BEZ235, BKM120 AND BYL719
Inhibiting tumor proliferation and survival by blocking the phosphatidylinositol-3-kinase (PI3K) pathway
- PI3K and the mammalian target of rapamycin (mTOR) are important components of an intracellular signaling network, the PI3K-AKT-mTOR pathway, which regulates cellular metabolism, proliferation and survival.18
- Abnormal activation of the PI3K-AKT-mTOR pathway has been validated as an important step towards the initiation and maintenance of human tumors by epidemiological and preclinical studies.18 This signaling cascade is also a key regulator of angiogenesis and upregulated metabolic activities in tumor cells.
- Targeting the PI3K/AKT/mTOR pathway could arrest tumor growth and induce cell death in cancers that are resistant to currently available therapies.19-21
- BEZ235, BKM120 and BYL719 are all novel, oral, targeted anticancer agents: BEZ235 is a PI3K/mTOR dual inhibitor;22 BKM120 is a pan-PI3K inhibitor;23 and BYL719 selectively inhibits PI3Kα. These compounds have shown significant cell growth inhibition and induction of apoptosis in a variety of tumor cell lines as well as in animal models.23-25 In addition, in preclinical models they have been shown to possess antiangiogenic properties.26,27 BEZ235 and BKM120 are currently being investigated in Phase I/II clinical trials in advanced solid tumor patients as a single agent as well as in combination with other agents. Single-agent first-in-man study of BYL719 in advanced solid tumor patients is also ongoing.
All compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available.
- Collins I, Workman P. Design and development of signal transduction inhibitors for cancer treatment: experience and challenges with kinase targets. Curr Signal Transduct Ther. 2006;1:1323.
- Lobbezoo MW, Giaccone G, van Kalken C. Signal transduction modulators for cancer therapy: from promise to practice? The Oncologist. 2003;8:210213.
- Folkman J. Tumor angiogenesis. In: Holland JF, Frei E, eds. Cancer Medicine. 5th ed. Hamilton, Ontario: B.C. Decker Inc.; 2000:132152.
- Drysdale MJ, Brough PA, Massey A, Jensen MR, Schoepfer J. Targeting Hsp90 for the treatment of cancer. Curr Opin Drug Discov Devel. 2006;9:483495.
- Liu X, Yao W, Newton RC, Scherle PA. Targeting the c-Met signaling pathway for cancer therapy. Expert Opin Investig Drugs. 2008;17:9971011.
- Koblish HK, Liu X, Hall L, et al. Preclinical in vivo characterization of INCB028060, a novel, potent and highly selective c-Met inhibitor. J Clin Oncol. 2008;26(15S):14561.
- Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood. 2002;100(5):15321542.
- Garcia-Montero AC, Jara-Acevedo M, Teodosio C, et al. KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients. Blood. 2006;108:23662372.
- Fabbro D, Ruetz S, Bodis S, et al. PKC412a protein kinase inhibitor with a broad therapeutic potential. Anti-Cancer Drug Design. 2000;15:1728.
- Elsheikh SE, Green AR, Lambros MBK, et al. FGFR1 amplification in breast carcinomas: a chromogenic in situ hybridisation analysis. Breast Cancer Res. 2007;9(2):R23.
- Plowright EE, Li Z, Bergsagel PL, et al. Ectopic expression of fibroblast growth factor receptor 3 promotes myeloma cell proliferation and prevents apoptosis. Blood. 2000;95(3):992998.
- Knowles MA. Role of FGFR3 in urothelial cell carcinoma: biomarker and potential therapeutic target. World J Urol. 2007;25(6):581593.
- Wu X, Ge H, Lemon B, et al. FGF19-induced hepatocyte proliferation is mediated through FGFR4 activation. J Biol Chem. 2010;285(8):51655170.
- Emoto N, Isozaki O, Ohmura E, et al. Basic fibroblast growth factor (FGF-2) in renal cell carcinoma, which is indistinguishable from that in normal kidney, is involved in renal cell carcinoma growth. J Urol. 1994;152(5 Pt 1):16261631.
- Tomlinson DC, Baldo O, Harnden P, Knowles MA. FGFR3 protein expression and its relationship to mutation status and prognostic variables in bladder cancer. J Pathol. 2007;213(1):9198.
- Shi M, Kim KB, Chesney J, et al. Effect of TKI258 in plasma biomarkers and pharmacokinetics in patients with advanced melanoma. J Clin Oncol. 2009;27(suppl.) Abstract 9020.
- Novartis, data on file.
- Wymann MP, Zvelebil M, Laffargue M. Phosphoinositide 3-kinase signaling which way to target? Trends Pharmacol Sci. 2003;24:366376.
- Paez GP, Sellers WR. PI3K/PTEN/AKT Pathway. Cancer Treat Res. 2003;115:145.
- Liu P, et al. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Disc. 2009;8:627.
- Courtney KD, et al. The PI3K Pathway As Drug Target in Human Cancer. J Clin Oncol. 2010;28:1075.
- Maira SM, Stauffer F, Brueggen J, et al. Identification and development of NVP-BEZ235, a new orally available dual PI3K/mTOR inhibitor with potent in vivo antitumor activity. Mol Cancer Ther. 2008;7:18511863.
- Maira M, Menezes D, Pecchi S, et al. Biological characterization of NVP-BKM120, a novel inhibitor of phosphoinosotide 3-kinase in Phase I/II clinical trials. Presented at: 101st American Association for Cancer Research Congress. April 1721, 2010; Washington DC, US. Poster.
- Serra V, Markman B, Scaltriti M, et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res. 2008;68:80228030.
- Engelman JA, Chen L, Tan X, et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancer. Nat Med. 2008;14:13151316.
- Schnell CR, Stauffer F, Allegrini PR, et al. Effects of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 on the tumor vasculature: implications for clinical imaging. Cancer Res. 2008;68:65986607.
- Schnell CR, Arnal S, Becket M, et al. NVP-BKM120, a pan class I PI3K inhibitor impairs microvascular permeability and tumor growth as detected by DCE-MRI and IFP measurements via radio-telemetry. Comparison with NVP-BEZ235. Presented at: 101st American Association for Cancer Research Congress. April 1721, 2010; Washington DC, US.
- Sturgill TW. MAP kinase: it's been longer than fifteen minutes. Biochem Biophys Res Commun. 2008;371:14.
- Frémin C, Meloche S. From basic research to clinical development of MEK1/2 inhibitors for cancer therapy. J Hematol Oncol. 2010;3:8.
- Kamal A, Thao L, Sensintaffar J, et al. A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature. 2003;425:407410.
- GSI GIST Support International. http://www.gistsupport.org/treatments-for-gist/emerging-treatments/hsp90-inhibitors/hsp990.php. Accessed November 17, 2010.
- Brough PA, Aherne W, Barril X, et al. 4,5-diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer. J Med Chem. 2008;51:196218.
- Wong KK. Recent developments in anti-cancer agents targeting the RAS/RAF/MEK/ERK pathway. Recent Pat Anticancer Drug Discov. 2009;4(1):2835.
- Garnett MJ, Marais R. Guilty as charged: B-RAF is a human oncogene. Cancer Cell. 2004;6:313319.
- García-Echeverría C. Protein and lipid kinase inhibitors as targeted anticancer agents of the RAS/RAF/MEK and PI3K/PKB pathways. Purinergic Signal. 2009;5:117125.
- Amiri P, Aikawa ME, Dove J, et al. CHIR-265 is a potent selective inhibitor of c-Raf/B-Raf/mutB-Raf that effectively inhibits proliferation and survival of cancer cell lines with RAS/RAF pathway mutations. Proc Am Assoc Cancer Res. 2006;47:Abstract 4855.
- Deveraux QL, Takahashi R, Salveen GS, and Reed JC. X-linked IAP is a direct inhibitor of cell-death proteases. Nature 1997;388:3004.
- Vince JE, Wong WW, Khan N, et al. IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis. Cell 2007;131:68293.
- Du C, Fang M, Li Y, et al. Smac, a mitochondrial protein that promotes cytochrome cdependent caspase activation by eliminating IAP inhibition. Cell. 2000;102:3342.
- Ortega S, Malumbres M, Barbacid M. Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochim Biophys Acta. 2002 Mar 14;1602(1):7387.
- Shapiro GI. Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol. 2006 Apr 10;24(11):177083.
- Pasca di Magliano M, Hebrok M. Hedgehog signaling in cancer formation and maintenance. Nature. 2003;3:903911.
- Quintαs-Cardama A, Vaddi K, Liu P, et al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood. 2010;115:31093117.
- Verstovsek S, Kantarjian HM, Pardanani AD, et al. The JAK inhibitor, INCB018424, demonstrates durable and marked clinical responses in primary myelofibrosis (PMF) and post-polycythemia/essential thrombocythemia myelofibrosis (post-PV/ET-MF). Presented at: 50th American Society of Hematology (ASH) Annual Meeting and Exposition; December 69, 2008; San Francisco, CA.
- Huang HM, Lin YL, Chen CH, Chang TW. Simultaneous activation of JAK1 and JAK2 confers IL-3 independent growth on Ba/F3 pro-B cells. J Cell Biochem. 2005;96:361375.
- Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia. 2008;22:1422.
- Verstovsek S, Kantarjian H, Mesa RA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010;363(12):11171127.
- Kouzarides T. Histone acetylases and deacetylases in cell proliferation. Curr Opin Genet Dev. 1999;9:4048.
- George P, Bali P, Annavarapu S, et al. Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3. Blood. 2005;105:17681776.
- Minucci S, Pelicci PG. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer. 2006;6:3851.
- Marks PA, Richon VM, Rifkind RA. Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells. J Natl Cancer Inst. 2000;92:12101216.
- Marks PA, Rifkind RA, Richon VM, et al. Histone deacetylases and cancer: causes and therapies. Nat Rev. 2001;1:194202.
- Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov. 2006;5:769784.
- Maiso P, Carvajal-Vergara X, Ocio EM, et al. The histone deacetylase inhibitor LBH589 is a potent antimyeloma agent that overcomes drug resistance. Cancer Res. 2006;66:57815789.
- Catley L, Weisberg E, Kiziltepe T, et al. Aggresome induction by proteasome inhibitor bortezomib and alpha-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells. Blood. 2006;108:34413449.
- Weiner LM, Adams GP, von Mehren M. Therapeutic monoclonal antibodies: general principles. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001:495508.
- Luqman M, Klabunde S, Lin K, et al. The antileukemia activity of a human anti-CD40 antagonist antibody, HCD122, on human chronic lymphocytic leukemia cells. Blood. 2008;112:711720.
- Tai Y-T, Li X-F, Tong X, et al. 46th Annual Meeting of the American Society of Hematology, December 47, 2004; San Diego, US. Poster 2414.
- Tian E, Zhan F, Walker R, et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med. 2003;349:24832494.
- Ohnaka K, Taniguchi H, Kawate H, Nawata H, Takayanagi R. Glucocorticoid enhances the expression of dickkopf-1 in human osteoblasts: novel mechanism of glucocorticoid-induced osteoporosis. Biochem Biophys Res Commun. 2004;318:259264.
- Ettenberg S, Cong F, Shulok J, et al. BHQ880, a novel anti-DKK1 neutralizing antibody, inhibits tumor-induced osteolytic bone disease. Presented at: American Association for Cancer Research Annual Meeting. April 1216, 2008; San Diego, Calif. Abstract.
- Bruns C, Lewis I, Briner U, Meno-Tetang G, Weckbecker G. SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile. Eur J Endocrinol. 2002;146:707716.
- Hejna M, Schmidinger M, Raderer M. The clinical role of somatostatin analogues as antineoplastic agents: much ado about nothing? Ann Oncol. 2002;13:653668.
- Pawlikowski M, Melen-Mucha G. Somatostatin analogs from new molecules to new applications. Curr Opin Pharmacol. 2004;4(6):60813.
- Villaume K, Blanc H, Gouysse G, et al. VEGF secretion by neuroendicrine tumor cells is inhibited by octreotide and by inhibitors of the PI3K/AKT/mTOR pathway. Neuroendocrinology. 2010;91(3):26878.
- Bauer W, Briner U, Doepfner W, et al. SMS 201-995: a very potent and selective octapeptide analog of somatostatin with prolonged action. Life Sci. 1982;31:11331140.
- Cozzi R, Attanasio R, Montini M, et al. Four-year treatment with octreotide-long-acting repeatable in 110 acromegalic patients: predictive value of short-term results? J Clin Endocrinol Metab. 2003;88(7):30903098.
- Zatelli MC, Piccin D, Vignali C, et al. Pasireotide, a multiple somatostatin receptor subtypes ligand, reduces cell viability in non-functioning pituitary adenomas by inhibiting vascular endothelial growth factor secretion. Endocr Relat Cancer. 2007;14:91102.
- Fedele M, De Martino I, Pivonello R, et al. SOM230, a new somatostatin analogue, is highly effective in the therapy of growth hormone/prolactin-secreting pituitary adenomas. Clin Cancer Res. 2007;13:27382744.
- Boscaro, Ludlam WH, Atkinson B, et al. Treatment of pituitary-dependent Cushing's disease with the multireceptor ligand somatostatin analog pasireotide (SOM230): a multicenter, phase II trial. J Clin Endocrinol Metab. 2009;94:115122.
- van der Hoek J, de Herder WW, Feelders RA, et al. A single-dose comparison of the acute effects between the new somatostatin analog SOM230 and octreotide in acromegalic patients. J Clin Endocrinol Metab. 2004;89(2):638645.
- Petersenn S, Glusman JE, Schopohl J, et al. Pasireotide (SOM230) is a potential new therapy in acromegaly: Preliminary results of a Phase II study. Proceedings of the Endocrine Society Annual Meeting 2006.
- Kvols L, Wiedenmann B, Oberg K, et al. Safety and efficacy of pasireotide (SOM230) in patients with metastatic carcinoid tumors refractory or resistant to octreotide LAR: Results of a phase II study.. 2006;24(185): Abstract 4082.
ABOUT NOVARTIS ONCOLOGY
We are one of the premier companies providing you with the best oncology treatments available.
We are committed to building the smartest and most capable team in the industry.