Download 1 - Molecular Therapeutics for Cancer Ireland

RESEARCH PROGRAMME OVERVIEW – WORK PACKAGE 4
WP4.1: MOLECULAR DETERMINANTS OF ENDOCRINE-RESISTANCE AND TUMOUR
PROGRESSION IN BREAST CANCER
Hormonal therapy is focused on modulating the activity of steroid hormone receptors, by down-regulating
the levels of the receptors themselves, blocking the production of steroid hormones, or inhibiting the
action of those hormones. However, when used either as adjuvant therapy following surgery or as first line
treatment in advanced disease, significant numbers of patients do not respond and eventually succumb to
their disease. Tumours resistant to endocrine-directed therapies demonstrate a phenotypic shift away from
steroid hormone dependence towards that of hormone independence, altered growth factor signalling and
an increased resistance to pro-apoptotic signals. In understanding the molecular mechanisms behind these
phenomena, we can identify alternative points of intervention in therapeutically relevant pathways. Our
research programme centres on the identification and characterisation of molecular mediators of resistance
to anti-endocrine therapies and key factors controlling the progression of breast cancer, using a
combination of innovative bioinformatics, functional genomics, proteomics, translational pathology and
state-of-the-art in vivo imaging capacities. Currently, we are focussed on the role of the transcription
factor NF-B, novel microRNA targets and the neuropeptide hormone CART, all of which we have
identified as playing central roles in the progression of breast cancer and response to anti-estrogens.
4.1 RESEARCH OBJECTIVES
a. To identify key molecular regulators of anti-endocrine therapy resistance and progression in breast
cancer.
b. Specifically to examine the role of NF-B in mediating resistance to anti-endocrine therapy.
c. To identify microRNA regulators of poor response to anti-endocrine therapy and the progression
of breast cancer.
d. To investigate the role of the neuropeptide hormone CART in ER+ breast cancer.
WP4.2: MOLECULAR DETERMINANTS OF APOPTOTIC RESISTANCE IN ANDROGENRESISTANT PROSTATE CANCER
Unfortunately, there are no effective treatment options for androgen-independent prostate cancer, with
death usually occurring between 6-18 months after its development. Defining the precise mechanisms of
resistance represents a key challenge facing clinicians and scientists. In collaboration with international
collaborators, we have derived and started to characterise the anti-apoptotic phenotype of androgenindependent sublines. It is clear from these preliminary studies that there is a complex interplay between
changes in the expression of both pro- and anti-apoptotic proteins. Targeting these individually may not
lead to alterations in the resistant phenotype but understanding the central signalling pathways and
transcription factors would represent a more appropriate therapeutic targeting approach.
Hypothesis: The mechanisms of apoptotic resistance in androgen-independent prostate cancer are
centrally regulated by common transcription factors which would represent a more appropriate target for
therapeutic manipulation.
4.2. RESEARCH OBJECTIVES
a. Derive in vitro and ex vivo androgen-independent prostate cancer cells.
b. Transcriptomic profiling and enriched analysis of gene expression datasets.
c. Functional genomic analysis of downstream regulated genes.
RESEARCH TEAM
Name: Prof William Gallagher
Position: Associate Professor of Cancer Biology, UCD School of Biomolecular and Biomedical Science;
Vice-Principal for Research and Innovation, UCD College of Life Sciences;
Conway Fellow, UCD Conway Institute, University College Dublin.
Telephone: +35317166743
Email: [email protected]
Name: Prof Ronald William Gordon Watson
Position: Associate Professor of Cancer Biology, UCD School of Medicine and Medical Science
Email: [email protected]
Name: Dr Darran O’Connor
Position: Senior Research Fellow & Lecturer, UCD School of Biomolecular and Biomedical Science
Email: [email protected]
Name: Dr Amanda O’Neill
Position: Post Doctoral Research Fellow
Email: [email protected]
Name: Dr Maria Prencipe
Position: Post Doctoral Research Fellow
Email: [email protected]
Name: Ms Henriette Laursen
Position: PhD Student, UCD School of Biomolecular and Biomedical Science
Email: [email protected]
Name: Ms Laoighse Mulrane
Position: PhD Student, UCD School of Biomolecular and Biomedical Science
Email: [email protected]
RECENT PUBLICATIONS/KEY OUTPUTS
Ursini-Siegel J, Cory S, Zuo D, Hardy WR, Rexhepaj E, Lam S, Schade B, Jirstrom K, Bjur E, Piccirillo
CA, Denardo D, Coussens LM, Brennan DJ, Gallagher WM, Park M, Pawson T, Hallett M, Muller WJ.
Receptor Tyrosine Kinase Signaling Favors a Protumorigenic State in Breast Cancer Cells by Inhibiting
the Adaptive Immune Response. Cancer Res. 2010 Oct 5.
Brennan DJ, O’Connor DP, Rexhepaj E, Ponten F & Gallagher WM. Antibody-based proteomics: fasttracking molecular diagnostics in oncology. Nat Rev Cancer, 2010 Sep;10(9):605-17.
Lanigan F, Gremel G, Hughes R, Brennan DJ, Martin F, Jirstrom K & Gallagher WM. Homeobox
transcription factor muscle segment homeobox 2 (Msx2) correlates with good prognosis in breast cancer
patients and induces apoptosis in vitro. Breast Cancer Res. 2010 Aug 3;12(4):R59
Lau TY, Power KA, Dijon S, de Gardelle I, McDonnell S, Duffy MJ, Pennington SR, Gallagher WM.
Prioritization of candidate protein biomarkers from an in vitro model system of breast tumor progression
toward clinical verification. J Proteome Res. 2010 Mar 5;9(3):1450-9.
Brennan DJ, Hewitt SM, Rexhepaj E, O’Brien SL, McSherry E, O’Connor DP, Fagan A, Culhane AC,
Higgins DG, Jirstrom K, Millikan RC, Landberg G, Duffy MJ & Gallagher WM. Altered nuclearcytoplasmic ratio of survivin is a prognostic indicator in breast cancer. Clin Cancer Res, 14, 2681-2689.
CONFERENCE PRESENTATIONS
ORALS
Maria Prencipe, Stephen Madden, Amanda O’Neill, Helmut Klocker, William Watson. “Transcriptomic
profiling of castrate resistant prostate cancer cells”.
Irish Society of Urology Annual Meeting. Dublin, 10th-11th September 2010.
POSTERS
Amanda J. O’Neill, Catherine Gill, Yue Fan, Maeve Mullooly, Robert Cunningham, John M. Fitzpatrick,
R. William Watson. “The role of TRAF-1 in Resveratrol Induced Susceptibility to TRAIL Triggered
Apoptosis in Advanced Prostate Cancer Cells”.
19th Meeting of the European Association of Urology (EAU) Section of Urological Research. Vilnius,
Lithuania, 7th-9th October 2010.
Maria Prencipe, Stephen Madden, Amanda O’Neill, Helmut Klocker, William Watson. “Transcriptomic
profiling of castrate resistant prostate cancer cells”.
19th Meeting of the European Association of Urology (EAU) Section of Urological Research. Vilnius,
Lithuania, 7th-9th October 2010.