Medulloblastoma (MB) is an invasive pediatric brain tumor caused by morphogenetic anomalies, consequent to alterations of specific signaling pathways. The management of this type of tumor requires aggressive treatments consisting in surgical resection followed by radiation and standard chemotherapy. Unfortunately, current therapies have serious adverse effects and patients with recurrent disease after primary therapy have a particularly poor prognosis.
In the last years, Hedgehog (Hh) pathway has emerged as a druggable therapeutic target in cancer, since its crucial role in development, proliferation and tissue homeostasis. Inappropriate reactivation of Hh is responsible for the formation and progression of several human cancers. Deregulation of Hh pathway occurs in MB, also confirmed by mouse models of the human disease in which mutations in key component genes of the pathway (Smoothened, Patched, SuFu) result in tumor development.
Experimental use of the Hh antagonists has demonstrated an inhibitory effect on tumor growth and a number of Hh inhibitors have been developed and patented. Major progress has been made in the development of Smoothened (Smo, the activating receptor of Hh signaling) antagonists, although they have shown several limitations due to Smo-downstream pathway activation or the occurrence of drug-resistant Smo mutations.
Recently, particular interest has been elicited by the identification of small molecules able to hit Gli factors, the final effectors of the Hh pathway, which provide a valid tool to overcome anti-Smo resistance.
The aim of this proposal is to discover novel powerful Gli inhibitors targeting Hh signaling at downstream level, and to investigate their pharmacological effects on MB.
Medulloblastoma (MB) is considered the most common brain malignant childhood cancer and aberrant activation of Hh pathway is responsible for the occurrence of about 30% of cases. Current treatments including surgery, cranio-spinal radiation and high-dose chemotherapy have led to improvement in survival, but most treated patients suffer devastating side effects. Other current treatment options largely target Smo, but they have demonstrated limitations such as drug resistance due to acquired Smo mutations or oncogenic mutations downstream this receptor (19).
The need to develop less invasive and toxic therapies and overcome drug resistance represents for the research an important goal that can be pursued through the discovery of novel antagonists able to block the Hh pathway especially at downstream level. Indeed, FDA-approved anti-Hh drugs for the treatment of MB (i.e. GDC-0449) and drug-candidates inhibiting the receptor Smo suffer of acquired resistance, caused by Smo mutations or activation of downstream signals, raising the need to identify novel small molecules targeting the final effector of Hh pathway, Gli1. Transcription factors are generally considered interesting targets in drug discovery and Gli factors are among the most promising for the development of new anti-cancer therapies.
Hence, the identification of novel Hh antagonists, acting individually or in a combined fashion, could represent a newsworthy strategy for targeting MB and other Hh-dependent tumors by increasing selectivity, lowering adverse collateral effects and overcoming drug-resistance.
References
19. Huang SY and Yang JY, Cancers 2015, 7.4: 2110-2123.