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  • br Mechanism of HH pathway

    2022-06-23


    Mechanism of HH pathway activation in NSCLC Despite the role of the HH pathway in basal cell carcinoma and medulloblastoma, it has been postulated that epithelial tumors do not demonstrate cell autonomous HH ligand activity. The main evidence comes from the study by Yauch et al showing no correlation between GLI1 expression levels and sensitivity of a large range of colorectal, pancreatic and lung cancer cell lines to SMO inhibitors. [96] Additionally, the concentrations of HH inhibitors required to inhibit proliferation in pancreatic and lung cancer cell lines are in the micromolar range whereas the concentrations needed to inhibit GLI1 luciferase activity as well as proliferation in known hedgehog responsive mesenchymal cell lines are 10 and 20 times lower respectively. Instead, the HH ligands secreted by the epithelial neoplastic CBL0137 hydrochloride may have a paracrine effect in mesenchymal cells in the tumor microenvironment [96]. This paracrine loop in HH ligand expressing tumor models is pro-tumorigenic supporting a therapeutic role for SMO inhibitors. Nevertheless, a growing body of evidence, including experiments with specific knock downs of SMO, supports the autocrine activity of HH ligands in lung cancers in addition to the paracrine model. [[79], [80], [81]] The autocrine model is particularly active in the subpopulation of cancer initiating cells rather than cancer cells from the bulk of the tumor [76].
    Ongoing clinical trials with HH inhibitors in lung cancer HH pathway inhibition has been explored in clinical trials in unselected populations over the past decade. Despite approval in patients with non-resectable basal cell carcinoma and activity in patients with SHH type of medulloblastoma, the trials in epithelial solid tumors yielded negative results. Currently, few clinical trials are ongoing as summarized in Table 1. In one of them (NCT02357836), itraconazole is administered at a dose of 600 mg twice daily for 10-14 days as neoadjuvant treatment prior to surgery for patients with resectable NSCLC. This dose of itraconazole was selected to reflect the higher dose required to inhibit the HH pathway compared to the typical itraconazole dose when the drug is used for its antifungal properties. The study, which has a strong translational rationale will evaluate the resection specimen for changes in the HH pathway and tumor angiogenesis.
    Areas of uncertainty and concluding remarks Clinical trials did not show any benefit from HH inhibition in SCLC or other solid tumors of epithelial origin. Given the role of the HH pathway in lung carcinogenesis and lung cancer biology, we believe that further study of the mechanisms of lack of response to HH inhibitors might explain the failure to translate preclinical work. To this end, we identify three areas of uncertainty, where further research might propose novel directions for this domain. First, formation of complexes of SMO with other transmembrane receptors like MET [94] or generation of oxysterols that function as SMO activators [57] might limit the activity of SMO inhibitors and could support combination strategies with MET inhibitors and statins respectively. Second, activity of HH inhibition in selected squamous cell lung cancer population on the basis of SOX2 and PRKCi amplification is currently unknown and could be the focus of future studies. Last but not least, GLI inhibition could be a novel strategy in the treatment of lung cancer and the clinical value of GLI inhibitors should further be explored.
    Disclaimer
    Author Declaration
    Hedgehogs are spiny mammals belonging to the family Erinaceidae. The two most familiar hedgehog species are the central African hedgehog () and the European hedgehog (). The central African hedgehog, also known as the four-toed hedgehog or African pygmy hedgehog, is native to the savannah and steppe regions of central and eastern Africa. These animals have been increasingly popular as exotic pets in many countries, including Japan. Unfortunately, this species is predisposed to neoplastic disease. In retrospective studies of hedgehogs at necropsy, the prevalence of neoplasia was 53%. To date, a wide variety of neoplasias have been reported, and the most frequently involved organ systems are integumentary, hemolymphatic, digestive, endocrine, and reproductive. The most common specific histologic tumor types reported are mammary gland adenocarcinoma, lymphoma, and oral squamous cell carcinoma., However, reports on neoplasia involving the central nervous system (CNS) are scarce, with only a few single case reports of astrocytoma and oligodendroglioma described., , This report describes the details of a case of spontaneous meningioma in a pet African pygmy hedgehog, which was initially suspected to be suffering wobbly hedgehog syndrome (WHS).