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Title: | PI3K pathway inhibitors: Better not left alone. | Authors: | Tao J.J.;Scaltriti M.;Markman B. | Institution: | (Markman) Monash Medical Centre, Southern Health, Melbourne, 3165, Australia (Markman) Monash Institute of Medical Research, Monash University, Melbourne, 3168, Australia (Tao, Scaltriti) Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Harvard Medical School, CNY 149, 13th Street, Charlestown, MA, 02129, United States (Tao, Scaltriti) Harvard Medical School, Boston, MA, United States | Issue Date: | 7-May-2013 | Copyright year: | 2013 | Publisher: | Bentham Science Publishers B.V. (P.O. Box 294, Bussum 1400 AG, Netherlands) | Place of publication: | Netherlands | Publication information: | Current Pharmaceutical Design. 19 (5) (pp 895-906), 2013. Date of Publication: 2013. | Abstract: | The PI3K/Akt/mTOR signaling pathway plays a key role in diverse physiologic processes. It is also central to many aspects of the malignant process. Genetic phenomena that lead to constitutive pathway activation are common in human cancer; the most relevant are mutations affecting the catalytic subunit of PI3K and loss of function of the PTEN tumor suppressor. These factors have made this important cascade attractive as a potential target for cancer therapeutics. A host of inhibitors are now in various stages of development that target key nodes within the PI3K pathway. To date, however, the efficacy of these agents has fallen short of expectation, with at least one possible explanation being the presence of feedback loops and cross-talk that exists within and between PI3K and other signaling pathways. Accordingly, enthusiasm is again high as strategies employing therapeutic combinations are gaining pace, with encouraging results documented in both preclinical studies and emerging clinical trials. Here, we review the agents that have reached evaluation in early phase clinical studies of human subjects with cancer, and discuss the rationale for and use of novel drug combinations. © 2013 Bentham Science Publishers. | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.2174/138161213804547213 | PubMed URL: | 22973958 [http://www.ncbi.nlm.nih.gov/pubmed/?term=22973958] | ISSN: | 1381-6128 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/27530 | Type: | Review | Subjects: | endometrium cancer/dt [Drug Therapy] enzyme inhibition estrogen receptor positive breast cancer/dt [Drug Therapy] fatigue/si [Side Effect] gastrointestinal symptom/si [Side Effect] gene mutation genetic transcription human hyperglycemia/si [Side Effect] hyperlipidemia/si [Side Effect] hypertension/si [Side Effect] hypoglycemia/si [Side Effect] hypophosphatemia/si [Side Effect] interstitial pneumonia/si [Side Effect] ischemic cardiomyopathy/si [Side Effect] kidney carcinoma/dt [Drug Therapy] lactic acidosis/si [Side Effect] lung non small cell cancer/dt [Drug Therapy] mantle cell lymphoma/dt [Drug Therapy] maximum tolerated dose molecular interaction mood disorder/si [Side Effect] mucosa inflammation/si [Side Effect] myeloma/dt [Drug Therapy] nausea/si [Side Effect] *neoplasm nonhuman pancreas cancer/dt [Drug Therapy] pancreatic neuroendocrine tumor/dt [Drug Therapy] pharmacodynamics phase 1 clinical trial (topic) priority journal review side effect/si [Side Effect] signal transduction skin toxicity/si [Side Effect] solid tumor/dt [Drug Therapy] Streptomyces hygroscopicus thrombocyte rich plasma thrombocytopenia/si [Side Effect] treatment response urogenital tract cancer/dt [Drug Therapy] uterine cervix cancer/dt [Drug Therapy] vomiting/si [Side Effect] 1 (1 cyano 1 methylethyl) 3 methyl 8 (3 quinolinyl)imidazo[4,5 c]quinolin 2(1h,3h) one/ct [Clinical Trial] 1 (1 cyano 1 methylethyl) 3 methyl 8 (3 quinolinyl)imidazo[4,5 c]quinolin 2(1h,3h) one/dt [Drug Therapy] 1 (1 cyano 1 methylethyl) 3 methyl 8 (3 quinolinyl)imidazo[4,5 c]quinolin 2(1h,3h) one/pd [Pharmacology] 2 (2 difluoromethylbenzimidazol 1 yl) 4,6 dimorpholino 1,3,5 triazine/ct [Clinical Trial] 2 (2 difluoromethylbenzimidazol 1 yl) 4,6 dimorpholino 1,3,5 triazine/pd [Pharmacology] 4 (4 amino 5 (7 methoxy 1h indol 2 yl)imidazo[5,1 f][1,2,4]triazin 7 yl)cyclohexanecarboxylic acid/ae [Adverse Drug Reaction] 4 (4 amino 5 (7 methoxy 1h indol 2 yl)imidazo[5,1 f][1,2,4]triazin 7 yl)cyclohexanecarboxylic acid/ct [Clinical Trial] 4 (4 amino 5 (7 methoxy 1h indol 2 yl)imidazo[5,1 f][1,2,4]triazin 7 yl)cyclohexanecarboxylic acid/pd [Pharmacology] 4 [2 (4 amino 1,2,5 oxadiazol 3 yl) 1 ethyl 7 (3 piperidinylmethoxy) 1h imidazo[4,5 c]pyridin 4 yl] 2 methyl 3 butyn 2 ol/ct [Clinical Trial] 4 [2 (4 amino 1,2,5 oxadiazol 3 yl) 1 ethyl 7 (3 piperidinylmethoxy) 1h imidazo[4,5 c]pyridin 4 yl] 2 methyl 3 butyn 2 ol/pd [Pharmacology] 4 diallylaminomethylene 1,3,4,7,10,11,12,13,14,15,16,17 dodecahydro 6 hydroxy 1 methoxymethyl 10,13 dimethyl 3,7,17 trioxo 2 oxacyclopenta[a]phenanthren 11 yl acetate/ae [Adverse Drug Reaction] 4 diallylaminomethylene 1,3,4,7,10,11,12,13,14,15,16,17 dodecahydro 6 hydroxy 1 methoxymethyl 10,13 dimethyl 3,7,17 trioxo 2 oxacyclopenta[a]phenanthren 11 yl acetate/ct [Clinical Trial] 4 diallylaminomethylene 1,3,4,7,10,11,12,13,14,15,16,17 dodecahydro 6 hydroxy 1 methoxymethyl 10,13 dimethyl 3,7,17 trioxo 2 oxacyclopenta[a]phenanthren 11 yl acetate/pd [Pharmacology] [1 (4 oxo 8 phenyl 4h 1 benzopyran 2 yl)morpholinio]methoxysuccinylarginylglycylaspartylserine acetate/pd [Pharmacology] azd 2014/ae [Adverse Drug Reaction] azd 2014/ct [Clinical Trial] azd 2014/dt [Drug Therapy] azd 2014/pk [Pharmacokinetics] azd 2014/pd [Pharmacology] azd 8055/ae [Adverse Drug Reaction] azd 8055/ct [Clinical Trial] azd 8055/dt [Drug Therapy] azd 8055/pd [Pharmacology] buparlisib/ae [Adverse Drug Reaction] buparlisib/ct [Clinical Trial] buparlisib/pd [Pharmacology] everolimus/ct [Clinical Trial] everolimus/dt [Drug Therapy] everolimus/pd [Pharmacology] interferon/cb [Drug Combination] interferon/dt [Drug Therapy] *phosphatidylinositol 3 kinase inhibitor/ct [Clinical Trial] *phosphatidylinositol 3 kinase inhibitor/dt [Drug Therapy] *phosphatidylinositol 3 kinase inhibitor/iv [Intravenous Drug Administration] *phosphatidylinositol 3 kinase inhibitor/po [Oral Drug Administration] *phosphatidylinositol 3 kinase inhibitor/pk [Pharmacokinetics] *phosphatidylinositol 3 kinase inhibitor/pd [Pharmacology] pictilisib/ae [Adverse Drug Reaction] pictilisib/ct [Clinical Trial] pictilisib/dt [Drug Therapy] pictilisib/pd [Pharmacology] ridaforolimus/ae [Adverse Drug Reaction] ridaforolimus/ct [Clinical Trial] ridaforolimus/pd [Pharmacology] temsirolimus/ct [Clinical Trial] temsirolimus/cb [Drug Combination] temsirolimus/dt [Drug Therapy] temsirolimus/pd [Pharmacology] unclassified drug unindexed drug xl 147/ae [Adverse Drug Reaction] xl 147/ct [Clinical Trial] xl 147/dt [Drug Therapy] xl 147/pd [Pharmacology] xl 765/ae [Adverse Drug Reaction] xl 765/ct [Clinical Trial] xl 765/pd [Pharmacology] azd 5363/ct [Clinical Trial] azd 5363/po [Oral Drug Administration] azd 5363/pd [Pharmacology] bay 80 6946/ae [Adverse Drug Reaction] bay 80 6946/ct [Clinical Trial] bay 80 6946/dt [Drug Therapy] bay 80 6946/iv [Intravenous Drug Administration] bay 80 6946/pd [Pharmacology] ds 7423/ct [Clinical Trial] gdc 0980/ae [Adverse Drug Reaction] gdc 0980/ct [Clinical Trial] gdc 0980/dt [Drug Therapy] gdc 0980/pd [Pharmacology] gsk 141795/ae [Adverse Drug Reaction] gsk 141795/ct [Clinical Trial] gsk 141795/pd [Pharmacology] gsk 2126458/ae [Adverse Drug Reaction] gsk 2126458/ct [Clinical Trial] gsk 2126458/dt [Drug Therapy] gsk 2126458/pd [Pharmacology] ink 128/ct [Clinical Trial] ink 128/dt [Drug Therapy] ink 128/pd [Pharmacology] ly 2780301/ct [Clinical Trial] ly 2780301/pk [Pharmacokinetics] ly 2780301/pd [Pharmacology] pf 04691502/ae [Adverse Drug Reaction] pf 04691502/ct [Clinical Trial] pf 04691502/dt [Drug Therapy] pf 04691502/po [Oral Drug Administration] pf 04691502/pd [Pharmacology] pki 587/ae [Adverse Drug Reaction] pki 587/ct [Clinical Trial] pki 587/dt [Drug Therapy] pki 587/iv [Intravenous Drug Administration] pki 587/pd [Pharmacology] pwt 33597/ct [Clinical Trial] pwt 33597/dt [Drug Therapy] pwt 33597/pd [Pharmacology] sar 254409/ae [Adverse Drug Reaction] sar 254409/ct [Clinical Trial] sar 254409/pd [Pharmacology] phase 3 clinical trial (topic) adrenal cortex carcinoma/dt [Drug Therapy] aminotransferase blood level anorexia/si [Side Effect] bladder cancer/dt [Drug Therapy] breast cancer/dt [Drug Therapy] *cancer chemotherapy cancer survival clinical trial (topic) diarrhea/si [Side Effect] drug dose escalation drug dose increase drug efficacy drug eruption/si [Side Effect] drug intermittent therapy drug dose escalation drug dose increase drug efficacy drug eruption / side effect drug intermittent therapy endometrium cancer / drug therapy enzyme inhibition estrogen receptor positive breast cancer / drug therapy fatigue / side effect gastrointestinal symptom / side effect gene mutation genetic transcription human hyperglycemia / side effect hyperlipidemia / side effect hypertension / side effect hypoglycemia / side effect hypophosphatemia / side effect interstitial pneumonia / side effect ischemic cardiomyopathy / side effect kidney carcinoma / drug therapy lactic acidosis / side effect lung non small cell cancer / drug therapy mantle cell lymphoma / drug therapy maximum tolerated dose molecular interaction mood disorder / side effect mucosa inflammation / side effect myeloma / drug therapy nausea / side effect *neoplasm nonhuman pancreas cancer / drug therapy pancreatic neuroendocrine tumor / drug therapy pharmacodynamics phase 1 clinical trial (topic) adrenal cortex carcinoma / drug therapy priority journal review side effect / side effect signal transduction skin toxicity / side effect solid tumor / drug therapy Streptomyces hygroscopicus thrombocyte rich plasma thrombocytopenia / side effect treatment response urogenital tract cancer / drug therapy uterine cervix cancer / drug therapy vomiting / side effect phase 3 clinical trial (topic) aminotransferase blood level anorexia / side effect bladder cancer / drug therapy breast cancer / drug therapy *cancer chemotherapy cancer survival clinical trial (topic) diarrhea / side effect |
Type of Clinical Study or Trial: | Review article (e.g. literature review, narrative review) |
Appears in Collections: | Articles |
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