High-Throughput Screening for Novel Prostate Cancer Drug Targets: Getting Personal: Dissertation

Paula Vainio

Research output: ThesisDissertation

Abstract

Prostate cancers form a heterogeneous group of diseases and there is a need for novel biomarkers, and for more efficient and targeted methods of treatment. In this thesis, the potential of microarray data, RNA interference (RNAi) and compound screens were utilized in order to identify novel biomarkers, drug targets and drugs for future personalized prostate cancer therapeutics. First, a bioinformatic mRNA expression analysis covering 9873 human tissue and cell samples, including 349 prostate cancer and 147 normal prostate samples, was used to distinguish in silico prevalidated putative prostate cancer biomarkers and drug targets. Second, RNAi based high-throughput (HT) functional profiling of 295 prostate and prostate cancer tissue specific genes was performed in cultured prostate cancer cells. Third, a HT compound screen approach using a library of 4910 drugs and drug-like molecules was exploited to identify potential drugs inhibiting prostate cancer cell growth. Nine candidate drug targets, with biomarker potential, and one cancer selective compound were validated in vitro and in vivo. In addition to androgen receptor (AR) signaling, endoplasmic reticulum (ER) function, arachidonic acid (AA) pathway, redox homeostasis and mitosis were identified as vital processes in prostate cancer cells. ERG oncogene positive cancer cells exhibited sensitivity to induction of oxidative and ER stress, whereas advanced and castrate-resistant prostate cancer (CRPC) could be potentially targeted through AR signaling and mitosis. In conclusion, this thesis illustrates the power of systems biological data analysis in the discovery of potential vulnerabilities present in prostate cancer cells, as well as novel options for personalized cancer management.
Original languageEnglish
QualificationDoctor Degree
Awarding Institution
  • University of Turku
Supervisors/Advisors
  • Iljin, Kristiina, Supervisor
  • Kallioniemi, Olli, Supervisor, External person
Place of PublicationTurku
Publisher
Print ISBNs978-951-29-4822-2
Electronic ISBNs978-951-29-4823-9
Publication statusPublished - 2011
MoE publication typeG5 Doctoral dissertation (article)

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Prostatic Neoplasms
Pharmaceutical Preparations
Biomarkers
Androgen Receptors
RNA Interference
Mitosis
Prostate
Neoplasms
Endoplasmic Reticulum Stress
Tumor Biomarkers
Computational Biology
Oncogenes
Arachidonic Acid
Endoplasmic Reticulum
Computer Simulation
Oxidation-Reduction
Homeostasis
Messenger RNA
Growth
Genes

Keywords

  • Prostate cancer
  • high-throughput screening
  • gene expression
  • RNA interference
  • drug target
  • biomarker
  • drug
  • eturauhassyöpä
  • tehoseulonta
  • RNA interferenssi
  • geenin ilmentyminen
  • lääkehoidon kohde
  • merkkiaine
  • lääke

Cite this

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title = "High-Throughput Screening for Novel Prostate Cancer Drug Targets: Getting Personal: Dissertation",
abstract = "Prostate cancers form a heterogeneous group of diseases and there is a need for novel biomarkers, and for more efficient and targeted methods of treatment. In this thesis, the potential of microarray data, RNA interference (RNAi) and compound screens were utilized in order to identify novel biomarkers, drug targets and drugs for future personalized prostate cancer therapeutics. First, a bioinformatic mRNA expression analysis covering 9873 human tissue and cell samples, including 349 prostate cancer and 147 normal prostate samples, was used to distinguish in silico prevalidated putative prostate cancer biomarkers and drug targets. Second, RNAi based high-throughput (HT) functional profiling of 295 prostate and prostate cancer tissue specific genes was performed in cultured prostate cancer cells. Third, a HT compound screen approach using a library of 4910 drugs and drug-like molecules was exploited to identify potential drugs inhibiting prostate cancer cell growth. Nine candidate drug targets, with biomarker potential, and one cancer selective compound were validated in vitro and in vivo. In addition to androgen receptor (AR) signaling, endoplasmic reticulum (ER) function, arachidonic acid (AA) pathway, redox homeostasis and mitosis were identified as vital processes in prostate cancer cells. ERG oncogene positive cancer cells exhibited sensitivity to induction of oxidative and ER stress, whereas advanced and castrate-resistant prostate cancer (CRPC) could be potentially targeted through AR signaling and mitosis. In conclusion, this thesis illustrates the power of systems biological data analysis in the discovery of potential vulnerabilities present in prostate cancer cells, as well as novel options for personalized cancer management.",
keywords = "Prostate cancer, high-throughput screening, gene expression, RNA interference, drug target, biomarker, drug, eturauhassy{\"o}p{\"a}, tehoseulonta, RNA interferenssi, geenin ilmentyminen, l{\"a}{\"a}kehoidon kohde, merkkiaine, l{\"a}{\"a}ke",
author = "Paula Vainio",
note = "TK401 SDA: BIC",
year = "2011",
language = "English",
isbn = "978-951-29-4822-2",
series = "Annales Universitatis Turkuensis Series D: Medica-Odontologica",
publisher = "University of Turku",
address = "Finland",
school = "University of Turku",

}

High-Throughput Screening for Novel Prostate Cancer Drug Targets : Getting Personal: Dissertation. / Vainio, Paula.

Turku : University of Turku, 2011. 74 p.

Research output: ThesisDissertation

TY - THES

T1 - High-Throughput Screening for Novel Prostate Cancer Drug Targets

T2 - Getting Personal: Dissertation

AU - Vainio, Paula

N1 - TK401 SDA: BIC

PY - 2011

Y1 - 2011

N2 - Prostate cancers form a heterogeneous group of diseases and there is a need for novel biomarkers, and for more efficient and targeted methods of treatment. In this thesis, the potential of microarray data, RNA interference (RNAi) and compound screens were utilized in order to identify novel biomarkers, drug targets and drugs for future personalized prostate cancer therapeutics. First, a bioinformatic mRNA expression analysis covering 9873 human tissue and cell samples, including 349 prostate cancer and 147 normal prostate samples, was used to distinguish in silico prevalidated putative prostate cancer biomarkers and drug targets. Second, RNAi based high-throughput (HT) functional profiling of 295 prostate and prostate cancer tissue specific genes was performed in cultured prostate cancer cells. Third, a HT compound screen approach using a library of 4910 drugs and drug-like molecules was exploited to identify potential drugs inhibiting prostate cancer cell growth. Nine candidate drug targets, with biomarker potential, and one cancer selective compound were validated in vitro and in vivo. In addition to androgen receptor (AR) signaling, endoplasmic reticulum (ER) function, arachidonic acid (AA) pathway, redox homeostasis and mitosis were identified as vital processes in prostate cancer cells. ERG oncogene positive cancer cells exhibited sensitivity to induction of oxidative and ER stress, whereas advanced and castrate-resistant prostate cancer (CRPC) could be potentially targeted through AR signaling and mitosis. In conclusion, this thesis illustrates the power of systems biological data analysis in the discovery of potential vulnerabilities present in prostate cancer cells, as well as novel options for personalized cancer management.

AB - Prostate cancers form a heterogeneous group of diseases and there is a need for novel biomarkers, and for more efficient and targeted methods of treatment. In this thesis, the potential of microarray data, RNA interference (RNAi) and compound screens were utilized in order to identify novel biomarkers, drug targets and drugs for future personalized prostate cancer therapeutics. First, a bioinformatic mRNA expression analysis covering 9873 human tissue and cell samples, including 349 prostate cancer and 147 normal prostate samples, was used to distinguish in silico prevalidated putative prostate cancer biomarkers and drug targets. Second, RNAi based high-throughput (HT) functional profiling of 295 prostate and prostate cancer tissue specific genes was performed in cultured prostate cancer cells. Third, a HT compound screen approach using a library of 4910 drugs and drug-like molecules was exploited to identify potential drugs inhibiting prostate cancer cell growth. Nine candidate drug targets, with biomarker potential, and one cancer selective compound were validated in vitro and in vivo. In addition to androgen receptor (AR) signaling, endoplasmic reticulum (ER) function, arachidonic acid (AA) pathway, redox homeostasis and mitosis were identified as vital processes in prostate cancer cells. ERG oncogene positive cancer cells exhibited sensitivity to induction of oxidative and ER stress, whereas advanced and castrate-resistant prostate cancer (CRPC) could be potentially targeted through AR signaling and mitosis. In conclusion, this thesis illustrates the power of systems biological data analysis in the discovery of potential vulnerabilities present in prostate cancer cells, as well as novel options for personalized cancer management.

KW - Prostate cancer

KW - high-throughput screening

KW - gene expression

KW - RNA interference

KW - drug target

KW - biomarker

KW - drug

KW - eturauhassyöpä

KW - tehoseulonta

KW - RNA interferenssi

KW - geenin ilmentyminen

KW - lääkehoidon kohde

KW - merkkiaine

KW - lääke

M3 - Dissertation

SN - 978-951-29-4822-2

T3 - Annales Universitatis Turkuensis Series D: Medica-Odontologica

PB - University of Turku

CY - Turku

ER -