Fenretinide, TRAIL Receptors, Histone Deacetylase Inhibitors (HDAC)
Vinay Puduvalli, M.D.
Research in my laboratory focuses on understanding programmed cell death (apoptosis) in brain tumors and mechanisms of resistance against this process. Preliminary studies in my laboratory demonstrated that TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) induces apoptosis in glioma cells in vitro in a p53- and cell-cycle-independent manner. We have also identified an important role for Akt in protecting cells against TRAIL-induced apoptosis. Determining the nature of the interaction between these two pathways may be important to therapeutic application. We have constructed viral vectors to deliver TRAIL locoregionally to gliomas and are testing these vectors in rodent glioma models to determine their therapeutic efficacy. More recently, we developed a novel ex vivo living tumor slice model to test the effects of various agents against brain tumors. We have recently been scored in the funding range for a R01 grant for this project.
We have received an R21 NIH Quick Trials Grant to support a clinical trial aimed at identifying markers of fenretinide activity in glioma tissue and serum, in order to identify subsets of patients who may benefit from such treatment. Further, as an extension to our work on retinoids in gliomas, we recently initiated laboratory studies on chromatin regulation by histone deacetylase (HDAC) inhibitors and demethylating agents against gliomas in vitro, either singly or in combination with retinoids. We have previously shown that retinoids such as 13-cis retinoic acid and fenretinide are active against gliomas in vitro but encounter resistance in human tumors. To develop strategies to overcome resistance to retinoids, we are studying the relevant signaling pathways activated by HDAC inhibitors and demethylating agents in vitro and assessing their effects against gliomas in combination with retinoids.
Samples obtained from clinical trials provide material for tumor profiling and understanding the molecular pathways that determine the activity of agents in the target tissue. Such approaches may help prospectively identify subsets of patients in whom a particular treatment will be most effective. The results of our studies may provide insights into the clinical behavior of gliomas and serve as a basis for new therapeutic approaches against gliomas.
Groves MD, Puduvalli VK, Chang SM, Conrad CA, Gilbert MR, Tremont-Lukats IW, Liu TJ, Peterson P, Schiff D, Cloughesy TF, Wen PY, Greenberg H, Abrey LE, DeAngelis LM, Hess KR, Lamborn KR, Prados MD, Yung WK. A North American brain tumor consortium (NABTC 99-04) phase II trial of temozolomide plus thalidomide for recurrent glioblastoma multiforme. J Neurooncol 81: 271-277, 2007.
Wen PY, Yung WK, Lamborn KR, Dahia PL, Wang Y, Peng B, Abrey LE, Raizer J, Cloughesy TF, Fink K, Gilbert M, Chang S, Junck L, Schiff D, Lieberman F, Fine HA, Mehta M, Robins HI, DeAngelis LM, Groves MD, Puduvalli VK, Levin V, Conrad C, Maher EA, Aldape K, Hayes M, Letvak L, Egorin MJ, Capdeville R, Kaplan R, Murgo AJ, Stiles C, Prados MD. Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99-08. Clin Cancer Res 12: 4899-4907, 2006.
Levin VA, Giglio P, Puduvalli VK, Jochec J, Groves MD, Yung WK, Hess K. Combination chemotherapy with 13-cis-retinoic acid and celecoxib in the treatment of glioblastoma multiforme. J Neurooncol 78: 85-90, 2006.
Groves MD, Puduvalli VK, Conrad CA, Gilbert MR, Yung WK, Jaeckle K, Liu V, Hess KR, Aldape KD, Levin VA. Phase II trial of temozolomide plus marimastat for recurrent anaplastic gliomas: a relationship among efficacy, joint toxicity and anticonvulsant status. J Neurooncol 80: 83-90, 2006.
Puduvalli VK, Sampath D, Bruner JM, Nangia J, Xu R, Kyritsis AP. TRAIL-induced apoptosis in gliomas is enhanced by Akt-inhibition and is independent of JNK activation. Apoptosis 10: 233-243, 2005.
Puduvalli VK, Li JT, Chen L, McCutcheon IE. Induction of apoptosis in primary meningioma cultures by fenretinide. Cancer Res 65: 1547-1553, 2005.
Puduvalli VK, Yung WK, Hess KR, Kuhn JG, Groves MD, Levin VA, Zwiebel J, Chang SM, Cloughesy TF, Junck L, Wen P, Lieberman F, Conrad CA, Gilbert MR, Meyers CA, Liu V, Mehta MP, Nicholas MK, Prados M. Phase II study of fenretinide (NSC 374551) in adults with recurrent malignant gliomas: A North American Brain Tumor Consortium study. J Clin Oncol 22: 4282-4289, 2004.Puduvalli VK, Li JT, Chen L, McCutcheon IE. Induction of apoptosis in primary meningioma cultures by fenretinide. Cancer Res. 2005 Feb 15;65(4):1547-53.
Puduvalli VK, Yung WK, Hess KR, Kuhn JG, Groves MD, Levin VA, Zwiebel J, Chang SM, Cloughesy TF, Junck L, Wen P, Lieberman F, Conrad CA, Gilbert MR, Meyers CA, Liu V, Mehta MP, Nicholas MK, Prados M; North American Brain Tumor Consortium. Phase II study of fenretinide (NSC 374551) in adults with recurrent malignant gliomas: A North American Brain Tumor Consortium study. J Clin Oncol. 2004 Nov 1;22(21):4282-9.
Tran HT, Blumenschein GR Jr, Lu C, Meyers CA, Papadimitrakopoulou V, Fossella FV, Zinner R, Madden T, Smythe LG, Puduvalli VK, Munden R, Truong M, Herbst RS. Clinical and pharmacokinetic study of TNP-470, an angiogenesis inhibitor, in combination with paclitaxel and carboplatin in patients with solid tumors. Cancer Chemother Pharmacol. 2004 Oct;54(4):308-14. Epub 2004 Jun 4.
Wang LE, Bondy ML, Shen H, El-Zein R, Aldape K, Cao Y, Pudavalli V, Levin VA, Yung WK, Wei Q. Polymorphisms of DNA repair genes and risk of glioma. Cancer Res. 2004 Aug 15;64(16):5560-3.