Accession Number : AD1048444


Title :   Overcoming CRPC Treatment Resistance via Novel Dual AKR1C3 Targeting


Descriptive Note : Technical Report,30 Sep 2016,29 Sep 2017


Corporate Author : University of California, Davis Davis United States


Personal Author(s) : Evans, Christopher P


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/1048444.pdf


Report Date : 01 Oct 2017


Pagination or Media Count : 10


Abstract : AKR1C3 is the major AKR1C isozyme expressed in the human prostate; and elevated expression of this enzyme has been associated with prostate cancer progression and aggressiveness. Our hypothesis is that targeting AKR1C3 decreases intracrine androgens and AR variants and improves enzalutamide therapy against metastatic CRPC. During the first funding year, we demonstrated that AKR1C3 affected intracrine androgen biosynthesis. We introduced constructs expressing AKR1C3 under the control of doxycycline into LNCaP cells. We validated the biological function of the tet-inducible ARK1C3 in LNCaP/TR/AKR1C3 cells. When the gene was not induced, cell growth was readily inhibited by anti-androgens abiraterone (ABI) and enzalutamide (Enza). With doxycycline induction, the control treatment would benefit from overexpression of AKR1C3 and partially overcome the ABI and Enza inhibition. We measured intracellular and intratumor androgen levels by LC-MS induced by AKR1C3 and found that AKR1C3 expression induces intracrine androgen synthesis. We also demonstrated that overexpression of AKR1C3 in orthotopic model of LNCaP-AKR1C3 tumor confers resistance to enzalutamide treatment. These studies support the roles of AKR1C3 in intracrine androgen synthesis and confers resistance to enzalutamide.


Descriptors :   drug resistance , prostate cancer , androgens , genes , neoplasms


Subject Categories : Medicine and Medical Research
      Genetic Engineering and Molecular Biology
      Pharmacology


Distribution Statement : APPROVED FOR PUBLIC RELEASE