Abstract
Targeting the hedgehog (HH) pathway to treat aggressive cancers of the brain, breast, pancreas, and prostate has been ongoing for decades. Gli gene amplifications have been long discovered within malignant glioma patients, and since then, inhibitors against HH pathway-associated molecules have successfully reached the clinical stage where several of them have been approved by the FDA. Albeit this success rate implies suitable progress, clinically used HH pathway inhibitors fail to treat patients with metastatic or recurrent disease. This is mainly due to heterogeneous tumor cells that have acquired resistance to the inhibitors along with the obstacle of effectively targeting the tumor microenvironment (TME). Severe side effects such as hyponatremia, diarrhea, fatigue, amenorrhea, nausea, hair loss, abnormal taste, and weight loss have also been reported. Furthermore, HH signaling is known to be involved in the regulation of immune cell maturation, angiogenesis, inflammation, and polarization of macrophages and myeloid-derived suppressor cells. It is critical to determine key mechanisms that can be targeted at different levels of tumor development and progression to address various clinical issues. Hence current research focus encompasses understanding how HH controls TME to develop TME altering and combinatorial targeting strategies. In this review, we aim to discuss the pros and cons of targeting HH signaling molecules, understand the mechanism involved in treatment resistance, reveal the role of the HH pathway in anti-tumor immune response, and explore the development of potential combination treatment of immune checkpoint inhibitors with HH pathway inhibitors to target HH-driven cancers.
Highlights
Challenges of targeting brain tumors include intrinsic immunosuppressive environment, lack of antigen targets, antigenic variability, and immune-restrictive site of the central nervous system [1]
Research on 100 most influential MB studies indicates that sonic hedgehog (SHH) pathway aberration is the main culprit for SHH-MB initiation and progression [6]
SHH pathway is extensively implicated in other malignancies, including estrogen receptor (ER+)-positive and triple-negative breast cancer (TNBC), for which overall survival and disease-free survival are 62% and 57%, respectively [13,14,15,16]
Summary
Challenges of targeting brain tumors include intrinsic immunosuppressive environment, lack of antigen targets, antigenic variability, and immune-restrictive site of the central nervous system [1]. The SHH enriched MB significantly increases gene expression of tumor-associated macrophages, resulting in an abundance of M2 subtype-tumor-associated macrophages, and patients with increased macrophage M2 show significantly worse prognosis [46,47,48] In addition to this canonical function, the SHH pathway cross talks with other tumorigenic pathways such as MAPK, mTOR, AKT, and PI3K, driving cancer progression [46,47,49]. The non-canonical activation of these GLI proteins contributes to resistance to SMO inhibitors Some of those pathways include RAS-RAF-MEK-ERK (rat sarcoma Raf protooncogene, serine/threonine kinase-mitogen-activated protein kinase kinase-MAPK extracellular signal-regulated kinase), AMPK-mTOR-S6K [78,106], TGFβ, and others [107]. None of these inhibitors have been employed in any clinical trials to date [91]
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