More recently Vismodegib was administered in

More recently, Vismodegib was administered in combination with Gemcitabine in a pilot clinical trial that enrolled 23 patients affected by metastatic pancreatic adenocarcinoma. This type of malignancy is the most frequent form of pancreas cancer and is ranked in fourth place for cancer mortality in Europe and United States, with a survival rate lower than any other cancer. Unfortunately, surgery, radio- and chemo-therapy are frequently ineffective in metastatic pancreatic adenocarcinoma [77]. In this single arm pilot clinical study, patients were given 150 mg/day of Vismodegib orally for four weeks (Cycle 1). Then, the same patients were treated weekly intravenously (1000 mg/m2) with a combination of Vismodegib and Gencitabine, for four further weeks (Cycle 2). The results showed that this combination therapy induced a decrease in target byl719 within the Hh signaling pathway (i.e. Gli1 and PTCH1). Nevertheless, no significant differences were found for the other parameters studied, including SHh, Gli1, and PTCH1 levels before and after the treatment, and no dissimilarities were found in PFS and overall survival in comparison with a sole Gemcitabine treatment in the same population. These results countered a negative attitude towards this type of therapy in patients suffering from metastatic pancreatic cancer [78]. More recently, the same conclusions were achieved by Catenacci et al. whom reported that the combination of Vismodegib and Gencitabine did not lead to additional benefits (in terms of PFS and overall survival) in comparison with sole Gemcitabine in a randomized phase II clinical trial comprising of 106 patients with metastatic pancreatic cancer [79]. This same research group continued the investigation of this therapeutic strategy with the study of IPI-926, another Hh inhibitor, in combination with a mixture of chemotherapy drugs including 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) in patients with advanced pancreatic cancer. In this case too, the authors concluded that while antitumor activity and safety were registered with this combination, they were rather skeptical about the development of Hh inhibitors for the treatment of pancreatic cancer [80].
Natural and synthetic inhibitors of Hedgehog pathway Natural compounds have emerged as potent therapeutic alternatives or adjutants for different types of cancer [[81], [82], [83], [84]]. Several natural and synthetic compounds have been proposed as being effective as Hh pathway inhibitors, many of them targeting the Smo receptor. In this context, several synthetic drugs that target Smo have been developed, including the aformentioned Vismodegib (GDC-0449), which is still in the clinical trial phase for advanced and metastatic basal cell carcinoma [85]. Another Hh pathway inhibitor, Erismodegib (Sonidegib, NVP-LDE225), inhibits the proliferation, migration and/or invasion of renal cell carcinoma cells (RCC) by reducing the activation of proteins and acting as a Smo antagonist [86]. An orally bioavailable Smo antagonist, BMS-833923 (XL139), yielded a significant decrease in cellular proliferation and tumor growth in preclinical testing (in vitro and in vivo) [87,88]. LEQ506, TAK-441 and NVP-LEQ506 possess varying levels of in vitro and in vivo effects [[89], [90], [91]] through the same principle - smoothened antagonists. On the other hand, a benzimidazole derivative Hh antagonist, showed the strongest efficacy in animal models [92,93]. IPI-926 (a Smo antagonist) in conjunction with gemcitabine, demonstrated a decrease in fibrotic reaction [34,94]. In cell viability assays, another compound, robotnikinin, was found to act as a Hh pathway inhibitor by binding the amino terminal region of SHh (SHhN) [95,96]. Taladegib (LY2940680) was reported to restrain Smo-resistant mutant cells [97] and Itraconazole showed the capability to bind the Smo receptor and inhibit its accumulation in the cilium [98]. A member of the aminoproline group of compounds, CUR61414, reduced tumor growth through binding of Smo and inhibition of the Hh signaling pathway [92]. PF-04449913 was identified as a selective Hh signaling antagonist that binds to Smo and blocks signal transduction, reducing tumor growth in in vivo colorectal and pancreatic cancer models when used in combination with other anticancer agents [88,99].