The Hedgehog (Hh) pathway is a signalling cascade that plays an essential role in many fundamental processes including morphogenesis, tissue homeostasis and stemness. Constitutive activation of Hh signalling leads to uncontrolled proliferation and it is associated with neoplastic transformation and tumorigenesis. Mutations in components of this pathway have been identified in basal-cell carcinoma (BCC) and in medulloblastoma (MB).
Medulloblastoma is a highly malignant childhood brain tumour. Current treatment for medulloblastoma combines surgery, radiotherapy and chemotherapy, which have severe adverse effects. In the last years, the identification of small molecules able to block the pathway at the upstream receptor Smoothened (Smo, the activating receptor) or the downstream effector Gli1 (final and most powerful effector of Hh signalling) have thus emerged as valuable anticancer agents.
Major progress has been made in the development of Smo antagonists, although they have shown several limitations due to Smo-downstream pathway activation or the occurrence of drug-resistant Smo mutations. Therefore the discovery of novel Hh inhibitors able to overcome anti-Smo resistance is needed. A significant contribution to the Hh inhibitors toolbox is made by natural compounds, particularly isoflavone molecules. New Hh inhibitors take advantage of the highly versatile isoflavone scaffold. The introduction of specific substituents on the isoflavone ring B allowed the identification of molecules targeting key components of the pathway.
This research proposes a pharmacological inhibition of Hh signalling both at upstream and downstream levels as an innovative therapeutic approach for Hh-driven cancer, and as a way of promoting the development of a less aggressive therapy for MB and other diseases that are also Hh-dependent.
Abnormal Hh activation is a hallmark of many cancers, and several germline or somatic mutations in the Hh pathway components have been documented in BCC, MB, rhabdomyosarcoma (RMS), meningioma, and many other tumours. Pharmacological Hh inhibition has emerged as a valuable anticancer strategy as underlined by Vismodegib and Sonidegib, two Smo antagonists approved by the FDA in 2012 and 2015, respectively, for the treatment of metastatic or locally-advanced BCC. However, drug-resistant mutations occurring at the Smo receptor as a consequence of pharmacological pressure, coupled with Hh activation downstream or independently of Smo, have raised the need to identify novel strategies to inhibit Hh signalling. One of the most promising Hh targets is the final and most powerful effector Gli1. Isoflavones are a newly emerged class of natural compounds with a scaffold that can be exploited for Hh inhibition. Developing a number of isoflavones able to interact preferentially with the Smo receptor or the Gli protein could represent an efficient strategy for targeting MB and other Hh-dependent tumours. According to recent observations in anticancer clinical trials, the combination of two (or more) drugs with distinct mechanisms of action has been shown to be more effective than the administration of either agent alone.
The project proposes to evaluate and test binary drugs combinations as a form of targeted therapy to increase efficacy and to decrease toxicity of individual anticancer agents.