[Frontiers In Bioscience, Landmark, 23, 1292-1309, January 1, 2018]

LINE-1 as a therapeutic target for castration-resistant prostate cancer

Nadine Houede1,2 , Pier Vincenzo Piazza3, Philippe Pourquier1,2

1Medical Oncology Department, Nimes University Hospital, Nimes, France, 2INSERM U1194, Montpellier Cancer Research Institute, and Montpellier University, France, 3INSERM U1215, Physiopathology of Neuronal Plasticity, Neurocentre Magendie and Bordeaux University, France

TABLE OF CONTENTS

1. Abstract
2. Introduction
2.1. Epidemiology of prostate cancers
2.2. The genetic background of prostate tumors
3. The treatments of prostate cancer
3.1. Drugs that are clinically approved
3.2. Drugs that are in development
4. LINE-1 as a rational target for prostate cancer
4.1. Role of LINE-1 in tumorigenesis
4.2. Targeting LINE-1 in prostate cancers
4.3. The clinical evaluation of efavirenz in mCRPC patients
5. Conclusion and perspectives
6. References

1. ABSTRACT

Prostate cancer is the third leading cause of death by cancer in men. Surgery or hormone deprivation usually contains the progression of the local forms of the disease. In metastatic situations, chemotherapy or second generation hormone therapies are used with an overall survival that never exceeds 36 months when tumors become resistant to castration. In the search for new alternatives, clinical trials with various classes of anticancer drugs have been performed, including chemotherapies, targeted therapies with kinase inhibitors, radium-223, or immunotherapies with somehow limited efficacy. Targeting LINE-1 with reverse transcriptase inhibitors was also proposed as an attractive strategy as retrotransposons may play a role in the initiation and the progression of prostate cancers. After reviewing the biological rational to use RT inhibitors in the treatment of prostate cancers, we will discuss the results of the phase II trial evaluating the efficacy of Efavirenz in the treatment of castration-resistant prostate cancers with a particular emphasis on pharmacokinetics data that were obtained. We will also discuss the positioning of other RT inhibitors in the current therapeutic armamentarium.

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Abbreviations: AR: androgen receptor; CDH1: cadherin 1; CNS: central nervous system; EGFR: epidermal growth factor receptor; ERG: ETS-related gene; ETS: E26 transformation-specific; ETV: ETS variant gene; FGFR: fibroblast growth factor receptor; GM-CSF: granulocyte-macrophage colony-stimulating factor; HAART: highly active antiretroviral therapy; HIV: human immunodeficiency virus; HSP: heat shock protein; IDH1: isocitrate dehydrogenase NADP+ 1; LHRH: luteinizing hormone releasing hormone; LINE-1: long interspersed nuclear elements-1; mCRPC: metastatic castration resistant prostate cancer; mTOR: mammalian target of rapamycin; NNRTI: non-nucleoside reverse transcriptase inhibitor; NRTI: nucleoside reverse transcriptase inhibitor; PDGFR: platelet derived growth factor receptor; PI3K: phosphatidylinositol 3 kinase; PPARG: peroxisome proliferator activated receptor gamma; PSA: prostate specific antigen; PTEN: phosphatase and tensin homolog; RT: reverse transcriptase; SLC45A3: solute carrier transporter 45A3; SPINK1: serine peptidase inhibitor kazal type 1; SPOP: speckle type BTB/POZ protein; TMPRSS2: transmembrane serine protease 2; TP53: tumor protein 53; VEGFR: vascular endothelial growth factor receptor

Key Words: Prostate Cancer, Resistance to castration, LINE-1, Efavirenz

Send correspondence to: Philippe Pourquier, INSERM U1194, Montpellier Cancer Research Institute, Montpellier, France, Tel: 334676137 45, Fax: 33467613787, E-mail: philippe.pourquier@inserm.fr