Blocking the Regulatory Mechanisms of Brain Cancer Cells
W. K. Alfred Yung, M.D.
The overall objective of my research program is to develop molecular therapeutic strategies to modulate the aberrant growth and angiogenic regulatory mechanisms that govern human gliomagenesis and progression. Recent studies demonstrate that in glioma aberrant expression of the tumor suppressor phosphatase and tensin homologue (PTEN; deleted on chromosome 10, cloned in our laboratory by the late Dr. Peter Steck) contributes to the activation of the PI3kinase/Akt pathway and its transcription factor mediators. Ectopic expression of PTEN down-regulates the proliferation of glioma cells through the suppression of AP-1, and this target may be essential for its central role in the growth and survival of glioma cancer cells.
To control this abnormal activity, we have screened inhibitors of the PI3K/Akt pathway to select those with optimal activity and to understand the mechanisms of that activity. We are also combining agents to inhibit multiple therapeutic targets simultaneously. Dr. Yung serves as principal investigator and project co-leader for a Brain Tumor SPORE. Dr. Yung’s project will test PI3K inhibitor PX-866 in the clinic and develop rational combination therapies based on it
A novel dual PI3K and mTOR inhibitor, NVP-BEZ235, was shown to be effective both in vitro and in vivo. Intracranial xenograft animals treated with BEZ235 survived significantly longer than controls without any obvious toxicity. Tumor extracts harvested from treated animals showed that BEZ235 inhibited activity of target genes in the PI3K/Akt/mTOR cascade and reduced VEGF secretion. Clinical trials of BEZ235 for cancers with altered PTEN/PI3K signaling are being pursued.
Focal adhesion kinase (FAK) regulates tumor migration and invasion. Insulin-like growth factor-I receptor (IGF-IR), whose expression correlates with tumor grade, is involved in proliferation and survival. We investigated the antitumor activity of a novel compound TAE226, a potent ATP competitive inhibitor of several tyrosine protein kinases, in particular FAK and IGF-IR kinases. TAE226 antagonized both FAK and IGF-IR signaling pathways, resulting in growth inhibition, cell cycle arrest, attenuation of tumor invasion and induction of apoptosis. More importantly, TAE226 significantly prolonged the survival of animals bearing intracranial glioma xenografts, showing the potential therapeutic efficacy of TAE226 for patients with glioblastomas.
Parallel with my laboratory research focus is my work as principal investigator on NCI-sponsored Brain Tumor Consortium phase I and II trials of several newly developed agents and novel combinations of targeted inhibitors designed to attack multiple involved pathways.
de Groot JF, Piao Y, Lu L, Fuller GN, Yung WK. Knockdown of GluR1 expression by RNA interference inhibits glioma proliferation. J Neurooncol. 2008 Mar 4.
Alonso MM, Gomez-Manzano C, Bekele BN, Yung WK, Fueyo J. Adenovirus-based strategies overcome temozolomide resistance by silencing the O6-methylguanine-DNA methyltransferase promoter. Cancer Res. 2007 Dec 15;67(24):11499-504.
Scheurer ME, Etzel CJ, Liu M, El-Zein R, Airewele GE, Malmer B, Aldape KD, Weinberg JS, Yung WK, Bondy ML. Aggregation of cancer in first-degree relatives of patients with glioma.
Cancer Epidemiol Biomarkers Prev. 2007 Nov;16(11):2491-5.Koul D, Shen R, Shishodia S, Takada Y, Bhat KP, Reddy SA, Aggarwal BB, and Yung WK. PTEN down regulates AP-1 and targets c-fos in human glioma cells Via PI3-kinase/Akt pathway. Mol Cell Biochem, 2007.
Pelloski CE, Ballman KV, Furth AF, Zhang L, Lin E, Sulman EP, Bhat K, McDonald JM, Yung WK, Colman H, Woo SY, Heimberger AB, Suki D, Prados MD, Chang SM, Barker FG, 2nd, Buckner JC, James CD, Aldape K. Epidermal growth factor receptor variant III status defines clinically distinct subtypes of glioblastoma. J Clin Oncol 25: 2288-2294, 2007.
Liu JL, Mao Z, LaFortune TA, Alonso MM, Gallick GE, Fueyo J, Yung WK. Cell cycle-dependent nuclear export of phosphatase and tensin homologue tumor suppressor is regulated by the phosphoinositide-3-kinase signaling cascade. Cancer Res 67: 11054-11063, 2007.
Koul D, Shen R, Bergh S, Sheng X, Shishodia S, Lafortune TA, Lu Y, de Groot JF, Mills GB, Yung WK. Inhibition of Akt survival pathway by a small-molecule inhibitor in human glioblastoma. Mol Cancer Ther 5: 637-644, 2006.
Pelloski CE, Lin E, Zhang L, Yung WK, Colman H, Liu JL, Woo SY, Heimberger AB, Suki D, Prados M, Chang S, Barker FG, 3rd, Fuller GN, Aldape KD. Prognostic associations of activated mitogen-activated protein kinase and Akt pathways in glioblastoma. Clin Cancer Res 12: 3935-3941, 2006.
Liu JL, Sheng X, Hortobagyi ZK, Mao Z, Gallick GE, Yung WK. Nuclear PTEN-mediated growth suppression is independent of Akt down-regulation. Mol Cell Biol. 2005 Jul;25(14):6211-24.
de Groot JF, Liu TJ, Fuller G, Yung WK. The excitatory amino acid transporter-2 induces apoptosis and decreases glioma growth in vitro and in vivo. Cancer Res. 2005 Mar 1;65(5):1934-40.
Nigro JM, Misra A, Zhang L, Smirnov I, Colman H, Griffin C, Ozburn N, Chen M, Pan E, Koul D, Yung WK, Feuerstein BG, Aldape KD. Integrated array-comparative genomic hybridization and expression array profiles identify clinically relevant molecular subtypes of glioblastoma. Cancer Res. 2005 Mar 1;65(5):1678-86.