Gene Transfer Vectors Targeted to Human Prostate Cancer: Do We Need Better Preclinical Testing Systems?

Maitland, Norman J.; Chambers, Karen; Georgopoulos, Lindsay; Simpson-Holley, Martha; Leadley, Regina M.; Evans, Helen H.; Essand, Magnus; Danielsson, Anna; Weerden, Wytske van; Ridder, Corrina de; Kraaij, Robert; Bangma, Chris H.

doi:10.1089/hum.2009.210

Cited by 8 publications

(3 citation statements)

References 75 publications

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“…The primary patient-derived prostate epithelial cell cultures used in this study represented a clinically relevant model for assessing the BV vector [47]. These cultures, like the prostate tumour itself, contained a heterogeneous mix of malignant and non-malignant cells, represented in varying proportions between patient samples.…”

Section: Discussionmentioning

confidence: 99%

Evaluating Baculovirus as a Vector for Human Prostate Cancer Gene Therapy

et al. 2013

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Gene therapy represents an attractive strategy for the non-invasive treatment of prostate cancer, where current clinical interventions show limited efficacy. Here, we evaluate the use of the insect virus, baculovirus (BV), as a novel vector for human prostate cancer gene therapy. Since prostate tumours represent a heterogeneous environment, a therapeutic approach that achieves long-term regression must be capable of targeting multiple transformed cell populations. Furthermore, discrimination in the targeting of malignant compared to non-malignant cells would have value in minimising side effects. We employed a number of prostate cancer models to analyse the potential for BV to achieve these goals. In vitro, both traditional prostate cell lines as well as primary epithelial or stromal cells derived from patient prostate biopsies, in two- or three-dimensional cultures, were used. We also evaluated BV in vivo in murine prostate cancer xenograft models. BV was capable of preferentially transducing invasive malignant prostate cancer cell lines compared to early stage cancers and non-malignant samples, a restriction that was not a function of nuclear import. Of more clinical relevance, primary patient-derived prostate cancer cells were also efficiently transduced by BV, with robust rates observed in epithelial cells of basal phenotype, which expressed BV-encoded transgenes faster than epithelial cells of a more differentiated, luminal phenotype. Maximum transduction capacity was observed in stromal cells. BV was able to penetrate through three-dimensional structures, including in vitro spheroids and in vivo orthotopic xenografts. BV vectors containing a nitroreductase transgene in a gene-directed enzyme pro-drug therapy approach were capable of efficiently killing malignant prostate targets following administration of the pro-drug, CB1954. Thus, BV is capable of transducing a large proportion of prostate cell types within a heterogeneous 3-D prostate tumour, can facilitate cell death using a pro-drug approach, and shows promise as a vector for the treatment of prostate cancer.

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Section: Discussionmentioning

confidence: 99%

Evaluating Baculovirus as a Vector for Human Prostate Cancer Gene Therapy

et al. 2013

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“…Such models can be good for hypothesis building and testing, however they should be used with caution due to the genetic changes the cells have endured to induce immortalisation, and results should be followed up in primary samples. For prostate there is a broad panel of cell lines available [75], for example, androgen-independent PC3 cancer cells, androgen-responsive LNCaP cancer cells, PNT1a and PNT2C2 normal cells (transformed by large T antigen). LNCaPs and PC3 cells are derived from metastases, and so to provide a cell line that was derived from a primary localised prostate adenocarcinoma, Miki et al derived two cell lines RC-92a/hTERT (cancer) and RC-165N/ hTERT (normal) from primary prostate epithelial cells using a retroviral vector encoding hTERT to immortalise the cells [76].…”

Section: Culture Conditions To Study Cancer Stem Cellsmentioning

confidence: 99%

Cancer Stem Cells, Models of Study and Implications of Therapy Resistance Mechanisms

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Maitland

2011

Advances in Experimental Medicine and Biology

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There is now compelling evidence for tumour initiating or cancer stem cells (CSCs) in human cancers. The current evidence of this CSC hypothesis, the CSC phenotype and methods of identification, culture and in vitro modelling will be presented, with an emphasis on prostate cancer. Inherent in the CSC hypothesis is their dual role, as a tumour-initiating cell, and as a source of treatment-resistant cells; the mechanisms behind therapeutic resistance will be discussed. Such resistance is a consequence of the unique CSC phenotype, which differs from the differentiated progeny, which make up the bulk of a tumour. It seems that to target the whole tumour, employing traditional therapies to target bulk populations alongside targeted CSC-specific drugs, provides the best hope of lasting treatment or even cure.

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“…As the prostate cancer cell lines used in these experiments tended to show a more differentiated phenotype in comparison to the benign cell lines PNT1A and PNT2C2, the real Bv target could be differentiated cells instead of prostate cancer cells. However, the origin and features of the prostate cancer cell lines tested spanned both differentiated state and normal/tumour origin (recently reviewed in Maitland et al, 2010) eliminating the possibility that positive Bv transduction is simply dependent on cellular differentiation. For example, the cancer lines LNCaP and PC3 were obtained from lymph node and bone metastasis respectively, while PC346C and P4E6 were isolated from a solid tumour.…”

Section: Baculovirus Selectively Tranduces Luminal-like Prostate Cancmentioning

confidence: 99%