TARP Promoter-Based Prostate Cancer Gene Therapy: From Development to Application

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Cheng, Wing-Shing,1974-Uppsala universitet,Enheten för klinisk immunologi (författare)

TARP Promoter-Based Prostate Cancer Gene Therapy : From Development to Application

BokEngelska2005

Förlag, utgivningsår, omfång ...

Uppsala :Acta Universitatis Upsaliensis,2005
57 s.
electronicrdacarrier

Nummerbeteckningar

LIBRIS-ID:oai:DiVA.org:uu-5736
ISBN:9155462057
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-5736URI

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Språk:engelska
Sammanfattning på:engelska

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Ämneskategori:vet swepub-contenttype
Ämneskategori:dok swepub-publicationtype

Serie

Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine,1651-6206 ;24

Anmärkningar

Prostate cancer is one leading cause of cancer-related death among men in Western countries. The standard therapies for localized prostate cancer include radical prostatectomy and radiation therapy. Such measures are relatively effective in the short term, but many patients ultimately relapse. These patients may benefit from a combination of standard therapy and oncolytic virus therapy. My work aimed to develop viruses for this purpose.TARP is a protein that in males is specifically expressed in prostate epithelial and cancer cells. In my thesis, I characterized the TARP promoter and showed that TARP expression is regulated at the transcriptional level by testosterone through binding of the androgen receptor in the proximal TARP promoter. I further developed TARP promoter-based regulatory sequences for prostate-specific gene expression. A sequence comprising a PSA enhancer, a PSMA enhancer and the TARP promoter was constructed and designated PPT. An adenoviral vector containing the PPT sequence shielded from transcriptional interference by an H19 insulator showed high prostate-specific transcriptional activity in human cells both in the presence and absence of testosterone. However, in experimental murine prostate cancer the PPT sequence is not active. Therefore, a two-step transcriptional amplification (TSTA) system was used together with the PPT sequence to develop an adenovirus that confers prostate-specific transgene expression also in murine cells.I constructed a conditionally replicating adenovirus where the E1A gene expression is controlled by an H19 insulator-shielded PPT regulatory sequence, Ad[I/PPT-E1A]. This virus exhibited absolute prostate specificity in terms of E1A expression, viral replication and cytolysis in vitro and in vivo. Importantly, our virus is active both in the presence and absence of testosterone, which may prove beneficial for patients treated by hormonal withdrawal. Hopefully, my work will improve existing gene therapy strategies for prostate cancer and in the long term improve the prognosis for patients with prostate cancer.

Ämnesord och genrebeteckningar

TEKNIK OCH TEKNOLOGIER Industriell bioteknik Annan industriell bioteknik hsv//swe
ENGINEERING AND TECHNOLOGY Industrial Biotechnology Other Industrial Biotechnology hsv//eng
Genetic engineering
TARP
PPT
TSTA
promoter
gene regulation
prostate specificity
hormone- independent
adenovirus
prostate cancer
gene therapy
conditionally replicating adenovirus
Genteknik
Genetic engineering including functional genomics
Genteknik inkl. funktionsgenomik

Biuppslag (personer, institutioner, konferenser, titlar ...)

Essand, Magnus (preses)
Tötterman, Thomas H. (preses)
Lundberg, Cecilia,DocentInstitutionen för fysiologiska vetenskaper, Wallenberg Neuroscience Center, Lund Universitet, Lund (opponent)
Uppsala universitetEnheten för klinisk immunologi (creator_code:org_t)

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Av författaren/redakt...: Cheng, Wing-Shin ...; Essand, Magnus; Tötterman, Thoma ...; Lundberg, Cecili ...

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Av lärosätet: Uppsala universitet

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