Glioblastoma multiforme (GBM) is one of the most lethal malignancies in part due to its highly invasive nature and due to the relative resistance of GBM cells to fully respond to radio- or chemo-therapies. A series of compounds have been derived from the chemical backbone of the NSAID Celecoxib that do not possess COX2 inhibitory activity, but are highly bio-available, can cross the blood-brain barrier, and are an order of magnitude more potent at suppressing tumor cell viability than the parent drug. We have shown that the most potent lead compound, OSU-03012, causes a strong induction cell death in established and primary human GBM cells in vitro, but not in cultures of non-transformed primary astrocytes or primary hepatocytes, at concentrations in the 1-5 ?M range, which is lower than the 15-20 ?M achievable plasma concentration of this agent in rodents. This compound was selected by the NCI RAID program for development, in part based on our data, and a phase I trial with this drug as a single agent will commence in other tumor types in 2009. We have demonstrated in primary and established human GBM cells that OSU-03012 suppresses short-term viability and colony formation in vitro and that OSU-03012 -induced killing occurs primarily via in the induction of a toxic endoplasmic reticulum (ER) stress / autophagy signal. In vivo we have noted in one GBM model that OSU-03012 can enhance animal survival and interact with radiotherapy to further prolong survival. We have published that the lethality of OSU-03012 is magnified by inhibition of HSP90 or by exposure to ionizing radiation. We hypothesize that: geldanamycin HSP90 agonists via ROS and ceramide production cause CD95 activation in parallel to OSU-03012 -induced toxic autophagy which is responsible for the synergy of GBM cell killing. We hypothesize that: ionizing radiation enhances OSU-03012 toxicity by promoting expression/ activation of ceramide synthase genes which enhances OSU-03012 -induced toxic autophagy.
Specific Aim 1 : Will determine the molecular mechanism(s) by which OSU-03012 toxicity in primary human GBM cells is promoted by exposure to the HSP90 antagonists (geldanamycins) 17AAG / 17DMAG.
Specific Aim 2 : Will determine the molecular mechanisms by which OSU-03012 radio-sensitizes primary human GBM cells with specific focus on the regulatory roles of ceramide synthase genes.
Specific Aim 3 : Will determine, using orthotopic xenograft models of primary human GBM cells, whether OSU-03012 enhances the tumoricidal effects of ionizing radiation or of 17AAG, in vivo. The goal of the studies in this proposal is to provide detailed mechanistic evidence to move OSU-03012 as a therapeutic for GBM from the bench into the clinic.

Public Health Relevance

OSU-03012 was licensed in 2008 to a biotechnology company (Arno) in part based on our data published in three manuscripts, and a phase I trial with this drug as a single agent will commence in 2009 in a variety of malignancies but not with any likely accrual in GBM patients. The goal of the studies in this proposal is to determine in molecular detail using primary human GBM cells the mechanisms of action of OSU-03012 as a single agent and in combination with ionizing radiation;and in combination with geldanamycins to inhibit HSP90 function. Our goal is to provide detailed mechanistic evidence to move OSU-03012 as a therapeutic for GBM into the clinic.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Developmental Therapeutics Study Section (DT)
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Bernhard, Eric J
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Virginia Commonwealth University
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Booth, Laurence; Roberts, Jane L; Tavallai, Mehrad et al. (2015) OSU-03012 and Viagra Treatment Inhibits the Activity of Multiple Chaperone Proteins and Disrupts the Blood-Brain Barrier: Implications for Anti-Cancer Therapies. J Cell Physiol 230:1982-98
Tavallai, Mehrad; Hamed, Hossein A; Roberts, Jane L et al. (2015) Nexavar/Stivarga and viagra interact to kill tumor cells. J Cell Physiol 230:2281-98
Hamed, Hossein A; Tavallai, Seyedmehrad; Grant, Steven et al. (2015) Sorafenib/regorafenib and lapatinib interact to kill CNS tumor cells. J Cell Physiol 230:131-9
Roberts, Jane L; Tavallai, Mehrad; Nourbakhsh, Aida et al. (2015) GRP78/Dna K Is a Target for Nexavar/Stivarga/Votrient in the Treatment of Human Malignancies, Viral Infections and Bacterial Diseases. J Cell Physiol 230:2552-78
Booth, Laurence; Roberts, Jane L; Cash, Devin R et al. (2015) GRP78/BiP/HSPA5/Dna K is a universal therapeutic target for human disease. J Cell Physiol 230:1661-76
Azab, Belal M; Dash, Rupesh; Das, Swadesh K et al. (2014) Enhanced prostate cancer gene transfer and therapy using a novel serotype chimera cancer terminator virus (Ad.5/3-CTV). J Cell Physiol 229:34-43
Booth, Laurence A; Tavallai, Seyedmehrad; Hamed, Hossein A et al. (2014) The role of cell signalling in the crosstalk between autophagy and apoptosis. Cell Signal 26:549-55
Tavallai, Seyedmehrad; Hamed, Hossein A; Grant, Steven et al. (2014) Pazopanib and HDAC inhibitors interact to kill sarcoma cells. Cancer Biol Ther 15:578-85
Booth, Laurence; Roberts, Jane L; Cruickshanks, Nichola et al. (2014) Phosphodiesterase 5 inhibitors enhance chemotherapy killing in gastrointestinal/genitourinary cancer cells. Mol Pharmacol 85:408-19
Booth, Laurence; Roberts, Jane L; Cruickshanks, Nichola et al. (2014) Regulation of OSU-03012 toxicity by ER stress proteins and ER stress-inducing drugs. Mol Cancer Ther 13:2384-98

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