Targeted Inhibition of Hh, Wnt, TGF-B Signalling Complex - Therapeutic Strategies in Cancer Biology and Pathology - page 36

2011). A limited phase I study of LDE225 of medulloblastoma, BCC, lung adeno-
carcinoma, spindle cell sarcoma and breast cancer has been reported. Some tumour
inhibition has been found (Rodon et al., 2011, Tawbi et al., 2011). The safety, phar-
macokinetics and pharmacodynamics of LDE225 administered orally on a daily
dosing schedule to children with recurrent or refractory medulloblastoma is under
way at present. Many other forms of human tumours are also included in this study
(Novartis, NCT01125800). Several other trials are also in progress. Another SMO
inhibitor is IPI-926 (Saridegib) that is currently in clinical trial in patients with chon-
drosarcoma (NCT01310816). The effects of combination of IPI-926 with Gemcitabine
in pancreatic cancer have been reported by Infinity Pharmaceuticals (ASCO 2012
Gastrointestinal Cancers Symposium). Of 16 patients, five showed partial responses
and median progression-free survival was 7.6 months and median overall survival was
10.2 months. Three further SMO inhibitors undergoing clinical trials are BMS-833923
(XL139), LEQ506 and TAK-441. The paucity of information in the public domain
concerning the biological effects of these compounds is somewhat surprising.
A putative SMO inhibitor was described some time ago. CUR61414 ( N -((3S,5S)-
1-(benzo[d][1,3]dioxol-5-ylmethyl)-5-(piperazine-1-carbonyl)pyrrolidin-3-yl)- N -
(3-methoxybenzyl)-3,3-dimethylbutanamide) was highly active in BCC carrying
PTCH1 mutations, achieving inhibition of signalling with IC 50 in the 100-200nM
range, causing regression by inhibiting proliferation and inducing apoptosis
(Williams et al., 2003). According to Frank-Kamenetsky et al. (2002), CUR61414
directly binds to SMO. When tested in vivo on murine BCCs in Ptch1(+/−) K14-
CreER2 p53 fl/fl mice CUR61414 seemed able to induce regression of BCCs.
However, it was ineffective when applied topically (at 0.09%, 0.35%, 1.1% and
3.1%) for up to 28 days in human superficial or nodular BCCs (Tang et al., 2011c).
Combination of Hh inhibitors with other agents, for example inhibitors of PARP
(poly (ADP-ribose) polymerase) and HDAC (histone deacetylase) inhibitors, has
been attempted with some success in vitro and xenograft models. GDC-0449 has
been tested in combination with other inhibitors. Bahra et al. (2012) tested the
effects of the steroidal alkaloid cyclopamine and Gemcitabine allied with GDC-
0449. Cyclopamine and GDC-0449 inhibited tumour cell growth in vitro and
in vivo . When combined with Gemcitabine, cyclopamine showed synergistic growth
inhibition of pancreatic adenocarcinoma xenografts. Cyclopanine binds SMO (Chen
et al., 2002) and has been previously shown to be able to inhibit the proliferation of
medulloblastoma cells in culture and the growth of murine allografts and xenografts
(Berman et al., 2002). However, although GDC-0449 showed no signs of toxicity
when administered to mice it produced permanent skeletal abnormalities (Kimura
et al., 2008).
A cyclopamine based derivative called IPI-926 (Infinity Pharmaceuticals) has
shown complete tumour regression in an allograft medulloblastoma model with
active Hh (Tremblay et al., 2008, 2009). IPI-926 is under several clinical trials for
the assessment of safety and activity in BCC and Chondrosarcoma (NCT01609179),
metastatic pancreatic cancer in combination with Gemcitabine (NCT01130142l) and
with FOLFIRINOX (leucovorin) (NCT01383538) and recurrent head and neck can-
cer in combination with Cetuximab (EGFR inhibitor).