘤微环境 Notch信号通路 髓样 信号转导 细胞生物学 遗传学
作者
Peter W. Krenn,Fritz Aberger
出处
期刊:Blood [Elsevier BV]
卷期号:142 (23): 1945-1959 被引量:1
标识
DOI:10.1182/blood.2021014761
摘要

Abstract Understanding the genetic alterations, disrupted signaling pathways, and hijacked mechanisms in oncogene-transformed hematologic cells is critical for the development of effective and durable treatment strategies against liquid tumors. In this review, we focus on the specific involvement of the Hedgehog (HH)/GLI pathway in the manifestation and initiation of various cancer features in hematologic malignancies, including multiple myeloma, T- and B-cell lymphomas, and lymphoid and myeloid leukemias. By reviewing canonical and noncanonical, Smoothened-independent HH/GLI signaling and summarizing preclinical in vitro and in vivo studies in hematologic malignancies, we elucidate common molecular mechanisms by which HH/GLI signaling controls key oncogenic processes and cancer hallmarks such as cell proliferation, cancer stem cell fate, genomic instability, microenvironment remodeling, and cell survival. We also summarize current clinical trials with HH inhibitors and discuss successes and challenges, as well as opportunities for future combined therapeutic approaches. By providing a bird's eye view of the role of HH/GLI signaling in liquid tumors, we suggest that a comprehensive understanding of the general oncogenic effects of HH/GLI signaling on the formation of cancer hallmarks is essential to identify critical vulnerabilities within tumor cells and their supporting remodeled microenvironment, paving the way for the development of novel and efficient personalized combination therapies for hematologic malignancies.
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