Table 2 |.
Selected drugs _targeting the PI3K–AKT–mTOR pathway that is activated in tumours deficient for PTEN
| Drug | _target | Human trials | Human results | Mouse results |
|---|---|---|---|---|
| XL147 | PI3K | Phase I/II | One partial response in NSCLC in Phase Ia176 | Not reported |
| GDC-0941 | PI3K | Phase I | One partial response in breast cancer in Phase Ia177 | Growth inhibition but not regression in xenografts178 and prolonged tumour regression in combination with imatinib179 |
| PX-866 | PI3K | Phase I/II | Best response reported: stable disease in 7 of 31 evaluable patients in Phase Ia180 | Prevents TGFα-induced pulmonary fibrosis in mice181 |
| BKM120 | PI3K | Phase I/II | One partial response in triple-negative breast cancer in Phase Ia182 | Prevents emergence of resistance to inhibitors of SMO in medulloblastoma xenografts183 |
| CAL-101 | PI3K (delta) | Phase I/II | Objective response rate 9 of 15 in indolent NHL, 6 of 7 mantle cell lymphoma and 4 of 17 CLL in Phase Ia184 | Not reported |
| BEZ235 | PI3K and mTOR (TORC1 and TORC2) | Phase I/II | Two partial responses in Cowden syndrome and breast cancer in Phase Ia185 | Prevents emergence of resistance to inhibitors of SMO in medulloblastoma xenografts183 |
| SF1126 (h) | PI3K | Phase I | Best response reported: stable disease in Phase Ia186 | Prevents tumour growth in xenografts187 |
| GDC-0980 | PI3K and mTOR (TORC1 and TORC2) | Phase I | One partial response in mesothelioma in Phase Ia188 | Not reported |
| XL765 | PI3K and mTOR (TORC1 and TORC2) | Phase I/II | Best response reported: stable disease in Phase Ia189 | Decreased xenograft growth and increased survival in combination with temozolomide190 |
| PKI-402 | PI3K and mTOR (TORC1 and TORC2) | Not reported | Xenograft tumour regression with subsequent regrowth191 | |
| PKI-587 (also known as PF-05212384) | PI3K and mTOR (TORC1 and TORC2) | Phase I | Not reported | Xenograft tumour regression192 |
| Rapalogues (rapamycin, sirolimus, everolimus and temsirolimus) | mTOR (TORC1) | Approved | Improved overall survival and progression-free survival in RCC193,194, improved progression-free survival in PNET195, 75% response rate in subependymal giant-cell astrocytoma in TSC136, 40% response rate in MCL and lower in other tumour types (reviewed in REF. 196) | Prevention of uterine and adrenal tumours in Pten+/− mice132, prolonged survival in a mouse model of Cowden syndrome197, decreased Pten−/− prostate tumour growth198, prevention of lung tumours199, anal tumours200, lymphoma201, bladder tumours202, mammary tumours203, prostate tumours198 and regression of salivary gland tumours204 and PNET205 |
| AZD8055 | mTOR | Phase I/II | Not reported | Growth inhibition or tumour regression in xenografts206 |
| Perifosine | AKT | Phase III | Improved TTP and overall survival in randomized Phase II of capecitabine with or without perifosine in refractory colorectal cancer207 | Growth inhibition and increased survival in multiple myeloma xenograft208, growth inhibition in neuroblastoma xenograft209 |
| MK-2206 | AKT | Phase I/II | Best response reported: stable disease in Phase Ia210 | Modest xenograft growth inhibition as a single agent211 |
CLL, chronic lymphoid leukaemia; MCL, mantle cell lymphoma; NHL, non-Hodgkin’s lymphoma; NSCLC, non-small-cell lung cancer; PNET, pancreatic neuroendocrine tumour; RCC, renal cell carcinoma; SMO, smoothened; TGFα, tumour growth factor-α; TSC, tuberous sclerosis; TTP, time to progression.