Table 2.
Examples of preclinical combination studies of SMO inhibitors and other agents
| Inhibitors (target) | Indication | Effects in preclinical study | References |
|---|---|---|---|
| HHi + RAS/RAF/MEKi | |||
| Cyclopamine + U0126 (MEK)/SH6 (AKT) | Melanoma | Combination synergistically reduces cell growth in vitro | (78) |
| Cyclopamine + U0126 (MEK) | Cholangiocarcinoma | Additive antiproliferative effect | (275) |
| HHi + EGFRi | |||
| Cyclopamine + Gefitinib | Pancreatic cancer | Combination decreases cell viability in vitro and tumour growth in vivo | (276) |
| Cyclopamine + Gefitinib + Docetaxel | Prostate cancer | Combination decreases tumour growth and invasion in vitro | (277) |
| Cyclopamine + Erlotinib | GBM | Combination decreases tumour sphere formation | (278) |
| Saridegib + Cetuximab | HNSCC | Combination abrogates tumour growth in vivo | (279) |
| HHi + PI3K/mTORi | |||
| Sonidegib + Buparlisib (PI3K) or BEZ235 (PI3K/mTOR) | MB | Combination delays resistance observed with sonidegib alone | (254) |
| Sonidegib + Buparlisib (PI3K) | GBM | Combination synergistically reduces tumour growth in vitro and in vivo | (280) |
| Cyclopamine or CUR199691 + Rapamycin (mTOR) + Gemcitabine | Pancreatic cancer | Triple combination leads to CSC elimination in vitro and in vivo and increases survival | (281) |
| Vismodegib + Everolimus (mTOR) | Oesophageal adenocarcinoma | Everolimus enhances vismodegib inhibition in vivo | (41) |
| SIBI-C1 + Rapamycin (mTOR) + Gemcitabine | Pancreatic cancer | Triple combination eliminates CSC, reduces tumour growth in vivo and increases survival | (282) |
| HHi + NOTCHi | |||
| Cyclopamine + GSI-XXI | Leukaemia | Combination inhibits growth in vitro | (283) |
| Cyclopamine + MRK-003 | GBM | Combination decreases cell growth and increases apoptosis | (218) |
| Cyclopamine + GSI-1 | Glioma | Combination enhances the effect of temozolomide | (284) |
| Cyclopamine or Vismodegib + DBZ or compound E | Prostate | Combination depletes docetaxel-resistant prostate cancer cells in vitro and in vivo | (285) |
| HHi + BCR-ABLi | |||
| Cyclopamine + Nilotinib | CML | Combination prolongs survival in mouse model | (89) |
| Vismodegib + Dasadegib | CML | Combination enhances cytotoxicity | (288) |
| Vismodegib + Ponatinib (pan-ABL) | Leukaemia | Combination leads to decreased CD19+ cells, overall tumour burden and increases survival | (289) |
| HHi + others | |||
| Cyclopamine + Gemcitabine | Pancreatic cancer | Combination abrogates metastases and reduces primary tumours | (71) |
| Saridegib + Gemcitabine | Pancreatic cancer | Saridegib facilitates gemcitabine delivery and extends survival | (139) |
| Cyclopamine + Temozolomide | GBM | Combination synergistically reduces CSC proliferation in vitro | (75) |
| SEN-450 + Temozolomide | GBM | Combination reduces tumour growth in vivo | (290) |
| Sonidegib + VX-680 (Aurora kinase) or BI-2536 (Polo-like kinase) | MB | Combination reduces proliferation in vitro and in vivo | (292) |
| Cyclopamine + CCT (WIP1) | Melanoma, breast cancer | Combination synergistically reduces tumour growth in vitro | (215) |
Abbreviations: CCT, CCT007093; CML: chronic myeloid leukaemia; CSC, cancer stem cells; GBM: glioblastoma; HNSCC, head and neck squamous cell cancer; MB, medulloblastoma.