The potency and safety of TRAIL has prompted clinical trials with the recombinant protein as a novel treatment for human cancer. While TRAIL is very active in killing tumor cells, recombinant TRAIL possesses drug properties that limit its efficacy such as short serum half-life, instability, and the inability to cross the intact blood-brain barrier. To overcome these limitations we identified a small molecule inducer of the TRAIL gene, TIC10 that is superior to recombinant TRAIL in terms of stability, bioavailability, ability to cross the blood-brain barrier, cost of production, and spectrum of activity. Importantly, our data shows that TIC10 is highly active in several aggressive and therapy-resistant cancers. On a mechanistic level, TIC10 causes potent antitumor effects and TRAIL-induction that is mediated by the transcription factor Foxo3a, which directly regulates the TRAIL gene promoter. Furthermore, we found that TIC10 results in the dual inactivation of Akt and ERK, thereby inhibiting their constitutive phosphorylation of Fox3a and potentiating its translocation to the nucleus and binding to the TRAIL gene promoter (Allen et al, Science Translational Medicine, In Press, 2013). We hypothesize that TIC10 induces potent antitumor effects that require Akt- and ERK-mediated Foxo3a nuclear translocation and transcriptional activation of the TRAIL gene. To address the hypothesis we propose the following specific aims:
Specific Aim #1 : Identify TIC10-induced effects on Foxo3a expression, phosphorylation, and subcellular localization;
Specific Aim #2 : Elucidate the role of Akt and ERK kinases in the mechanism of action of TIC10;
Specific Aim #3 : Determine the differential regulation of TRAIL gene transcription by FOXO family members. These studies will create a comprehensive molecular understanding of how TIC10 harnesses Foxo3a to achieve its potent antitumor activity and also has the potential to undercover novel regulatory mechanisms of Foxo3a activity that are biologically significant. Preclinical cancer models including orthotopic xenografts and transgenic mice along with primary human tumor specimens will substantiate the efficacy and validate the mechanistic findings regarding TIC10 and Foxo3a. Together, these studies will elucidate key and novel regulatory mechanisms involving Foxo3a with the first-in-class molecule TIC10 to yield insight regarding its mechanism of action as well as in clinical samples in the context of colon cancer disease progression. Our studies will facilitate the clinical translation of a novel anti-cancer therapeutic agent through further development in preclinical laboratory studies.

Public Health Relevance

We have discovered a new drug called TIC10 that uses normal and cancer cells to make a substance in your body called TRAIL that kills cancer cells. The compound is active in treating many different types of tumors, including brain tumors that are very difficult to treat. These studies will help understand how TIC10 works, will identify how key cell signaling molecules are changed by TIC10, and see if similar changes are seen in actual tumors of patients. This work will help greatly to advance TIC10 to the clinic in the future

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA173453-01A1
Application #
8641075
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Kondapaka, Sudhir B
Project Start
2013-09-30
Project End
2018-08-31
Budget Start
2013-09-30
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$316,682
Indirect Cost
$109,182
Name
Pennsylvania State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
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Finnberg, Niklas K; Gokare, Prashanth; Navaraj, Arunasalam et al. (2016) Agonists of the TRAIL Death Receptor DR5 Sensitize Intestinal Stem Cells to Chemotherapy-Induced Cell Death and Trigger Gastrointestinal Toxicity. Cancer Res 76:700-12
El-Deiry, Wafik S (2016) p21(WAF1) Mediates Cell-Cycle Inhibition, Relevant to Cancer Suppression and Therapy. Cancer Res 76:5189-91
Allen, Joshua E; Prabhu, Varun V; Talekar, Mala et al. (2015) Genetic and Pharmacological Screens Converge in Identifying FLIP, BCL2, and IAP Proteins as Key Regulators of Sensitivity to the TRAIL-Inducing Anticancer Agent ONC201/TIC10. Cancer Res 75:1668-74
Allen, Joshua E; Crowder, Roslyn N; Crowder, Roslyn et al. (2015) First-In-Class Small Molecule ONC201 Induces DR5 and Cell Death in Tumor but Not Normal Cells to Provide a Wide Therapeutic Index as an Anti-Cancer Agent. PLoS One 10:e0143082
Prabhu, Varun V; Allen, Joshua E; Dicker, David T et al. (2015) Small-Molecule ONC201/TIC10 Targets Chemotherapy-Resistant Colorectal Cancer Stem-like Cells in an Akt/Foxo3a/TRAIL-Dependent Manner. Cancer Res 75:1423-32
Talekar, Mala K; Allen, Joshua E; Dicker, David T et al. (2015) ONC201 induces cell death in pediatric non-Hodgkin's lymphoma cells. Cell Cycle 14:2422-8
Allen, Joshua E; Krigsfeld, Gabriel; Patel, Luv et al. (2015) Identification of TRAIL-inducing compounds highlights small molecule ONC201/TIC10 as a unique anti-cancer agent that activates the TRAIL pathway. Mol Cancer 14:99
Wagner, Jessica; Kline, Christina Leah; Pottorf, Richard S et al. (2014) The angular structure of ONC201, a TRAIL pathway-inducing compound, determines its potent anti-cancer activity. Oncotarget 5:12728-37
Allen, Joshua E; Krigsfeld, Gabriel; Mayes, Patrick A et al. (2013) Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects. Sci Transl Med 5:171ra17