Constitutive activation of hedgehog signaling, often caused by PTCH1 inactivation and leading to inappropriate activation of GLI target genes, is crucial for the development of several human tumors including basal cell carcinoma of the skin and medulloblastoma.
GLI1 transcript was expressed in medulloblastomas with ATOH1 transcript, whereas high levels of MYC transcript were unrelated to NEUROG1 or ATOH1 expression.
Two new patients with Curry-Jones syndrome with trichoblastoma and medulloblastoma suggest an etiologic role of the sonic hedgehog-patched-GLI pathway.
In addition, the targets suggest a pathway through which GLI1 may ultimately affect medulloblastoma cell proliferation, survival and genomic stability by converging on p53, SGK1, MGMT and NTRK2.
Therefore, by targeting multiple genes regulating the differentiation state of GNPs, Atoh1 collaborates with the pro-proliferative Gli1-dependent transcriptional program to influence medulloblastoma development.
Analysis of Hh pathway activity and PK/PD modeling reveals that vismodegib inhibits Gli1 with a similar IC(50) in both the medulloblastoma and D5123 models (0.165 μmol/L ±11.5% and 0.267 μmol/L ±4.83%, respectively).
Mathematical analysis of the relationship between the drug's pharmacokinetics and Gli1 pharmacodynamics in patched(+/-) medulloblastoma tumor models yielded similar tumor and skin Gli1 IC(50) values, suggesting that skin can be used as a surrogate tissue for the measurement of tumor Gli1 levels.
Compound 11d suppressed transcription factor Gli1 mRNA expression in tumor-associated stromal tissue and inhibited tumor growth (treatment/control ratio, 3%) in a mouse medulloblastoma allograft model owing to the improved PK profile based on increased solubility.
Compound 12b suppressed stromal Gli1 mRNA expression in a murine model and demonstrated antitumor activity in a murine medulloblastoma allograft model.
The GLI1 mRNA is highly edited at nucleotide 2179 by adenosine deamination in normal cerebellum, but the extent of this modification is reduced in cell lines from the cerebellar tumor medulloblastoma.
Synergism between Hedgehog-GLI and EGFR signaling in Hedgehog-responsive human medulloblastoma cells induces downregulation of canonical Hedgehog-target genes and stabilized expression of GLI1.
Five differentially expressed genes in medulloblastoma (GLI1, SPHK1, SHROOM2, PDLIM3, and OTX2) were found to associate with Hh pathway activation status.
When compared with MB as a reference, the median GLI1 mRNA expression in GBM appeared 14.8 fold lower than that of the "high-Hh" cluster of MB but 5.6 fold higher than that of the "low-Hh" cluster of MB.
Collectively, this data unveil a novel mechanism of inhibition of Gli1 function, which is exclusive for human cells and may be exploited for the treatment of Medulloblastoma or other Gli1 driven tumors.
These data demonstrated that Gli1 is an important mediator of the SHH pathway activity in MB, and may be a novel agent for use in combined chemotherapeutic regimens.
Together, these findings reveal a novel noncanonical GLI1 regulation and provide a potential therapeutic target for the treatment of cancers with aberrant Hh pathway activation, such as medulloblastoma.
Moreover, FOXS1 is both highly expressed and positively correlated with GLI1 in medulloblastoma samples of the Sonic HH subgroup, further arguing for the existence of FOXS1/GLI1 interplay in human tumors.
Numb is considered as a tumor suppressor playing critical roles in determining cell fate and has been shown to target the oncogenic transcription factor Gli1 for Itch-dependent ubiquitination, resulting in suppression of the oncogenic sonic hedgehog signaling in medulloblastoma.
In the present study, we show that concomitant inhibition of Hedgehog (HH) signaling by the glioma-associated oncogene homolog1 (GLI1)-targeting agent GANT61 and the antiapoptotic BCL-2 protein family member MCL-1 by A-1210477 synergistically induces cell death in HH-driven cancers, i.e. rhabdomyosarcoma (RMS) and medulloblastoma (MB) cells.