Complications of hyperglycaemia with PI3K-AKT-mTOR inhibitors in patients with advanced solid tumours on Phase I clinical trials

British Journal of Cancer

Volumn 113, Issue 11, 2015, Pages 1541-1547

  Geuna, E ^a,b   Roda, D ^a   Rafii, S ^a   Jimenez, B ^a   Capelan, M ^a   Rihawi, K ^a   Montemurro, F ^b   Yap, T A ^a   Kaye, S B ^a   De Bono, J S ^a   Molife, L R ^a   Banerji, U ^a  

^a INSTITUTE OF CANCER RESEARCH   (United Kingdom)

^b CANDIOLO CANCER INSTITUTE   (Italy)

Author keywords

AKT inhibitors; Hyperglycaemia; metabolic complications; mTOR inhibitors; PI3K inhibitors; PI3K AKT mTOR pathway

Indexed keywords

MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; METFORMIN; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PROTEIN KINASE B INHIBITOR; ANTIDIABETIC AGENT; ANTINEOPLASTIC AGENT; GLUCOSE BLOOD LEVEL; MTOR PROTEIN, HUMAN; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; PROTEIN KINASE INHIBITOR; TARGET OF RAPAMYCIN KINASE;

ADULT; ADVANCED CANCER; AGED; ARTICLE; CANCER INCIDENCE; CASE CONTROL STUDY; CONTROLLED STUDY; DIABETIC KETOACIDOSIS; DISEASE SEVERITY; DRUG DOSE INCREASE; FEMALE; GLYCEMIC CONTROL; HUMAN; HYPERGLYCEMIA; MAJOR CLINICAL STUDY; MALE; NONKETOTIC DIABETIC COMA; PHASE 1 CLINICAL TRIAL; PRIORITY JOURNAL; RETROSPECTIVE STUDY; SOLID TUMOR; TREATMENT OUTCOME; ADOLESCENT; ANTAGONISTS AND INHIBITORS; DRUG EFFECTS; GLUCOSE BLOOD LEVEL; MIDDLE AGED; NEOPLASMS; PATHOLOGY; PHASE 1 CLINICAL TRIAL (TOPIC); RISK FACTOR; SEVERITY OF ILLNESS INDEX; SIGNAL TRANSDUCTION; VERY ELDERLY; YOUNG ADULT;

ADOLESCENT; ADULT; AGED; AGED, 80 AND OVER; ANTINEOPLASTIC AGENTS; BLOOD GLUCOSE; CASE-CONTROL STUDIES; CLINICAL TRIALS, PHASE I AS TOPIC; FEMALE; HUMANS; HYPERGLYCEMIA; HYPOGLYCEMIC AGENTS; MALE; MIDDLE AGED; NEOPLASMS; PHOSPHATIDYLINOSITOL 3-KINASES; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS C-AKT; RETROSPECTIVE STUDIES; RISK FACTORS; SEVERITY OF ILLNESS INDEX; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES; YOUNG ADULT;

EID: 84949321820     PISSN: 00070920     EISSN: 15321827     Source Type: Journal    
DOI: 10.1038/bjc.2015.373     Document Type: Article

References (40)

1. Arkenau HT, Olmos D, Ang JE, de Bono J, Judson I, Kaye S. (2008). Clinical outcome and prognostic factors for patients treated within the context of a phase I study: the Royal Marsden Hospital experience. Br J Cancer 98(6): 1029-1033.
2. Banerji U, Dean EJ, Gonzalez M, Greystoke AP, Basu B, Krebs M, Puglisi M, Grinsted L, Oelmann E, Burke W, Harrington E, Green S, Ranson M. (2012). First-in-human phase I trial of the dual mTORC1 and mTORC2 inhibitor AZD2014 in solid tumors. J Clin Oncol ASCO Annu Meet Abstr 30(15 Suppl): 3004.
3. Banerji U, Ranson M, Schellens JHM, Esaki T, Dean E, Zivi A, Van der Noll R, Stockman PK, Marotti M, Garrett M, Davies B, Elvin P, Hastie A, Lawrence P, Cheung SYA, Stephens C, Tamura K. (2013). Results of two phase 1 multicenter trials of AZD5363, an inhibitor of AKT 1, 2 and 3: biomarker and early clinical evaluation in Western and Japanese patients with advanced solid tumors. Cancer Res AACR Annu Meet Abstr 73: LB-66.
4. Baselga J, Campone M, Piccart M, Burris 3rd HA, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Lebwohl D, Hortobagyi GN. (2012). Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366(6): 520-529.
5. Blagden S, Omlin A, Josephs DH, Stavraka C, Zivi A, Pinato DJ, Anthoney DA, Decordova S, Swales K, Riisnaes R, Pope L, Noguchi K, Shiokawa R, Inatani M, Prince J, Jones K, Twelves CJ, Spicer JF, Banerji U. (2014). First-in-Human study of CH5132799, an oral class I PI3K inhibitor, studying toxicity, pharmacokinetics and pharmacodynamics, in patients with metastatic cancer. Clin Cancer Res 20(23): 5908-5917.
6. Busaidy NL, Farooki A, Dowlati A, Perentesis JP, Dancey JE, Doyle LA, Brell JM, Siu LL. (2012). Management of metabolic effects associated with anticancer agents targeting the PI3K-Akt-mTOR pathway. J Clin Oncol 30(23): 2919-2928.
7. Capelan M, Kumar P, Tolcher A, Zivi A, Desai M, Papadopoulos K, Senaldi G, Patnaik A, Banerji U, Rasco D. A first-in-human Phase I study of DS-3078a, an oral TORC1/2 inhibitor, in patients with advanced solid tumors: preliminary results. Mol Cancer Ther; epub ahead of print 13 November 2013; doi:101158/1535-7163TARG-13-C173.
8. Crouthamel MC, Kahana JA, Korenchuk S, Zhang SY, Sundaresan G, Eberwein DJ, Brown KK, Kumar R. (2009). Mechanism and management of AKT inhibitor-induced hyperglycemia. Clin Cancer Res 15(1): 217-225.
9. Engelman JA. (2009). Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 9(8): 550-562.
10. Engelman JA, Luo J, Cantley LC. (2006). The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7(8): 606-619.
11. Falasca M, Hughes WE, Dominguez V, Sala G, Fostira F, Fang MQ, Cazzolli R, Shepherd PR, James DE, Maffucci T. (2007). The role of phosphoinositide 3-kinase C2alpha in insulin signaling. J Biol Chem 282(38): 28226-28236.
12. Fang Y, Westbrook R, Hill C, Boparai RK, Arum O, Spong A, Wang F, Javors MA, Chen J, Sun LY, Bartke A. (2013). Duration of rapamycin treatment has differential effects on metabolism in mice. Cell Metab 17(3): 456-462.
13. Foukas LC, Claret M, Pearce W, Okkenhaug K, Meek S, Peskett E, Sancho S, Smith AJ, Withers DJ, Vanhaesebroeck B. (2006). Critical role for the p110alpha phosphoinositide-3-OH kinase in growth and metabolic regulation. Nature 441(7091): 366-370.
14. Franz DN, Belousova E, Sparagana S, Bebin EM, Frost M, Kuperman R, Witt O, Kohrman MH, Flamini JR, Wu JY, Curatolo P, de Vries PJ, Whittemore VH, Thiele EA, Ford JP, Shah G, Cauwel H, Lebwohl D, Sahmoud T, Jozwiak S. (2013). Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 381(9861): 125-132.
15. Garcia VM, Baird RD, Shah KJ, Basu B, Tunariu N, Blanco M, Cassier PA, Pedersen JV, Puglisi M, Sarker D, Papadatos-Pastos D, Omlin AG, Biondo A, Ware JA, Koeppen H, Levy GG, Mazina KE, De Bono JS. (2011). A phase I study evaluating GDC-0941, an oral phosphoinositide-3 kinase (PI3K) inhibitor, in patients with advanced solid tumors or multiple myeloma. J Clin Oncol ASCO Annu Meet Abstr 1 29(15 Suppl): 3021.
16. Gonzalez-Angulo AM, Juric D, Argiles G, Schellens Jan HM, Burris H, Berlin J, Middleton MR, Schuler M, Van Geel R, Helgason T, Bootle D, Boehm M, Goggin TK, Demanse D, Quadt C, Baselga J. (2013). Safety, pharmacokinetics, and preliminary activity of the a-specific PI3K inhibitor BYL719: Results from the first-in-human study. J Clin Oncol ASCO Annu Meet Abstr 31(5 Suppl): 2531.
17. Hagiwara A, Cornu M, Cybulski N, Polak P, Betz C, Trapani F, Terracciano L, Heim MH, Ruegg MA, Hall MN. (2012). Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c. Cell Metab 15(5): 725-738.
18. Hong DS, Bowles DW, Falchook GS, Messersmith WA, George GC, O'Bryant CL, Vo AC, Klucher K, Herbst RS, Eckhardt SG, Peterson S, Hausman DF, Kurzrock R, Jimeno A. (2012). A multicenter phase I trial of PX-866, an oral irreversible phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res 18(15): 4173-4182.
19. Houde VP, Brule S, Festuccia WT, Blanchard PG, Bellmann K, Deshaies Y, Marette A. (2010). Chronic rapamycin treatment causes glucose intolerance and hyperlipidemia by upregulating hepatic gluconeogenesis and impairing lipid deposition in adipose tissue. Diabetes 59(6): 1338-1348.
20. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ, Global AT. (2007). Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356(22): 2271-2281.
21. Infante J, Tabernero J, Burris H, Macarulla T, Martin M, Liu Y, Jessen K, Koczon E, Rommel C, Klein P, Berk G, Bui L, Gordon M. (2012). A phase I, open label, dose escalation study of an oral mammalian target of rapamycin inhibitor INK128 administered once daily in patients with advanced malignancies. Cancer Res AACR 103rd Annu Meet Abstr 72: 5588.
22. Khamzina L, Veilleux A, Bergeron S, Marette A. (2005). Increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: possible involvement in obesity-linked insulin resistance. Endocrinology 146(3): 1473-1481.
23. Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, Davis JG, Salmon AB, Richardson A, Ahima RS, Guertin DA, Sabatini DM, Baur JA. (2012). Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335(6076): 1638-1643.
24. Laplante M, Sabatini DM. (2012). mTOR signaling in growth control and disease. Cell 149(2): 274-293.
25. Luo J, Sobkiw CL, Hirshman MF, Logsdon MN, Li TQ, Goodyear LJ, Cantley LC. (2006). Loss of class IA PI3K signaling in muscle leads to impaired muscle growth, insulin response, and hyperlipidemia. Cell Metab 3(5): 355-366.
26. Molife LR, Alam S, Olmos D, Puglisi M, Shah K, Fehrmann R, Trani L, Tjokrowidjaja A, de Bono JS, Banerji U, Kaye SB. (2012). Defining the risk of toxicity in phase I oncology trials of novel molecularly targeted agents: a single centre experience. Ann Oncol 23(8): 1968-1973.
27. Molife LR, Yan L, Vitfell-Rasmussen J, Zernhelt AM, Sullivan DM, Cassier PA, Chen E, Biondo A, Tetteh E, Siu LL, Patnaik A, Papadopoulos KP, de Bono JS, Tolcher AW, Minton S. (2014). Phase 1 trial of the oral AKT inhibitor MK-2206 plus carboplatin/paclitaxel, docetaxel, or erlotinib in patients with advanced solid tumors. J Hematol Oncol 7(1): 1.
28. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grunwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A. Group R-S. (2008). Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebocontrolled phase III trial. Lancet 372(9637): 449-456.
29. Roda D, Wong HH, Geuna E, Rafii S, Ruddle R, Hayes A, Swales KE, Stimpson SJ, Sathiyayogan N, Tinariu N, Turner AJ, Hall E, Yap TA, Banerjee SN, O'Brien M, Molife LR, Kaye SB, De Bono JS, Basu B, Banerji U. (2014). TAX-DORC: A phase I trial of the combination of AZD2014 (dual mTORC1/mTORC2 inhibitor) and weekly paclitaxel in patients with solid tumors. J Clin Oncol 32: 5s 2014 (suppl; abstr 2607
30. Rodon J, Brana I, Siu LL, De Jonge MJ, Homji N, Mills D, Di Tomaso E, Sarr C, Trandafir L, Massacesi C, Eskens F, Bendell JC. (2014). Phase I dose-escalation and-expansion study of buparlisib (BKM120), an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. Invest New Drugs 32(4): 670-681.
31. Saltiel AR, Kahn CR. (2001). Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414(6865): 799-806.
32. Schmelzle T, Hall MN. (2000). TOR, a central controller of cell growth. Cell 103(2): 253-262.
33. Shapiro GI, Rodon J, Bedell C, Kwak EL, Baselga J, Brana I, Pandya SS, Scheffold C, Laird AD, Nguyen LT, Xu Y, Egile C, Edelman G. (2014). Phase I safety, pharmacokinetic, and pharmacodynamic study of SAR245408 (XL147), an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. Clin Cancer Res 20(1): 233-245.
34. Sivendran S, Agarwal N, Gartrell B, Ying J, Boucher KM, Choueiri TK, Sonpavde G, Oh WK, Galsky MD. (2014). Metabolic complications with the use of mTOR inhibitors for cancer therapy. Cancer Treat Rev 40(1): 190-196.
35. Song MS, Salmena L, Pandolfi PP. (2012). The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol 13(5): 283-296.
36. Tabernero J, Cervantes A, Gordon M, Chiorean E, Burris H, Macarulla T, Perez-Fidalgo A, Martin M, Jessen K, Liu Y, Le T, Rommel C, Berk G, Bui L, Infante J. (2012). A phase I, open label, dose escalation study of oral mammalian target of rapamycin inhibitor INK128 administered by intermittent dosing regimens in patients with advanced malignancies. Cancer Res; epub ahead of print 15 April 2012; doi:101158/1538-7445AM2012-CT-0.
37. Um SH, Frigerio F, Watanabe M, Picard F, Joaquin M, Sticker M, Fumagalli S, Allegrini PR, Kozma SC, Auwerx J, Thomas G. (2004). Absence of S6K1 protects against age-And diet-induced obesity while enhancing insulin sensitivity. Nature 431(7005): 200-205.
38. Verges B, Walter T, Cariou B. (2014). Endocrine side effects of anti-cancer drugs: effects of anti-cancer targeted therapies on lipid and glucose metabolism. Eur J Endocrinol 170(2): R43-R55.
39. Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG, Tomassetti P, Pavel ME, Hoosen S, Haas T, Lincy J, Lebwohl D, Oberg K. Rad001 in Advanced Neuroendocrine Tumors TTSG. (2011). Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364(6): 514-523.
40. Yap TA, Yan L, Patnaik A, Fearen I, Olmos D, Papadopoulos K, Baird RD, Delgado L, Taylor A, Lupinacci L, Riisnaes R, Pope LL, Heaton SP, Thomas G, Garrett MD, Sullivan DM, de Bono JS, Tolcher AW. (2011). First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. J Clin Oncol 29(35): 4688-4695.