|
|
|
Alan DeSilva, B.Sc., Graduate Student |
 |
BACKGROUND
I graduated from the Honors
Molecular Genetics program at the University of Alberta with a
full-year project course (Bio 499) in the department of Medical
Genetics. My interest in patient-related, bench-to-bedside
(translational) research and virology led me to Dr. Mary Hitt’s lab
where I work on targeting adenoviral vectors to tumours as an
alternative cancer therapy. My Ph.D. project involves two distinct
strategies (transcriptional & translational targeting) to increase
adenovirus specificity to tumour cells.
RESEARCH PROJECT
While adenoviral (Ad) vectors are
the most commonly used gene delivery vector for gene therapy,
improvements must still be made to increase Ad specificity to the
tumours if they are to be used for cancer gene therapy. A balance
must be achieved between high levels of tumour cell killing and low
toxicity to non-tumour cells.My work involves two distinct levels of
targeting adenoviral vectors to tumour cells: transcriptional
targeting and translational targeting.
|
|
Transcriptional
targeting refers to controlling the expression of a
toxic gene at the transcriptional level through tumour-specific
promoters. A novel promoter from the mammaglobin (MGB)
gene has been isolated and appears to possess increased
activity in breast cancer cells relative to non-tumour
cells. By utilizing this promoter to drive expression of
suicide genes, it may be possible to limit expression of
a suicide gene to tumour cells (and thus maintaining the
safety of surrounding non-tumour cells). Translational
targeting refers to controlling the translation of a
toxic gene by manipulating its 5’ untranslated region (UTR).
Many studies have shown that mRNA with high levels of
secondary structure in the 5’ UTR (‘weak’ transcripts)
are not translated as efficiently in non-tumour cells as
mRNA with low secondary structure (‘strong’
transcripts). Tumour cells, however, have an increased
ability to translate ‘weak’ transcripts due to the
overexpression of eukaryotic initiation factor 4E
(eIF4E). Our goal is to generate ‘weak’ suicide genes
with high levels of secondary structure in the 5’ UTR to
limit translation of the suicide gene to tumour cells.
By combining these modifications, it may be possible to
generate an adenoviral vector which can achieve high
levels of suicide gene expression in tumour cells with
low toxicity in non-tumour cells.
|
PRESENTATIONS:
Selected Poster
Presentations:
Alan DeSilva, Leonard Wiebe, and Mary Hitt (November
2008). Transcriptionally Targeted Adenoviral Gene
Therapy for the Treatment of Breast Cancer. Alberta
Cancer Board Meeting. Banff AB.
Alan DeSilva, Leonard Wiebe, and Mary Hitt (November
2007). Targeted breast cancer gene therapy using
conditionally replicating adenoviral vectors. Alberta
Cancer Board Meeting. Banff AB.
Alan DeSilva, Leonard Wiebe, Chang-Xin Shi, Mabrouk
Elgadi, Gianluca Bossi, and Mary Hitt (June 2006).
Targeting adenoviral vectors for use in breast cancer
gene therapy. American Society of Gene Therapy
Conference. Baltimore MA.
Oral Presentations:
Alan DeSilva (August 2008). Breast
Cancer Treatment Using Targeted Adenoviral Gene Therapy.
HYRS Workshop. Edmonton AB.
Alan DeSilva (November 2007). Tumor cell migration and
metastasis. Guest lecturer (1 lecture) for Oncology 320
(Introduction to Oncology, M. Hitt, Instructor).
Edmonton AB.
Alan DeSilva (July 2007). Using oncolytic adenovirus for
targeted breast cancer gene therapy. HYRS Workshop.
Edmonton AB.
Alan DeSilva (March 2007). Targeted adenoviral vectors
for use in breast cancer gene therapy. Oncology 660
Seminar Series. Edmonton AB.
Alan DeSilva (August 2006). Breast cancer gene therapy
using targeted adenoviral vectors. HYRS Workshop.
Edmonton AB.
Alan DeSilva (March 2006). Modification of adenoviral
vectors for targeted breast cancer gene therapy.
Oncology 660 Seminar Series. Edmonton AB.
Alan DeSilva (November 2005). Modification of adenovirus
vectors for targeted breast cancer gene therapy. Alberta
Cancer Board Translational Research Training in Cancer
Meeting. Banff AB.
PUBLICATIONS:
Abstracts:
DeSilva, A.D., Wiebe, L.I., Shi, C.X., Elgadi, M., Bossi,
G., and HITT, M.M. (2006). Targeting adenoviral vectors
for use in breast cancer gene therapy. American Society
for Gene Therapy 9th Annual Meeting, Baltimore, MD, USA,
Mol. Therapy, 13 (Supplement 1): S252.
|
|
|
|
| |
|
