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Dissertation/Thesis Abstract

EIF4E Phosphorylation as a Mechanism of Resistance To mTOR and Androgen Receptor Inhibition in Advanced Prostate Cancer
by D'Abronzo, Leandro Salati, Ph.D., University of California, Davis, 2017, 148; 10624361
Abstract (Summary)

Treatment for prostate cancer patients who experience recurrent disease involves androgen deprivation therapy (ADT) as prostate tumors are primarily driven by activation of the androgen receptor (AR). However, most patients on this therapy relapse within a few years after which this treatment fails to extend survival and progresses to castration resistant prostate cancer (CRPC). Treatment for CRPC often involve inhibitors of the AR itself, however, patients on these treatments often fail as well. The main cause for the failure of many therapies is acquired resistance to treatment; therefore, there is an urgent need to better understand this resistance for improved disease management. Protein translation plays an important role in altering signaling pathways by modifying protein expression levels, and offer promising targets for preventing acquired resistance. mTOR (mechanistic target of rapamycin) is a key regulator of protein translation in humans, and multiple mTOR inhibitors have been developed over the years and used in many diseases as treatment, including prostate cancer. EIF4E is a key component of the translational mechanism in eukaryotic organisms and its phosphorylation has been implicated in resistance to several therapies in many cancer types. EIF4E is involved in both cap-dependent and –independent translation, however, mTOR regulates only cap-dependent translation. Here I demonstrate using my data from in vitro studies as well as human-derived tumor-xenograft models that phosphorylation of eIF4E at Ser209 plays a significant role in the resistance of prostate tumors to AR and mTOR inhibition, by changing the mechanism of protein translation from cap-dependent to cap-independent to maintain tumor cellular proliferation, growth and survival. In recent years, many clinical trials used combinations of mTOR and AR inhibitors in patients with CRPC who have failed first line therapy; many of these studies fail especially if they are conducted in patients who had been pre-treated with an AR inhibitor; whereas others partially succeed if they are used in untreated patients. The overall goal of my thesis is to study the role of eIF4E phosphorylation in the development of resistance to mTOR and AR inhibitors in prostate cancer. My data points to AR as a suppressor of eIF4E phosphorylation, therefore explaining why prior treatment with the AR inhibitor bicalutamide made patients resistant to a combination of bicalutamide with the mTOR inhibitor RAD001. Furthermore, our results show that the receptor tyrosine-protein kinase ErbB3 negatively regulates phosphorylation of eIF4E, and high levels of ErbB3 may be an indicative of tumors that would respond to the combination therapy. Taken together, our studies demonstrate the mechanisms by which prostate cancer acquires resistance to mTOR and AR inhibition and explain some of the responsible proteins and pathways that are involved in this process. We also indicate promising biomarkers for evaluation of therapy effectiveness with this combination in prostate cancer patients.

Indexing (document details)
Advisor: Ghosh, Paramita M.
Commitee: Carraway, Kermit L., Wilson, Dennis
School: University of California, Davis
Department: Integrative Pathobiology
School Location: United States -- California
Source: DAI-B 79/02(E), Dissertation Abstracts International
Subjects: Molecular biology, Oncology
Keywords: Androgen receptor, Eif4e phosphorylation, Erbb3, Mtor, Prostate cancer, Resistance
Publication Number: 10624361
ISBN: 978-0-355-45192-4
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