Traditional and Novel Treatments for Prostate Cancer Discoveries at the Molecular Level
Acta Universitatis Tamperensis No. 1745
By Saara Lehmusvaara
Tampere University Press
$87.50 Paper original
The efficient treatment of prostate cancer faces several challenges. Although an overwhelming majority of all prostate cancers can be efficiently treated by radical prostatectomy or radiation therapy, prostate cancer remains one of the main cancer killers in the Western world. The mortality rate is high for two reasons: prostate cancer has the most frequent occurrence of all cancers affecting men, and effective treatments against metastatic prostate cancer do not exist.
The lethal form of prostate cancer is aggressive and metastasizes to other tissues. For this form, the most efficient treatment is endocrine therapy. However, this therapy is not curative. Resistance against treatment develops in an average of 18-24 months, and after resistance has developed, the mean overall survival time of patients with metastatic prostate cancer is only 20 months. Despite intensive studies, the molecular mechanisms leading to resistance to endocrine therapy remain obscure. The understanding of these molecular mechanisms will enhance the development of more efficient treatment methods and will improve the survival of prostate cancer patients.
This study aimed to determine the molecular consequences of the two most commonly used endocrine therapies for prostate cancer. We utilized rare clinical material from 28 prostate cancer patients who had undergone neoadjuvant endocrine therapy and analyzed the expression levels of all known protein-coding genes and over 700 miRNAs from the prostate cancer samples by microarray. Furthermore, we determined the cancer-specific gene expression levels from heterogeneous prostate tissue samples using an in silico Bayesian modeling tool.
The rare clinical material enabled us to study events that have previously been studied using mainly in vitro or animal models. We detected great differences in transcriptome levels between the two endocrine therapies, GnRH agonist and antiandrogens, despite their similar clinical outcomes. In addition, we determined the frequency of the most common fusion gene in prostate cancer, TMPRSS2:ERG, from the samples and determined how the endocrine treatment affected the ERG-regulated genes. In non-treated patients, the TMPRSS2:ERG fusion enhanced the expression of proliferation-related genes. Interestingly, the endocrine therapies reduced the expression of these genes and diminished the differences between fusion-positive and fusion-negative samples.
In addition, we characterized possible androgen receptor dependent regulation and cancer specificity of the most differently expressed genes after endocrine therapy. Several miRNAs and two protein-coding genes (NEDD4L and TPD52) showed their potential as prognostic biomarkers for the formation of treatment resistance. However, more studies are needed to explore their potency fully. The last part of the study explored the capacity of novel polycationic peptides to enhance the transduction of viral gene transfer vectors into prostate and other cancer cells. With optimized transduction efficiency, viral gene therapy could be used as a novel treatment method for prostate and other cancers. However, our study revealed that polycationic peptides were not more efficient than polybrene and protamine sulphate, which are the small cationic compounds traditionally used in in vitro cell culture models. Thus, more studies with different approaches are needed to obtain clinically sufficient gene transfer efficiency with the current viral vectors.
This study provides valuable, novel information regarding the transcriptional events in prostate cancer and can assist in the development of more effective treatment methods for prostate cancer.
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