Glioblastoma multiform WHO IV (GBM) is the most common primary brain tumor with no current curative treatment, rapid progression and recurrence, leading to death within 12-18 month. The transcription factor ATF5, a member of the activating transcription factor (ATF)/cAMP response-element binding protein (CREB) family, is over-expressed in GBMs compared to non-neoplastic astrocytes and neurons. In this proposal ATF5 is targeted by a novel designed peptide drug, called CP-d/n-ATF5 (cell penetrating dominant-negative ATF5). Preliminary data show that CP-d/n-ATF5 effectively kills GBM cells in vitro and in vivo. We will determine the mechanism by which CP-d/n-ATF5 elicits its anti-glioma effects and test its suitability for drug combination therapy in vitro and in vivo. In our preliminry data, we have shown that CP-d/n-ATF5 mediates striking increases in p73, DR5 (a pro-apoptotic receptor for death ligand TRAIL) and PUMA (a pro-apoptotic Bcl-2 family protein) protein levels. P73 is a homolog of the tumor suppressor p53, which, in contrast to TP53 is not commonly mutated in GBM, but which shares similar downstream targets, e.g. DR5 and PUMA, that enhance apoptosis (programmed cell death) and promote cell cycle arrest. Therefore, reagents that induce p73 are highly valuable tumor therapeutics. We will test the hypothesis that CP-d/n-ATF5 kills GBM cells by up- regulating p73 that in turn induces death via PUMA-dependent apoptosis. We will also evaluate the hypotheses that induction of DR5 by CP-d/n-ATF5 is dependent on p73 and that elevated DR5 will permit a combination GBM therapy of CP-d/n-ATF5 with the DR5 ligand TRAIL. Our preliminary data with the TRAIL/CP-d/n-ATF5 combination demonstrate synergistic killing of GBM cells as compared to single treatments. These effects were mediated by CP-d/n-ATF5-induced up-regulation of DR5, and coincided with an increase of p73 protein levels. Specific suppression of DR5 by siRNA mitigates CP-d/n-ATF5/TRAIL mediated cell death. The research program will be conducted under the guidance of Dr. Lloyd Greene (Department of Pathology and Cell Biology at Columbia University) who has a significant track record of training physician-scientists and who has launched many careers of successful and accomplished biomedical researchers. As Co-Mentors will serve Drs. Peter Canoll (Department of Pathology and Cell Biology at Columbia University) and Jeffrey Bruce (Department of Neurosurgery). Dr. Canoll and Dr. Bruce are leading the Brain Tumor Center at Columbia and are highly accomplished. Both have active NIH-funded research projects related to glioblastoma animal models with sophisticated drug delivery systems. This proposed project along with its renowned and accomplished mentors, course work, training opportunities and career development plan will train the applicant in glioblastoma-related research with an emphasis on preclinical drug development and assist him to become an independent investigator.

Public Health Relevance

Glioblastoma multiforme WHO IV (GBM) is the most common primary brain tumor (brain cancer) in the United States of America with no current curative treatment, rapid progression and recurrence, leading to death within 12-18 month. This proposal establishes a novel, tumor-specific treatment approach for GBM, utilizing preclinical disease models.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS083732-03
Application #
9096229
Study Section
NST-2 Subcommittee (NST)
Program Officer
Fountain, Jane W
Project Start
2014-08-01
Project End
2019-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Ishida, Chiaki Tsuge; Bianchetti, Elena; Shu, Chang et al. (2017) BH3-mimetics and BET-inhibitors elicit enhanced lethality in malignant glioma. Oncotarget 8:29558-29573
Karpel-Massler, Georg; Ishida, Chiaki Tsuge; Bianchetti, Elena et al. (2017) Inhibition of Mitochondrial Matrix Chaperones and Antiapoptotic Bcl-2 Family Proteins Empower Antitumor Therapeutic Responses. Cancer Res 77:3513-3526
Ishida, Chiaki Tsuge; Shu, Chang; Halatsch, Marc-Eric et al. (2017) Mitochondrial matrix chaperone and c-myc inhibition causes enhanced lethality in glioblastoma. Oncotarget 8:37140-37153
Karpel-Massler, Georg; Ishida, Chiaki Tsuge; Bianchetti, Elena et al. (2017) Induction of synthetic lethality in IDH1-mutated gliomas through inhibition of Bcl-xL. Nat Commun 8:1067
Karpel-Massler, Georg; Horst, Basil A; Shu, Chang et al. (2016) A Synthetic Cell-Penetrating Dominant-Negative ATF5 Peptide Exerts Anticancer Activity against a Broad Spectrum of Treatment-Resistant Cancers. Clin Cancer Res 22:4698-711
Cates, Charles C; Arias, Angelo D; Nakayama Wong, Lynn S et al. (2016) Regression/eradication of gliomas in mice by a systemically-deliverable ATF5 dominant-negative peptide. Oncotarget 7:12718-30
Karpel-Massler, Georg; Ramani, Doruntina; Shu, Chang et al. (2016) Metabolic reprogramming of glioblastoma cells by L-asparaginase sensitizes for apoptosis in vitro and in vivo. Oncotarget 7:33512-28
Karpel-Massler, Georg; Banu, Matei A; Shu, Chang et al. (2016) Inhibition of deubiquitinases primes glioblastoma cells to apoptosis in vitro and in vivo. Oncotarget 7:12791-805
Nonnenmacher, Lisa; Hasslacher, Sebastian; Zimmermann, Julia et al. (2016) Cell Death Induction in Cancer Therapy - Past, Present, and Future. Crit Rev Oncog 21:253-267
Mohammad, Ramzi M; Muqbil, Irfana; Lowe, Leroy et al. (2015) Broad targeting of resistance to apoptosis in cancer. Semin Cancer Biol 35 Suppl:S78-S103

Showing the most recent 10 out of 16 publications