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Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
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BMC Medicine
Published in: BMC Medicine 1/2012

Open Access 01-12-2012 | Review

Clinical development of phosphatidylinositol 3-kinase inhibitors for cancer treatment

Authors: Irene Brana, Lillian L Siu

Published in: BMC Medicine | Issue 1/2012

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Abstract

The phosphatidylinositol 3-kinase (PI3K) pathway is commonly deregulated in cancer. In recent years, the results of the first phase I clinical trials with PI3K inhibitors have become available. In comparison to other targeted agents such v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors in melanoma or crizotinib in anaplastic lymphoma receptor tyrosine kinase (ALK) translocated tumors, the number of objective responses to PI3K inhibitors is less dramatic. In this review we propose possible strategies to optimize the clinical development of PI3K inhibitors: by exploring the potential role of PI3K isoform-specific inhibitors in improving the therapeutic index, molecular characterization as a basis for patient selection, and the relevance of performing serial tumor biopsies to understand the associated mechanisms of drug resistance. The main focus of this review will be on PI3K isoform-specific inhibitors by describing the functions of different PI3K isoforms, the preclinical activity of selective PI3K isoform-specific inhibitors and the early clinical data of these compounds.
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Literature
1.
Engelman JA: Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009, 9: 550-562. 10.1038/nrc2664.PubMed
2.
Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, Bilanges B: The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol. 2010, 11: 329-341. 10.1038/nrm2882.PubMed
3.
Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O'Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB: Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010, 363: 809-819. 10.1056/NEJMoa1002011.PubMedPubMedCentral
4.
Falchook GS, Long GV, Kurzrock R, Kim KB, Arkenau TH, Brown MP, Hamid O, Infante JR, Millward M, Pavlick AC, O'Day SJ, Blackman SC, Curtis CM, Lebowitz P, Ma B, Ouellet D, Kefford RF: Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet. 2012, 379: 1893-1901. 10.1016/S0140-6736(12)60398-5.PubMedPubMedCentral
5.
Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, Ou SH, Dezube BJ, Janne PA, Costa DB, Varella-Garcia M, Kim WH, Lynch TJ, Fidias P, Stubbs H, Engelman JA, Sequist LV, Tan W, Gandhi L, Mino-Kenudson M, Wei GC, Shreeve SM, Ratain MJ, Settleman J, Christensen JG, Haber DA, Wilner K, Salgia R, Shapiro GI, Clark JW, et al: Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010, 363: 1693-1703. 10.1056/NEJMoa1006448.PubMedPubMedCentral
6.
Edelman G, Bedell C, Shapiro G, Pandya SS, Kwak EL, Scheffold C, Nguyen LT, Laird A, Baselga J, Rodon J: A phase I dose-escalation study of XL147 (SAR245408), a PI3K inhibitor administered orally to patients (pts) with advanced malignancies [abstract]. ASCO Annual Meeting Proceedings: June 4-8 2010; Chicago, IL. 2010, Alexandria, VA: American Society of Clinical Oncology, Abstract 3004
7.
Bendell JC, Rodon J, Burris HA, De Jonge M, Verweij J, Birle D, Demanse D, De Buck SS, Ru QC, Peters M, Goldbrunner M, Baselga J: Phase I, dose-escalation study of BKM120, an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2012, 30: 282-290. 10.1200/JCO.2011.36.1360.PubMed
8.
Moreno Garcia V, 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: A phase I study evaluating GDC-0941, an oral phosphoinositide-3 kinase (PI3K) inhibitor, in patients with advanced solid tumors or multiple myeloma [abstract]. ASCO Annual Meeting Proceedings June 4-8 2011; Chicago, IL. 2011, Alexandria, VA: American Society of Clinical Oncology, Abstract 30211
9.
Von Hoff DD, LoRusso P, Demetri GD, Weiss GJ, Shapiro G, Ramanathan RK, Ware JA, Raja R, Jin J, Levy GG, Mazina KE, Wagner AJ: A phase I dose-escalation study to evaluate GDC-0941, a pan-PI3K inhibitor, administered QD or BID in patients with advanced or metastatic solid tumors [abstract]. ASCO Annual Meeting Proceedings: June 4-8 2011; Chicago, IL. 2011, Alexandria, VA: American Society of Clinical Oncology, Abstract 3052
10.
Patnaik A, Appleman LJ, Mountz JM, Ramanathan RK, Beeram M, Tolcher AW, Papadopoulos KP, Lotze MT, Petro DP, Laymon C, Paige L, Rajagopalan P, Jeffers M, Roth D, Dubowy RL: A first-in-human phase I study of intravenous PI3K inhibitor BAY 80-6946 in patients with advanced solid tumors: results of dose-escalation phase [abstract]. ASCO Annual Meeting Proceedings: June 4-8 2011; Chicago, IL. 2011, Alexandria, VA: American Society of Clinical Oncology, Abstract 3035
11.
Lotze MT, Appleman LJ, Ramanathan RK, Tolcher AW, Beeram M, Papadopoulos KP, Rasco DW, Weiss GJ, Mountz JM, Toledo FGS, Alvarez RJ, Oborski MJ, Rajagopalan P, Jeffers M, Roth D, Dubowy RL, Patnaik A: Phase I study of intravenous PI3K inhibitor BAY 80-6946: activity in patients (pts) with advanced solid tumors and non-Hodgkin lymphoma treated in MTD expansion cohorts [abstract]. ASCO Annual Meeting Proceedings: June 1-5 2012; Chicago, IL. 2012, Alexandria, VA: American Society of Clinical Oncology, Abstract 3019
12.
Omlin AG, Spicer JF, Sarker D, Pinato DJ, Agarwal R, Cassier PA, Stavraka C, Blanco M, Suder A, Allan S, Heaton S, Decordova S, Pope L, Prince J, Noguchi K, Jones K, Inatani M, Shiokawa R, Banerji U, Blagden SP: A pharmacokinetic (PK) pharmacodynamic (PD) driven first-in-human study of the oral class I PI3K inhibitor CH5132799, in patients with advanced solid tumors [abstract]. ASCO Annual Meeting Proceedings: June 1-5 2012; Chicago, IL. 2012, Alexandria, VA: American Society of Clinical Oncology, Abstract 3022
13.
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: A multicenter phase I trial of PX-866, an oral irreversible phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res. 2012, 18: 4173-4182. 10.1158/1078-0432.CCR-12-0714.PubMed
14.
Brana I, LoRusso P, Baselga J, Heath EI, Patnaik A, Gendreau S, Laird A, Papadopoulos K: A phase I dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics of XL765 (SAR245409), a PI3K/TORC1/TORC2 inhibitor administered orally to patients (pts) with advanced malignancies [abstract]. ASCO Annual Meeting Proceedings: June 4-8 2010; Chicago, IL. 2010, Alexandria, VA: American Society of Clinical Oncology, Abstract 3030
15.
Papadopoulos KP, Abrisqueta P, Chambers G, Rasco D, Patnaik A, Tabernero J, Rajangam K, Rockich K, Egile C, Kelly A, Xu Y, Lager J, Vose JM: A phase I dose expansion cohort study of the safety, pharmacokinetics and pharmacodynamics of SAR245409 (S09), an orally administered PI3K/mTOR inhibitor, in patients with lymphoma [abstract]. ASH Annual Meeting Abstracts: November 18 2011; San Diego, CA. 2011, Washington, DC: The American Society of Hematology, Abstract 1608
16.
Burris H, Rodon J, Sharma S, Herbst RS, Tabernero J, Infante JR, Silva A, Demanse D, Hackl W, Baselga J: First-in-human phase I study of the oral PI3K inhibitor BEZ235 in patients (pts) with advanced solid tumors [abstract]. ASCO Annual Meeting Proceedings: June 4-8 2010; Chicago, IL. 2010, Alexandria, VA: American Society of Clinical Oncology, Abstract 3005
17.
Arkenau H-T, Jones SF, Kurkjian C, Infante JR, Pant S, Burris HA, Moore KN, McMeekin DS, Greco FA, Ramsey S, Bendell JC: The PI3K/mTOR inhibitor BEZ235 given twice daily for the treatment of patients (pts) with advanced solid tumors [abstract]. ASCO Annual Meeting Proceedings: June 1-5 2012; Chicago, IL. 2012, A Alexandria, VA: American Society of Clinical Oncology, Abstract 3097
18.
Munster PN, van der Noll R, Voest EE, Dees EC, Tan AR, Specht JM, Falchook GS, Daud A, Lolkema MP, Grilley-Olson JE, Yu EY, Fu S, Bergsland EK, Kleha J, Peng S, Smith DA, Lampkin TA, Schellens JHM, Morris SR, Kurzrock R: Phase I first-in-human study of the PI3 kinase inhibitor GSK2126458 (GSK458) in patients with advanced solid tumors (study P3K112826) [abstract]. ASCO Annual Meeting Proceedings: June 3-7 2011; Chicago, IL. 2011, Alexandria, VA: American Society of Clinical Oncology, Abstract 3018
19.
Wagner AJ, Bendell JC, Dolly S, Morgan JA, Ware JA, Fredrickson J, Mazina KE, Lauchle JO, Burris HA, De Bono JS: A first-in-human phase I study to evaluate GDC-0980, an oral PI3K/mTOR inhibitor, administered QD in patients with advanced solid tumors [abstract]. ASCO Annual Meeting Proceedings: June 3-7 2011; Chicago, IL. 2011, Alexandria, VA: American Society of Clinical Oncology, Abstract 3020
20.
Hollebecque A, Clamp A, Horsley L, Morgan JA, Bahleda R, George S, Shaw D, Lauchle JO, Ware J, Desai R, Wu J, Fu L, Jayson GC, Soria JC, Wagner AJ: A phase I study evaluating the pharmacokinetics (PK) and pharmacodynamic (PD) activity of the dual PI3K/mTOR inhibitor GDC-0980 administered once weekly (QW) [abstract]. AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics: November 12-16 2011; San Francisco, CA. 2011, Philadelphia, PA: American Association for Cancer Research, Abstract B153
21.
Mahadevan D, Chiorean EG, Harris W, Von Hoff DD, Younger A, Rensvold DM, Cordova F, Qi W, Shelton CF, Becker MD, Garlich JR, Ramanathan RK: Phase I study of the multikinase prodrug SF1126 in solid tumors and B-cell malignancies [abstract]. ASCO Annual Meeting Proceedings: June 3-7 2011; Chicago, IL. 2011, Alexandria, VA: American Society of Clinical Oncology, Abstract 3015
22.
LoRusso P, Britten C, Millham R, Borzillo G, Houk B, Wainberg Z, Marburg L, Dy G, Adjei A: First-in-patient study of PF-04691502, a small molecule intravenous dual inhibitor of PI3K and mTOR in patients with advanced cancer: update on safety, efficacy, and pharmacology [abstract]. AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics: November 12 2011; San Francisco, CA. 2011, Philadelphia, PA: American Association for Cancer Research, Abstract B163
23.
Tabernero J, Bell-McGuinn K, Bendell J, Molina J, Kwak E, Millham R, Houk B, Borzillo G, Shapiro G: First-in-patient study of PF-05212384, a small molecule intravenous dual inhibitor of PI3K and mTOR in patients with advanced cancer: update on safety, efficacy, and pharmacology [abstract]. AACR-NCI-EORTC International Conference: Molecular Cancer Therapy: November 12-16 2011; San Francisco, CA. 2011, Philadelphia, PA: American Association for Cancer Research, Abstract A167
24.
Markman B, Tabernero J, Krop I, Shapiro GI, Siu L, Chen LC, Mita M, Melendez Cuero M, Stutvoet S, Birle D, Anak O, Hackl W, Baselga J: Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors. Ann Oncol. 2012, 23: 2399-2408. 10.1093/annonc/mds011.PubMed
25.
Juric D, Rodon J, Gonzalez-Angulo AM, Burris HA, Bendell J, Berlin JD, Middleton MR, Bootle D, Boehm M, Schmitt A, Rouyrre N, Quadt C, Baselga J: BYL719, a next generation PI3K alpha specific inhibitor: Preliminary safety, PK, and efficacy results from the first-in-human study [abstract]. Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research: March 31-April 4 2012; Chicago, IL. 2012, Philadelphia, PA: American Association for Cancer Research, Abstract CT-01
26.
Coutre SE, Byrd JC, Furman RR, Brown JR, Benson DM, Wagner-Johnston ND, Flinn IW, Kahl BS, Spurgeon SEF, Lannutti BJ, Hsu HKW, Ulrich R, Peterman S, Holes L, Miller LL, Yu AS: Phase I study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-kinase P110d, in patients with previously treated chronic lymphocytic leukemia [abstract]. ASCO Annual Meeting Proceedings: June 3-7 2011; Chicago, IL. 2011, Alexandria, VA: American Society of Clinical Oncology, Abstract 6631
27.
Kahl B, Byrd JC, Flinn IW, Wagner-Johnston N, Spurgeon S, Benson DM, Furman RR, Brown JR, Coutre S, Lannutti B, Giese NA, Ulrich RG, Webb HK, Peterman S, Holes L, Yu AS: Clinical safety and activity in a phase 1 study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-kinase P110{delta}, in patients with relapsed or refractory non-Hodgkin lymphoma [abstract]. ASH Annual Meeting Abstracts: December 4-7 2010; Orlando, FL. 2010, Washington, DC: The American Society of Hematology, Abstract 1777
28.
Chantry D, Vojtek A, Kashishian A, Holtzman DA, Wood C, Gray PW, Cooper JA, Hoekstra MF: p110δ, a novel phosphatidylinositol 3-kinase catalytic subunit that associates with p85 and is expressed predominantly in leukocytes. J Biol Chem. 1997, 272: 19236-19241. 10.1074/jbc.272.31.19236.PubMed
29.
Vanhaesebroeck B, Welham MJ, Kotani K, Stein R, Warne PH, Zvelebil MJ, Higashi K, Volinia S, Downward J, Waterfield MD: p110δ, A novel phosphoinositide 3-kinase in leukocytes. Proc Natl Acad Sci USA. 1997, 94: 4330-4335. 10.1073/pnas.94.9.4330.PubMedPubMedCentral
30.
Falasca M, Hughes WE, Dominguez V, Sala G, Fostira F, Fang MQ, Cazzolli R, Shepherd PR, James DE, Maffucci T: The role of phosphoinositide 3-kinase C2α in insulin signaling. J Biol Chem. 2007, 282: 28226-28236. 10.1074/jbc.M704357200.PubMed
31.
Sopasakis VR, Liu P, Suzuki R, Kondo T, Winnay J, Tran TT, Asano T, Smyth G, Sajan MP, Farese RV, Kahn CR, Zhao JJ: Specific roles of the p110alpha isoform of phosphatidylinsositol 3-kinase in hepatic insulin signaling and metabolic regulation. Cell Metabol. 2010, 11: 220-230. 10.1016/j.cmet.2010.02.002.
32.
Zhao JJ, Cheng H, Jia S, Wang L, Gjoerup OV, Mikaini A, Roberts TM: The p110α isoform of PI3K is essential for proper growth factor signaling and oncogenic transformation. Proc Natl Acad Sci USA. 2006, 103: 16296-16300. 10.1073/pnas.0607899103.PubMedPubMedCentral
33.
Knight ZA, Gonzalez B, Feldman ME, Zunder ER, Goldenberg DD, Williams O, Loewith R, Stokoe D, Balla A, Toth B, Balla T, Weiss WA, Williams RL, Shokat KM: A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell. 2006, 125: 733-747. 10.1016/j.cell.2006.03.035.PubMedPubMedCentral
34.
Zhao L, Vogt PK: Class I PI3K in oncogenic cellular transformation. Oncogene. 2008, 27: 5486-5496. 10.1038/onc.2008.244.PubMedPubMedCentral
35.
Ikenoue T, Kanai F, Hikiba Y, Obata T, Tanaka Y, Imamura J, Ohta M, Jazag A, Guleng B, Tateishi K, Asaoka Y, Matsumura M, Kawabe T, Omata M: Functional analysis of PIK3CA gene mutations in human colorectal cancer. Cancer Res. 2005, 65: 4562-4567. 10.1158/0008-5472.CAN-04-4114.PubMed
36.
Isakoff SJ, Engelman JA, Irie HY, Luo J, Brachmann SM, Pearline RV, Cantley LC, Brugge JS: Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. Cancer Res. 2005, 65: 10992-11000. 10.1158/0008-5472.CAN-05-2612.PubMed
37.
Zhao JJ, Liu Z, Wang L, Shin E, Loda MF, Roberts TM: The oncogenic properties of mutant p110alpha and p110beta phosphatidylinositol 3-kinases in human mammary epithelial cells. Proc Natl Acad Sci USA. 2005, 102: 18443-18448. 10.1073/pnas.0508988102.PubMedPubMedCentral
38.
Niedermeier M, Hennessy BT, Knight ZA, Henneberg M, Hu J, Kurtova AV, Wierda WG, Keating MJ, Shokat KM, Burger JA: Isoform-selective phosphoinositide 3'-kinase inhibitors inhibit CXCR4 signaling and overcome stromal cell-mediated drug resistance in chronic lymphocytic leukemia: a novel therapeutic approach. Blood. 2009, 113: 5549-5557. 10.1182/blood-2008-06-165068.PubMedPubMedCentral
39.
Jamieson S, Flanagan JU, Kolekar S, Buchanan C, Kendall JD, Lee WJ, Rewcastle GW, Denny WA, Singh R, Dickson J, Baguley BC, Shepherd PR: A drug targeting only p110alpha can block phosphoinositide 3-kinase signalling and tumour growth in certain cell types. Biochem J. 2011, 438: 53-62. 10.1042/BJ20110502.PubMedPubMedCentral
40.
Dan S, Okamura M, Seki M, Yamazaki K, Sugita H, Okui M, Mukai Y, Nishimura H, Asaka R, Nomura K, Ishikawa Y, Yamori T: Correlating phosphatidylinositol 3-kinase inhibitor efficacy with signaling pathway status: in silico and biological evaluations. Cancer Res. 2010, 70: 4982-4994. 10.1158/0008-5472.CAN-09-4172.PubMed
41.
Torbett NE, Luna-Moran A, Knight ZA, Houk A, Moasser M, Weiss W, Shokat KM, Stokoe D: A chemical screen in diverse breast cancer cell lines reveals genetic enhancers and suppressors of sensitivity to PI3K isoform-selective inhibition. Biochem J. 2008, 415: 97-110. 10.1042/BJ20080639.PubMedPubMedCentral
42.
Huang A, Fritsch C, Wilson C, Reddy A, Liu M, Lehar J, Quadt C, Hofmann F, Schlegel R: Single agent activity of PIK3CA inhibitor BYL719 in a broad cancer cell line panel [abstract]. Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research: March 31-April 4 2012; Chicago, IL. 2012, Philadelphia, PA: American Association for Cancer Research, Abstract 3749
43.
Jessen K, Kessler L, Kucharski J, Guo X, Staunton J, Janes M, Elia M, Banerjee U, Lan L, Wang S, Stewart J, Luzader A, Darjania L, Li L, Chan K, Martin M, Ren P, Rommel C, Liu Y: A potent and selective PI3K inhibitor, INK1117, targets human cancers harboring oncogenic PIK3CA mutations [abstract]. AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics: November 12-16 2011; San Francisco, CA. 2011, Philadelphia, PA: American Association for Cancer Research, Abstract A171
44.
Herman SEM, Gordon AL, Wagner AJ, Heerema NA, Zhao W, Flynn JM, Jones J, Andritsos L, Puri KD, Lannutti BJ, Giese NA, Zhang X, Wei L, Byrd JC, Johnson AJ: Phosphatidylinositol 3-kinase- inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood. 2010, 116: 2078-2088. 10.1182/blood-2010-02-271171.PubMedPubMedCentral
45.
Ikeda H, Hideshima T, Fulciniti M, Perrone G, Miura N, Yasui H, Okawa Y, Kiziltepe T, Santo L, Vallet S, Cristea D, Calabrese E, Gorgun G, Raje NS, Richardson P, Munshi NC, Lannutti BJ, Puri KD, Giese NA, Anderson KC: PI3K/p110 is a novel therapeutic target in multiple myeloma. Blood. 2010, 116: 1460-1468. 10.1182/blood-2009-06-222943.PubMedPubMedCentral
46.
Lannutti BJ, Meadows SA, Herman SEM, Kashishian A, Steiner B, Johnson AJ, Byrd JC, Tyner JW, Loriaux MM, Deininger M, Druker BJ, Puri KD, Ulrich RG, Giese NA: CAL-101, a p110δ selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood. 2011, 117: 591-594. 10.1182/blood-2010-03-275305.PubMedPubMedCentral
47.
Meadows SA, Kashishian A, Johnson D, Ulrich RG, Miller LL, Lannutti BJ: CAL-101 (GS-1101), a specific inhibitor of phosphatidylinositol-3-kinase-delta (PI3K{delta}), disrupts signals from the microenvironment, induces apoptosis, and enhances the antitumor activity of everolimus (RAD001), an inhibitor of mammalian target of rapamycin (mTOR), in mantle cell lymphoma (MCL) [abstract]. ASH Annual Meeting Abstracts: December 10-13 2011; San Diego, CA. 2011, Washington, DC: The American Society of Hematology, Abstract 3730
48.
Iyengar S, Clear AJ, Owen A, Maharaj L, Matthews J, Calaminici M, Auer R, Ghazaly E, Iqbal S, Gribben JG, Joel S: PI3K inhibition with GDC-0941 has greater efficacy compared to p110{delta}-selective inhibition with CAL-101 in mantle cell lymphoma and may be particularly advantageous in multiply relapsed patients [abstract]. ASH Annual Meeting Abstracts: December 10-13 2011; San Diego, CA. 2011, Washington, DC: The American Society of Hematology, Abstract 1654
49.
Meadows SA, Kashishian A, Johnson D: CAL-101 a potent selective inhibitor of the p110{delta} Isoform of phosphatidylinositol 3-kinase attenuates pathway signaling induces apoptosis and overcomes signals from the microenvironment in cellular models of Hodgkin lymphoma [abstract]. ASH Annual Meeting Abstracts: December 4-7 2010; Orlando, FL. 2010, Washington, DC: The American Society of Hematology, Abstract 3926
50.
Hoellenriegel J, Meadows SA, Sivina M, Wierda WG, Kantarjian H, Keating MJ, Giese N, O'Brien S, Yu A, Miller LL, Lannutti BJ, Burger JA: The phosphoinositide 3'-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood. 2011, 118: 3603-3612. 10.1182/blood-2011-05-352492.PubMedPubMedCentral
51.
Davids MS, Lannutti BJ, Brown JR, Letai AG: BH3 profiling demonstrates that CAL-101 restores apoptotic priming in stroma-exposed chronic lymphocytic leukemia cells [abstract]. XIV International Workshop on Chronic Lymphocytic Leukemia; October 28-30 2011; Houston, TX. 2011, Clinical Lymphoma, Myeloma and Leukemia, S174-S175. Abstract 172.125
52.
Sinclair A, Metz D, Cushing T, Liu L, Brake R, Starnes C, Means G, Henne K, Archibeque I, Mattson B, Drew A, Busse L, Wang L, Al-Assaad A-S, Molineux G: Phosphatidylinositol-3 kinase delta (PI3K{delta}) inhibitor AMG 319 is a potent, selective and orally bioavailable small molecule inhibitor that suppresses PI3K-mediated signaling and viability in neoplastic B cells [abstract]. ASH Annual Meeting Abstracts: December 10-13 2011; San Diego, CA. 2011, Washington, DC: The American Society of Hematology, Abstract 4964
53.
Liu L, Sun B-C, Pistillo J, Payton M, Wang L, Archibeque I, Molineux G, Sinclair A: Phosphatidylinsoitol-3 kinase delta (PI3K{delta}) inhibitor AMG 319 combined with vincristine enhances G2/M arrest and apoptotic death in neoplastic B cells [abstract]. ASH Annual Meeting Abstracts: December 10-13 2011; San Diego, CA. 2011, Washington, DC: The American Society of Hematology, Abstract 4963
54.
Flinn IW, Byrd JC, Furman RR, Brown JR, Benson DM, Coutre SE, Kahl BS, Smith BD, Wagner-Johnston ND, Spurgeon SE, Giese NA, Yu AS: Evidence of clinical activity in a phase 1 study of CAL-101, an oral P110{Delta} isoform-selective inhibitor of phosphatidylinositol 3-kinase, in patients with relapsed or refractory B-cell malignancies [abstract]. ASH Annual Meeting Abstracts: December 5-8 2009; New Orleans, LA. 2009, Washington, DC: The American Society of Hematology, Abstract 922
55.
Flinn IW, Byrd JC, Furman RR, Brown JR, Lin TS, Bello C, Giese NA, Yu AS: Preliminary evidence of clinical activity in a phase I study of CAL-101, a selective inhibitor of the p1108 isoform of phosphatidylinositol 3-kinase (P13K), in patients with select hematologic malignancies [abstract]. ASCO Annual Meeting Proceedings: May 29-June 2 2009; Orlando, FL. 2009, Alexandria, VA: American Society of Clinical Oncology, Abstract 3543
56.
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, Hillmen P, Keating MJ, Montserrat E, Rai KR, Kipps TJ: Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008, 111: 5446-5456. 10.1182/blood-2007-06-093906.PubMedPubMedCentral
57.
Sharman J, de Vos S, Leonard JP, Furman RR, Coutre SE, Flinn IW, Schreeder MT, Barrientos JC, Wagner-Johnston ND, Boyd T, Fowler NH, Holes L, Lannutti B, Johnson D, Jahn TM, Miller LL: A phase 1 study of the selective phosphatidylinositol 3-kinase-delta (PI3K{delta}) inhibitor, CAL-101 (GS-1101), in combination with rituximab and/or bendamustine in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) [abstract]. ASH Annual Meeting Abstracts: December 10-13 2011; San Diego, CA. 2011, Washington, DC: The American Society of Hematology, Abstract 1787
58.
de Vos S, Schreeder MT, Flinn IW, Coutre SE, Leonard JP, Wagner-Johnston ND, Fowler NH, Boccia RV, Barrientos JC, Boyd T, Sharman J, Holes L, Lannutti B, Johnson DM, Jahn TM, Miller LL: A phase 1 study of the selective phosphatidylinositol 3-kinase-delta (PI3K{delta}) inhibitor, Cal-101 (GS-1101), in combination with rituximab and/or bendamustine in patients with previously treated, indolent non-Hodgkin lymphoma (iNHL) [abstract]. ASH Annual Meeting Abstracts: December 10-13 2011; San Diego, CA. 2011, Washington, DC: The American Society of Hematology, Abstract 2699
59.
Furman RR, Barrientos JC, Sharman JP, De Vos S, Leonard J, Coutre SE, Schreeder MT, Wagner-Johnston ND, Boyd TE, Fowler NH, Flinn IW, Boccia RV, Holes L, Lannutti BJ, Johnson D, Jahn TM, Miller LL: A phase I/II study of the selective phosphatidylinositol 3-kinase-delta (PI3K{delta}) inhibitor, GS-1101 (CAL-101), with ofatumumab in patients with previously treated chronic lymphocytic leukemia (CLL) [abstract]. ASCO Annual Meeting Proceedings: June 1-5 2012; Chicago, IL. 2012, Alexandria, VA: American Society of Clinical Oncology, Abstract 6518
60.
García-Martínez JM, Wullschleger S, Preston G, Guichard S, Fleming S, Alessi DR, Duce SL: Effect of PI3K- and mTOR-specific inhibitors on spontaneous B-cell follicular lymphomas in PTEN/LKB1-deficient mice. Br J Cancer. 2011, 104: 1116-1125. 10.1038/bjc.2011.83.PubMedPubMedCentral
61.
Amrein L, Shawi M, Panasci L: Phosphatidylinositol-3 kinase I inhibitor BKM120 induces cell death in B-chronic lymphocytic leukemia cells in-vitro [abstract]. European Multidisciplinary Cancer Congress: September 23-27 2011; Brussels. 2011, Eur J Cancer, S649-S650. Abstract 9236
62.
Garlich J, Qi W, Becker M, Stejskal A, Mahadevan D: Translational studies of the novel prodrug PI3K/mTOR/PIM1 inhibitor SF1126 in DLBCL [abstract]. Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research: April 2-6 2011; Orlando, FL. 2011, Philadelphia, PA: American Association for Cancer Research, Abstract nr LB-383
63.
Mahadevan D, Qi W, Stejskal A, Cooke L, Garlich JR: SF1126, a pan-PI3K inhibitor has superior preclinical activity to CAL-101 a PI3K delta-specific inhibitor in aggressive B-cell non-Hodgkin's lymphoma [abstract]. ASH Annual Meeting Abstracts: December 10-13 2011; San Diego, CA. 2011, Washington, DC: The American Society of Hematology, Abstract 2720
64.
Brown JR, Davids MS, Rodon J, Abrisqueta P, DeCillis AP, Rockich K, Egile C, Kelly A, Xu Y, Lager J, Awan FT: Phase I trial of SAR245408 (S08), a pan-phosphatidylinositol 3 kinase (PI3K) inhibitor, in patients with chronic lymphocytic leukemia (CLL) and lymphoma [abstract]. ASH Annual Meeting Abstracts: December 10-13 2011; San Diego, CA. 2011, Washington, DC: The American Society of Hematology, Abstract 2683
65.
Jia S, Liu Z, Zhang S, Liu P, Zhang L, Lee SH, Zhang J, Signoretti S, Loda M, Roberts TM, Zhao JJ: Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis. Nature. 2008, 454: 776-779.PubMedPubMedCentral
66.
Guillermet-Guibert J, Bjorklof K, Salpekar A, Gonella C, Ramadani F, Bilancio A, Meek S, Smith AJH, Okkenhaug K, Vanhaesebroeck B: The p110β isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110γ. Proc Natl Acad Sci USA. 2008, 105: 8292-8297. 10.1073/pnas.0707761105.PubMedPubMedCentral
67.
Hazeki O, Okada T, Kurosu H, Takasuga S, Suzuki T, Katada T: Activation of PI 3-kinase by G protein betagamma subunits. Life Sci. 1998, 62: 1555-1559. 10.1016/S0024-3205(98)00106-4.PubMed
68.
Kubo H, Hazeki K, Takasuga S, Hazeki O: Specific role for p85/p110β in GTP-binding-protein-mediated activation of Akt. Biochem J. 2005, 392: 607-614. 10.1042/BJ20050671.PubMedPubMedCentral
69.
Roche S, Downward J, Raynal P, Courtneidge SA: A function for phosphatidylinositol 3-kinase beta (p85alpha-p110beta) in fibroblasts during mitogenesis: requirement for insulin- and lysophosphatidic acid-mediated signal transduction. Mol Cell Biol. 1998, 18: 7119-7129.PubMedPubMedCentral
70.
Yart A, Roche S, Wetzker R, Laffargue M, Tonks N, Mayeux P, Chap H, Raynal P: A function for phosphoinositide 3-kinase beta lipid products in coupling beta gamma to Ras activation in response to lysophosphatidic acid. J Biol Chem. 2002, 277: 21167-21178. 10.1074/jbc.M110411200.PubMed
71.
Edgar KA, Wallin JJ, Berry M, Lee LB, Prior WW, Sampath D, Friedman LS, Belvin M: Isoform-specific phosphoinositide 3-kinase inhibitors exert distinct effects in solid tumors. Cancer Res. 2010, 70: 1164-1172. 10.1158/0008-5472.CAN-09-2525.PubMed
72.
Crowder RJ, Phommaly C, Tao Y, Hoog J, Luo J, Perou CM, Parker JS, Miller MA, Huntsman DG, Lin L, Snider J, Davies SR, Olson JA, Watson MA, Saporita A, Weber JD, Ellis MJ: PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer. Cancer Res. 2009, 69: 3955-3962. 10.1158/0008-5472.CAN-08-4450.PubMedPubMedCentral
73.
Wu X, Senechal K, Neshat MS, Whang YE, Sawyers CL: The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway. Proc Natl Acad Sci USA. 1998, 95: 15587-15591. 10.1073/pnas.95.26.15587.PubMedPubMedCentral
74.
Hollander MC, Blumenthal GM, Dennis PA: PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nat Rev Cancer. 2011, 11: 289-301. 10.1038/nrc3037.PubMed
75.
Alvarez-Nuñez F, Bussaglia E, Mauricio D, Ybarra J, Vilar M, Lerma E, De Leiva A, Matias-Guiu X: PTEN promoter methylation in sporadic thyroid carcinomas. Thyroid. 2006, 16: 17-23. 10.1089/thy.2006.16.17.PubMed
76.
García JM, Silva J, Peña C, Garcia V, Rodriguez R, Cruz MA, Cantos B, Provencio M, España P, Bonilla F: Promoter methylation of the PTEN gene is a common molecular change in breast cancer. Genes Chromosomes Cancer. 2004, 41: 117-124. 10.1002/gcc.20062.PubMed
77.
Ho CM, Lin MC, Huang SH, Huang CJ, Lai HC, Chien TY, Chang SF: PTEN promoter methylation and LOH of 10q22-23 locus in PTEN expression of ovarian clear cell adenocarcinomas. Gynecol Oncol. 2009, 112: 307-313. 10.1016/j.ygyno.2008.09.040.PubMed
78.
Kang YH, Lee HS, Kim WH: Promoter methylation and silencing of PTEN in gastric carcinoma. Lab Invest. 2002, 82: 285-291. 10.1038/labinvest.3780422.PubMed
79.
Soria JC, Lee HY, Lee JI, Wang L, Issa JP, Kemp BL, Liu DD, Kurie JM, Mao L, Khuri FR: Lack of PTEN expression in non-small cell lung cancer could be related to promoter methylation. Clin Cancer Res. 2002, 8: 1178-1184.PubMed
80.
Huse JT, Brennan C, Hambardzumyan D, Wee B, Pena J, Rouhanifard SH, Sohn-Lee C, Le Sage C, Agami R, Tuschl T, Holland EC: The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivo. Genes Dev. 2009, 23: 1327-1337. 10.1101/gad.1777409.PubMedPubMedCentral
81.
Zhang JG, Wang JJ, Zhao F, Liu Q, Jiang K, Yang GH: MicroRNA-21 (miR-21) represses tumor suppressor PTEN and promotes growth and invasion in non-small cell lung cancer (NSCLC). Clin Chim Acta. 2010, 411: 846-852. 10.1016/j.cca.2010.02.074.PubMed
82.
Poliseno L, Salmena L, Riccardi L, Fornari A, Song MS, Hobbs RM, Sportoletti P, Varmeh S, Egia A, Fedele G, Rameh L, Loda M, Pandolfi PP: Identification of the miR-106b~25 microRNA cluster as a proto-oncogenic PTEN-targeting intron that cooperates with its host gene MCM7 in transformation. Sci Signal. 2010, 3: ra29-10.1126/scisignal.2000594.PubMedPubMedCentral
83.
Wang X, Jiang X: Post-translational regulation of PTEN. Oncogene. 2008, 27: 5454-5463. 10.1038/onc.2008.242.PubMed
84.
Trotman LC, Wang X, Alimonti A, Chen Z, Teruya-Feldstein J, Yang H, Pavletich NP, Carver BS, Cordon-Cardo C, Erdjument-Bromage H, Tempst P, Chi SG, Kim HJ, Misteli T, Jiang X, Pandolfi PP: Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell. 2007, 128: 141-156. 10.1016/j.cell.2006.11.040.PubMedPubMedCentral
85.
Wee S, Wiederschain D, Maira S-M, Loo A, Miller C, deBeaumont R, Stegmeier F, Yao Y-M, Lengauer C: PTEN-deficient cancers depend on PIK3CB. Proc Natl Acad Sci USA. 2008, 105: 13057-13062. 10.1073/pnas.0802655105.PubMedPubMedCentral
86.
Rivero RA, Hardwicke MA: Identification of GSK2636771, a potent and selective, orally bioavailable inhibitor of phosphatidylinositol 3-kinase-beta (PI3K{alpha}) for the treatment of PTEN deficient tumors [abstract]. Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research: March 31-April 4 2012; Chicago, IL. 2012, Philadelphia, PA: American Association for Cancer Research, Abstract 2913
87.
Ni J, Liu Q, Xie S, Carlson C, Von T, Vogel K, Riddle S, Benes C, Eck M, Roberts T, Gray N, Zhao J: Functional characterization of an isoform-selective inhibitor of PI3K-p110β as a potential anticancer agent. Cancer Discov. 2012, 2: 425-433. 10.1158/2159-8290.CD-12-0003.PubMedPubMedCentral
88.
Certal V, Halley F, Virone-Oddos A, Delorme C, Karlsson A, Rak A, Thompson F, Filoche-Romme B, El-Ahmad Y, Carry JC, Abecassis PY, Lejeune P, Vincent L, Bonnevaux H, Nicolas JP, Bertrand T, Marquette JP, Michot N, Benard T, Below P, Vade I, Chatreaux F, Lebourg G, Pilorge F, Angouillant-Boniface O, Louboutin A, Lengauer C, Schio L: Discovery and optimization of new benzimidazole- and benzoxazole-pyrimidone selective PI3Kbeta inhibitors for the treatment of phosphatase and TENsin homologue (PTEN)-deficient cancers. J Med Chem. 2012, 55: 4788-4805. 10.1021/jm300241b.PubMed
89.
Tanaka H, Yoshida M, Tanimura H, Fujii T, Sakata K, Tachibana Y, Ohwada J, Ebiike H, Kuramoto S, Morita K, Yoshimura Y, Yamazaki T, Ishii N, Kondoh O, Aoki Y: The selective class I PI3K inhibitor CH5132799 targets human cancers harboring oncogenic PIK3CA mutations. Clin Cancer Res. 2011, 17: 3272-3281. 10.1158/1078-0432.CCR-10-2882.PubMed
90.
Ihle NT, Lemos R, Wipf P, Yacoub A, Mitchell C, Siwak D, Mills GB, Dent P, Kirkpatrick DL, Powis G: Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic ras is a dominant predictor for resistance. Cancer Res. 2009, 69: 143-150. 10.1158/0008-5472.CAN-07-6656.PubMedPubMedCentral
91.
Serra V, Markman B, Scaltriti M, Eichhorn PJ, Valero V, Guzman M, Botero ML, Llonch E, Atzori F, Di Cosimo S, Maira M, Garcia-Echeverria C, Parra JL, Arribas J, Baselga J: NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res. 2008, 68: 8022-8030. 10.1158/0008-5472.CAN-08-1385.PubMed
92.
Shoji K, Oda K, Kashiyama T, Ikeda Y, Nakagawa S, Sone K, Miyamoto Y, Hiraike H, Tanikawa M, Miyasaka A, Koso T, Matsumoto Y, Wada-Hiraike O, Kawana K, Kuramoto H, McCormick F, Aburatani H, Yano T, Kozuma S, Taketani Y: Genotype-dependent efficacy of a dual PI3K/mTOR inhibitor, NVP-BEZ235, and an mTOR inhibitor, RAD001, in endometrial carcinomas. PLoS ONE. 2012, 7: e37431-10.1371/journal.pone.0037431.PubMedPubMedCentral
93.
Koul D, Fu J, Shen R, LaFortune TA, Wang S, Tiao N, Kim Y-W, Liu J-L, Ramnarian D, Yuan Y, Garcia-Echevrria C, Maira S-M, Yung WKA: Antitumor activity of NVP-BKM120 - a selective pan class I PI3 kinase inhibitor showed differential forms of cell death based on p53 status of glioma cells. Clin Cancer Res. 2012, 18: 184-195. 10.1158/1078-0432.CCR-11-1558.PubMed
94.
Janku F, Tsimberidou AM, Garrido-Laguna I, Wang X, Luthra R, Hong DS, Naing A, Falchook GS, Moroney JW, Piha-Paul SA, Wheler JJ, Moulder SL, Fu S, Kurzrock R: PIK3CA mutations in patients with advanced cancers treated with PI3K/AKT/mTOR axis inhibitors. Mol Cancer Ther. 2011, 10: 558-565. 10.1158/1535-7163.MCT-10-0994.PubMedPubMedCentral
95.
Janku F, Wheler JJ, Westin SN, Moulder SL, Naing A, Tsimberidou AM, Fu S, Falchook GS, Hong DS, Garrido-Laguna I, Luthra R, Lee JJ, Lu KH, Kurzrock R: PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. J Clin Oncol. 2012, 30: 777-782. 10.1200/JCO.2011.36.1196.PubMedPubMedCentral
96.
Rodon J, Saura C, Dienstmann R, Vivancos A, Cajal SR, Baselga J, Tabernero J: Molecular prescreening to select patient population in early clinical trials. Nat Rev Clin Oncol. 2012, 9: 359-366. 10.1038/nrclinonc.2012.48.PubMed
97.
Tsimberidou AM, Iskander NG, Hong DS, Wheler JJ, Fu S, Piha-Paul SA, Naing A, Falchook GS, Janku F, Luthra R, Wen S, Kurzrock R: Personalized medicine in a phase I clinical trials program: The M. D. Anderson Cancer Center Initiative [abstract]. ASCO Annual Meeting Proceedings: June 3-7 2011; Chicago, IL. 2011, Alexandria, VA: American Society of Clinical Oncology, Abstract CRA2500
98.
Krop IE, Saura C, Rodon Ahnert J, Becerra C, Britten CD, Isakoff SJ, Demanse D, Hackl W, Quadt C, Silva AP, Burris HA, Abu-Khalaf MM, Baselga J: A phase I/IB dose-escalation study of BEZ235 in combination with trastuzumab in patients with PI3-kinase or PTEN altered HER2+ metastatic breast cancer [abstract]. ASCO Annual Meeting Proceedings: June 1-5, 2012; Chicago, IL. 2012, Alexandria, VA: American Society of Clinical Oncology, Abstract 508
99.
Liu P, Cheng H, Santiago S, Raeder M, Zhang F, Isabella A, Yang J, Semaan DJ, Chen C, Fox EA, Gray NS, Monahan J, Schlegel R, Beroukhim R, Mills GB, Zhao JJ: Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway-dependent and PI3K pathway-independent mechanisms. Nat Med. 2011, 17: 1116-1121. 10.1038/nm.2402.PubMedPubMedCentral
100.
Eichhorn PJ, Gili M, Scaltriti M, Serra V, Guzman M, Nijkamp W, Beijersbergen RL, Valero V, Seoane J, Bernards R, Baselga J: Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res. 2008, 68: 9221-9230. 10.1158/0008-5472.CAN-08-1740.PubMedPubMedCentral
101.
Serra V, Scaltriti M, Prudkin L, Eichhorn PJ, Ibrahim YH, Chandarlapaty S, Markman B, Rodriguez O, Guzman M, Rodriguez S, Gili M, Russillo M, Parra JL, Singh S, Arribas J, Rosen N, Baselga J: PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer. Oncogene. 2011, 30: 2547-2557. 10.1038/onc.2010.626.PubMedPubMedCentral
102.
Inukai K, Funaki M, Anai M, Ogihara T, Katagiri H, Fukushima Y, Sakoda H, Onishi Y, Ono H, Fujishiro M, Abe M, Oka Y, Kikuchi M, Asano T: Five isoforms of the phosphatidylinositol 3-kinase regulatory subunit exhibit different associations with receptor tyrosine kinases and their tyrosine phosphorylations. FEBS Lett. 2001, 490: 32-38. 10.1016/S0014-5793(01)02132-9.PubMed
103.
Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, Maira M, McNamara K, Perera SA, Song Y, Chirieac LR, Kaur R, Lightbown A, Simendinger J, Li T, Padera RF, García-Echeverría C, Weissleder R, Mahmood U, Cantley LC, Wong KK: Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med. 2008, 14: 1351-1356. 10.1038/nm.1890.PubMedPubMedCentral
104.
Lee MJ, Ye AS, Gardino AK, Heijink AM, Sorger PK, Macbeath G, Yaffe MB: Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks. Cell. 2012, 149: 780-794. 10.1016/j.cell.2012.03.031.PubMedPubMedCentral
105.
Mayer IA, Abramson VG, Balko JM, Isakoff SJ, Kuba MG, Sanders M, Forero-Torres A, Yap JT, Van Den Abbeele AD, Li Y, Arteaga CL, Winer EP, Stand Up to Cancer - PI3K in Women's Cancers: SU2C phase Ib study of pan-PI3K inhibitor BKM120 with letrozole in ER+/HER2- metastatic breast cancer (MBC) [abstract]. ASCO Annual Meeting Proceedings: June 1-5 2012; Chicago, IL. 2012, Alexandria, VA: American Society of Clinical Oncology, Abstract 510
106.
Ihle NT, Byers LA, Kim ES, Saintigny P, Lee JJ, Blumenschein GR, Tsao A, Liu S, Larsen JE, Wang J, Diao L, Coombes KR, Chen L, Zhang S, Abdelmelek MF, Tang X, Papadimitrakopoulou V, Minna JD, Lippman SM, Hong WK, Herbst RS, Wistuba II, Heymach JV, Powis G: Effect of KRAS oncogene substitutions on protein behavior: implications for signaling and clinical outcome. J Natl Cancer Inst. 2012, 104: 228-239. 10.1093/jnci/djr523.PubMedPubMedCentral
107.
Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C: Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012, 366: 883-892. 10.1056/NEJMoa1113205.PubMedPubMedCentral
108.
109.
Andersson P, Kolaric A, Windahl T, Kirrander P, Soderkvist P, Karlsson MG: PIK3CA, HRAS and KRAS gene mutations in human penile cancer. The Journal of urology. 2008, 179: 2030-2034. 10.1016/j.juro.2007.12.040.PubMed
110.
Shi J, Yao D, Liu W, Wang N, Lv H, Zhang G, Ji M, Xu L, He N, Shi B, Hou P: Highly frequent PIK3CA amplification is associated with poor prognosis in gastric cancer. BMC Cancer. 2012, 12: 50-10.1186/1471-2407-12-50.PubMedPubMedCentral
111.
Byun DS, Cho K, Ryu BK, Lee MG, Park JI, Chae KS, Kim HJ, Chi SG: Frequent monoallelic deletion of PTEN and its reciprocal associatioin with PIK3CA amplification in gastric carcinoma. Int J Cancer. 2003, 104: 318-327. 10.1002/ijc.10962.PubMed
112.
Abubaker J, Jehan Z, Bavi P, Sultana M, Al-Harbi S, Ibrahim M, Al-Nuaim A, Ahmed M, Amin T, Al-Fehaily M, Al-Sanea O, Al-Dayel F, Uddin S, Al-Kuraya KS: Clinicopathological analysis of papillary thyroid cancer with PIK3CA alterations in a Middle Eastern population. J Clin Endocrinol Metab. 2008, 93: 611-618. 10.1210/jc.2007-1717.PubMed
113.
Pedrero JM, Carracedo DG, Pinto CM, Zapatero AH, Rodrigo JP, Nieto CS, Gonzalez MV: Frequent genetic and biochemical alterations of the PI 3-K/AKT/PTEN pathway in head and neck squamous cell carcinoma. Int J Cancer. 2005, 114: 242-248. 10.1002/ijc.20711.PubMed
114.
Woenckhaus J, Steger K, Werner E, Fenic I, Gamerdinger U, Dreyer T, Stahl U: Genomic gain of PIK3CA and increased expression of p110alpha are associated with progression of dysplasia into invasive squamous cell carcinoma. J Pathol. 2002, 198: 335-342. 10.1002/path.1207.PubMed
115.
Ji M, Guan H, Gao C, Shi B, Hou P: Highly frequent promoter methylation and PIK3CA amplification in non-small cell lung cancer (NSCLC). BMC Cancer. 2011, 11: 147-10.1186/1471-2407-11-147.PubMedPubMedCentral
116.
Massion PP, Kuo WL, Stokoe D, Olshen AB, Treseler PA, Chin K, Chen C, Polikoff D, Jain AN, Pinkel D, Albertson DG, Jablons DM, Grays JW: Genomic copy number analysis of non-small cell lung cancer using array comparative genomic hybridization: Implications of the phosphatidylinositol 3-kinase pathway. Cancer Res. 2002, 62: 3636-3640.PubMed
117.
Ma YY, Wei SJ, Lin YC, Lung JC, Chang TC, Whang-Peng J, Liu JM, Yang DM, Yang WK, Shen CY: PIK3CA as an oncogene in cervical cancer. Oncogene. 2000, 19: 2739-2744. 10.1038/sj.onc.1203597.PubMed
118.
Bertelsen BI, Steine SJ, Sandvei R, Molven A, Laerum OD: Molecular analysis of the PI3K-AKT pathway in uterine cervical neoplasia: frequent PIK3CA amplification and AKT phosphorylation. Int J Cancer. 2006, 118: 1877-1883. 10.1002/ijc.21461.PubMed
119.
Abubaker J, Bavi P, Al-Haqawi W, Jehan Z, Munkarah A, Uddin S, Al-Kuraya KS: PIK3CA alterations in Middle Eastern ovarian cancers. Mol Cancer. 2009, 8: 51-10.1186/1476-4598-8-51.PubMedPubMedCentral
120.
Agell L, Hernandez S, Salido M, de Muga S, Juanpere N, Arumi-Uria M, Menendez S, Lorenzo M, Lorente JA, Serrano S, Lloreta J: PI3K signaling pathway is activated by PIK3CA mRNA overexpression and copy gain in prostate tumors, but PIK3CA, BRAF, KRAS and AKT1 mutations are infrequent events. Mod Pathol. 2011, 24: 443-452. 10.1038/modpathol.2010.208.PubMed
121.
Konopka B, Janiec-Jankowska A, Kwiatkowska E, Najmola U, Bidzinski M, Olszewski W, Goluda C: PIK3CA mutations and amplification in endometrioid endometrial carcinomas: Relation to other genetic defects and clinicopathologic status of the tumors. Hum Pathol. 2011, 42: 1710-1719. 10.1016/j.humpath.2010.01.030.PubMed
122.
Salvesen HB, Carter SL, Mannelqvist M, Dutt A, Getz G, Stefansson IM, Raeder MB, Sos ML, Engelsen IB, Trovik J, Wik E, Greulich H, Bo TH, Jonassen I, Thomas RK, Zander T, Garraway LA, Oyan AM, Sellers WR, Kalland KH, Meyerson M, Akslen LA, Beroukhim R: Integrated genomic profiling of endometrial carcinoma associates aggressive tumors with indicators of PI3 kinase activation. Proc Natl Acad Sci USA. 2009, 106: 4834-4839. 10.1073/pnas.0806514106.PubMedPubMedCentral
123.
Wu G, Xing M, Mambo E, Huang X, Liu J, Guo Z, Chatterjee A, Goldenberg D, Gollin S, Sukumar S, Trink B, Sidransky D: Somatic mutation and gain of copy number of PIK3CA in human breast cancer. Breast Cancer Research. 2005, 7: R609-R616. 10.1186/bcr1262.PubMedPubMedCentral
124.
Oliveira MC, Pereira SR, Ribeiro EMF, Lima RS, Urban CA, Sebastiao APM, Marian C, Haddad BR, Cavalli IJ, Cavalli LR: DNA copy number changes in the PI3K signaling pathway genes in triple negative breast cancer [Abstract]. Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research: April 2-6 2011; Orlando, FL. 2011, Philadelphia, PA: American Association for Cancer Research, Abstract 3822
125.
Brown JR, Hanna M, Tesar B, Werner L, Pochet N, Asara JM, Wang YE, Dal Cin P, Fernandes SM, Thompson C, MacConaill L, Wu CJ, Van De Peer Y, Correll M, Regev A, Neuberg D, Freedman AS: Integrative genomic analysis implicates PIK3CA and myc in chronic lymphocytic leukemia. Clin Lymphoma Myeloma Leuk. 2011, 11: S147-S148.
126.
Chiariello E, Roz L, Albarosa R, Magnani I, Finocchiaro G: PTEN/MMAC1 mutations in primary glioblastomas and short-term cultures of malignant gliomas. Oncogene. 1998, 16: 541-545. 10.1038/sj.onc.1201689.PubMed
127.
Feilotter HE, Nagai MA, Boag AH, Eng C, Mulligan LM: Analysis of PTEN and the 10q23 region in primary prostate carcinomas. Oncogene. 1998, 16: 1743-1748. 10.1038/sj.onc.1200205.PubMed
128.
Gray IC, Stewart LMD, Phillips SMA, Hamilton JA, Gray NE, Watson GJ, Spurr NK, Snary D: Mutation and expression analysis of the putative prostate tumour-suppressor gene PTEN. Br J Cancer. 1998, 78: 1296-1300. 10.1038/bjc.1998.674.PubMedPubMedCentral
129.
Pesche S, Latil A, Muzeau F, Cussenot O, Fournier G, Longy M, Eng C, Lidereau R: PTEN/MMAC1/TEP1 involvement in primary prostate cancers. Oncogene. 1998, 16: 2879-2883. 10.1038/sj.onc.1202081.PubMed
130.
Wang SI, Parsons R, Ittmann M: Homozygous deletion of the PTEN tumor suppressor gene in a subset of prostate adenocarcinomas. Clin Cancer Res. 1998, 4: 811-815.PubMed
131.
Freihoff D, Kempe A, Beste B, Wappenschmidt B, Kreyer E, Hayashi Y, Meindl A, Krebs D, Wiestler OD, von Deimling A, Schmutzler RK: Exclusion of a major role for the PTEN tumour-suppressor gene in breast carcinomas. Br J Cancer. 1999, 79: 754-758. 10.1038/sj.bjc.6690121.PubMedPubMedCentral
132.
Feilotter HE, Coulon V, McVeigh JL, Boag AH, Dorion-Bonnet F, Duboue B, Latham WC, Eng C, Mulligan LM, Longy M: Analysis of the 10q23 chromosomal region and the PTEN gene in human sporadic breast carcinoma. Br J Cancer. 1999, 79: 718-723. 10.1038/sj.bjc.6690115.PubMedPubMedCentral
133.
Celebi JT, Shendrik I, Silvers DN, Peacocke M: Identification of PTEN mutations in metastatic melanoma specimens. J Med Genet. 2000, 37: 653-657. 10.1136/jmg.37.9.653.PubMedPubMedCentral
134.
Abdel-Rahman MH, Yang Y, Zhou XP, Craig EL, Davidorf FH, Eng C: High frequency of submicroscopic hemizygous deletion is a major mechanism of loss of expression of PTEN in uveal melanoma. J Clin Oncol. 2006, 24: 288-295.PubMed
135.
136.
Holway AH, Rieger-Christ KM, Miner WR, Cain JW, Dugan JM, Pezza JA, Silverman ML, Shapter A, McLellan R, Summerhayes IC: Somatic mutation of PTEN in vulvar cancer. Clin Cancer Res. 2000, 6: 3228-3235.PubMed
137.
COSMIC database: Distribution of somatic mutations in PTEN in grade IV astrocytoma and oligoastrocytoma. [http://​www.​sanger.​ac.​uk/​perl/​genetics/​CGP/​cosmic?​action=​bycancer&​ln=​PTEN&​sn=​central_​nervous_​system&​ss=​NS;&​ss=​basal_​ganglia;&​ss=​brain;&​ss=​brainstem;&​ss=​cerebellum;&​ss=​cerebral_​cortex;&​ss=​cerebral_​hemisphere;&​ss=​cerebrum;&​ss=​choroid_​plexus;&​ss=​corpus_​callosum;&​ss=​diencephalon;&​ss=​filum;&​ss=​fourth_​ventricle;&​ss=​frontal_​lobe;&​ss=​frontobasal;&​ss=​frontoparietal;&​ss=​frontotemporal;&​ss=​hypothalamus;&​ss=​infratentorial;&​ss=​intraventricular​;&​ss=​lateral_​ventricle;&​ss=​medulla;&​ss=​meninges;&​ss=​midbrain;&​ss=​occipital_​lobe;&​ss=​optic_​nerve;&​ss=​paracentral;&​ss=​parietal_​lobe;&​ss=​parietooccipital​;&​ss=​pineal_​gland;&​ss=​posterior_​fossa;&​ss=​sella_​turcica;&​ss=​septum_​pellucidum;&​ss=​spinal_​cord;&​ss=​supratentorial;&​ss=​tectum;&​ss=​temporal_​lobe;&​ss=​temporobasal;&​ss=​temporooccipital​;&​ss=​temporoparietal;&​ss=​thalamus;&​ss=​third_​ventricle;&​ss=​trigone&​sh=​astrocytoma_​Grade_​IV;&​sh=​oligoastrocytoma​_​Grade_​IV&​hn=​glioma]
138.
COSMIC database: Distribution of somatic mutations in PTEN in malignant melanoma. [http://​www.​sanger.​ac.​uk/​perl/​genetics/​CGP/​cosmic?​action=​byhist&​s=​4&​hn=​malignant_​melanoma&​sn=​skin&​ss=​NS&​ss=​abdomen&​ss=​acral&​ss=​ankle&​ss=​anorectal&​ss=​arm&​ss=​auditory_​meatus&​ss=​axilla&​ss=​back&​ss=​breast&​ss=​breast_​inframammary&​ss=​buttock&​ss=​chest&​ss=​chronically_​sun_​exposed_​site&​ss=​conjunctiva&​ss=​ear&​ss=​elbow&​ss=​extraocular&​ss=​extremity&​ss=​eye&​ss=​face&​ss=​flank&​ss=​foot&​ss=​forearm&​ss=​genital&​ss=​groin&​ss=​hand&​ss=​head_​neck&​ss=​hip&​ss=​intermittently_​sun_​exposed_​site&​ss=​knee&​ss=​labia&​ss=​labia_​major&​ss=​leg&​ss=​lip&​ss=​lower_​back&​ss=​lower_​extremity&​ss=​lower_​leg&​ss=​meninges&​ss=​mucosal&​ss=​neck&​ss=​nipple&​ss=​non_​chronically_​sun_​exposed_​site&​ss=​ovary&​ss=​penis&​ss=​perineum&​ss=​pubis&​ss=​scalp&​ss=​scrotum&​ss=​shoulder&​ss=​sinonasal&​ss=​sole&​ss=​subungual&​ss=​sun_​exposed_​site&​ss=​sun_​unexposed_​site&​ss=​trunk&​ss=​upper_​arm&​ss=​upper_​back&​ss=​upper_​extremity&​ss=​upper_​leg&​ss=​vulva&​ln=​PTEN&​sh=​NS&​sh=​mucosal_​lentiginous&​sh=​acral_​lentiginous&​sh=​nodular&​sh=​amelanotic&​sh=​radial_​growth_​phase&​sh=​desmoplastic&​sh=​spitzoid&​sh=​in_​situ_​melanotic_​neoplasm&​sh=​superficial_​spreading&​sh=​lentigo_​maligna&​sh=​vertical_​growth_​phase&​sh=​malignant_​blue_​nevus]
139.
Maira SM, Pecchi S, Huang A, Burger M, Knapp M, Sterker D, Schnell C, Guthy D, Nagel T, Wiesmann M, Brachmann S, Fritsch C, Dorsch M, Chène P, Shoemaker K, De Pover A, Menezes D, Martiny-Baron G, Fabbro D, Wilson CJ, Schlegel R, Hofmann F, García-Echeverría C, Sellers WR, Voliva CF: Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol Cancer Ther. 2012, 11: 317-328. 10.1158/1535-7163.MCT-11-0474.PubMed
140.
Folkes AJ, Ahmadi K, Alderton WK, Alix S, Baker SJ, Box G, Chuckowree IS, Clarke PA, Depledge P, Eccles SA, Friedman LS, Hayes A, Hancox TC, Kugendradas A, Lensun L, Moore P, Olivero AG, Pang J, Patel S, Pergl-Wilson GH, Raynaud FI, Robson A, Saghir N, Salphati L, Sohal S, Ultsch MH, Valenti M, Wallweber HJA, Nan CW, Wiesmann C, et al: The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1- ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer. J Med Chem. 2008, 51: 5522-5532. 10.1021/jm800295d.PubMed
141.
Maira SM, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, Brachmann S, Chene P, De Pover A, Schoemaker K, Fabbro D, Gabriel D, Simonen M, Murphy L, Finan P, Sellers W, Garcia-Echeverria C: Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther. 2008, 7: 1851-1863. 10.1158/1535-7163.MCT-08-0017.PubMed
142.
Yuan J, Mehta PP, Yin MJ, Sun S, Zou A, Chen J, Rafidi K, Feng Z, Nickel J, Engebretsen J, Hallin J, Blasina A, Zhang E, Nguyen L, Sun M, Vogt PK, McHarg A, Cheng H, Christensen JG, Kan JL, Bagrodia S: PF-04691502, a potent and selective oral inhibitor of PI3K and mTOR kinases with antitumor activity. Mol Cancer Ther. 2011, 10: 2189-2199. 10.1158/1535-7163.MCT-11-0185.PubMed
143.
Mallon R, Feldberg LR, Lucas J, Chaudhary I, Dehnhardt C, Delos Santos E, Chen Z, Dos Santos O, Ayral-Kaloustian S, Venkatesan A, Hollander I: Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitor. Clin Cancer Res. 2011, 17: 3193-3203. 10.1158/1078-0432.CCR-10-1694.PubMed
144.
Sutherlin DP, Bao L, Berry M, Castanedo G, Chuckowree I, Dotson J, Folks A, Friedman L, Goldsmith R, Gunzner J, Heffron T, Lesnick J, Lewis C, Mathieu S, Murray J, Nonomiya J, Pang J, Pegg N, Prior WW, Rouge L, Salphati L, Sampath D, Tian Q, Tsui V, Wan NC, Wang S, Wei B, Wiesmann C, Wu P, Zhu BY, et al: Discovery of a potent, selective, and orally available class i phosphatidylinositol 3-kinase (PI3K)/Mammalian target of rapamycin (mTOR) kinase inhibitor (GDC-0980) for the treatment of cancer. J Med Chem. 2011, 54: 7579-7587. 10.1021/jm2009327.PubMed
145.
Fritsch CM, Schnell C, Chatenay-Rivauday C, Guthy DA, Pover AD, Wartmann M, Brachmann S, Maira S-M, Huang A, Quadt C, Hofmann F, Caravatti G: NVP-BYL719, a novel PI3Kalpha selective inhibitor with all the characteristics required for clinical development as an anti-cancer agent [abstract]. Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research: March 31-April 4 2012; Chicago, IL. 2012, Philadelphia, PA: American Association for Cancer Research, Abstract 3748
Metadata
Title
Clinical development of phosphatidylinositol 3-kinase inhibitors for cancer treatment
Authors
Irene Brana
Lillian L Siu
Publication date
01-12-2012
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2012
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/1741-7015-10-161

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