Aws Abdul-Wahid, Marzena Cydzik
Angiogenesis as a
mandatory phenomenon during a
number of physiological processes, is also associated with wound healing and
various pathologies, including autoimmune diseases and tumorigenesis.
Vascular neogenesis is tightly regulated by a
number of stimuli, which include soluble growth factors as well as
dynamic changes in the interaction between ECs and extracellular matrix
(ECM) microenvironment. Important cellular mechanisms contributing to the
disease progression of many types of cancer include cellular
proliferation, adhesion, migration, and invasion; all of which are
influenced by the interaction between the tumour
cell and the extracellular matrix (ECM). .
Secreted Protein Acidic Rich in Cysteine (SPARC), a Ca2+-binding
ECM glycoprotein, was shown to display anti-angiogenic,
anti-proliferative and counter-adhesive activities. One mechanism by
which SPARC may exert its activity is by binding to Vascular Endothelial
Growth Factor (VEGF), known for its role in angiogenesis in ovarian
cancer, and preventing its interaction with cognate receptors.
Characterization of this molecular interaction holds the promise of
devising peptide mimetics capable of blocking VEGF binding to its cognate
receptors, thus inhibiting ovarian cancer cell proliferation and
invasion. We are presently characterizing the binding properties of VEGF
to SPARC and its peptide with a view to define a template for the design
of SPARC peptide-like anti-angiogenic and anticancer mimetics with
enhanced stability and activity . Antiangiogenic
agents will be used in conjunction with current chemotherapeutic drugs
for treating advanced ovarian cancer.
1) Cydzik M, Abdul-Wahid A, Park S, Bourdeau
A, Bowden K, Prodeus A, Kollara
A, Brown TJ, Ringuette MJ, Gariépy
J. (2015) Slow binding kinetics of SPARC-VEGF
interaction limit VEGF activation of VEGF-R2 and attenuates
angiogenesis. FASEB J, 29(8):3493-505.
Cancer Vaccines and Metastasis
cancers remain the primary cause of morbidity and mortality for cancer patients
despite significant advances in the treatment of localized tumours. The prevention of metastasis combines early
surgery (or radiation therapy in some cases) as well as systemic therapy
given before or after surgery to target disseminated tumour
cells that have detached from primary tumours
to engraft at distal sites, and/or were not detected or accessible to
surgical excision at the time of diagnosis. Tumor metastasis is a complex
phenomenon where intercellular and cell-matrix adhesion events involving tumour cells lead to the formation as well as
expansion of metastatic foci. The carcinoembryonic antigen (CEA) is an
important pro-metastatic oncoprotein that is
aberrantly over-expressed by epithelial cancers including cancers of the
gastrointestinal tract, breast, lung, ovary and pancreas.
Our group is the
first to define the exact CEA domains responsible for its homotypic
cellular adherence and its interaction with the ECM protein fibronectin (Fn). We showed that the CEA IgV-like
N domain serves a key role in the formation of at least two classes of
binding events leading to cellular engraftment and tumour
foci formation. The first binding event involved the direct association
of CEA with Fn KD 16 + 3 nM), independently of the presence of human α5β1 integrin.
The second binding event involved the formation of both cis- [N-to-N] and trans- [N-to-A3]
homotypic complexes(KD 100 + 17nM as well as KD 18
+ 3nM, respectively) (1).
this knowledge, we have devised DNA aptamers that can block homotypic as
well as heterotypic associations involving CEA (2). Importantly, we are
presently developing a preventive vaccine against metastatic cancer that
with generate immune responses able to block CEA-mediated tumour cell implantation both in vitro and in vivo, and
capable of killing of tumour cells by
complement - and antibody-dependent cellular cytotoxic mechanisms (3, 4).
vaccine project, we have engineered a semi-synthetic tumour
antigen called the Tn antigen MUC1, which has
been used recently in a Phase I/II clinical trial in patients with
castrate-resistant prostate cancer (5).
Abdul-Wahid A, Cydzik M, Prodeus
A, Alwash M, Stanojcic
M, Thompson M, Huang EH, Shively JE, Gray-Owen SD, Gariépy
J. (2016) Induction of antigen-specific TH 9 immunity accompanied by mast
cell activation blocks tumor cell engraftment. Int
J Cancer, 139(4):841-53.
2) Scheid E, Major P, Bergeron A, Finn OJ, Salter RD, Eady R, Yassine-Diab B,
Favre D, Peretz Y, Landry C, Hotte S, Mukherjee SD, Dekaban
GA, Fink C, Foster PJ, Gaudet J, Gariepy J, Sekaly RP,
Lacombe L, Fradet Y, Foley R. (2016) Tn-MUC1 DC
Vaccination of Rhesus Macaques and a Phase I/II Trial in Patients with Nonmetastatic Castrate Resistant Prostate Cancer. Cancer Immunol
Abdul-Wahid A, Huang EH, Cydzik M, Bolewska-Pedyczak
E, Gariépy J. (2014) The carcinoembryonic antigen
IgV-like N domain plays a critical role in the
implantation of metastatic tumor cells. Mol
4) Orava EW, Abdul-Wahid A, Huang EH, Mallick
AI, Gariépy J. (2013) Blocking the attachment
of cancer cells in vivo with DNA aptamers displaying anti-adhesive
properties against the carcinoembryonic antigen. Mol Oncol. 7(4):799-811.
5) Abdul-Wahid A, Huang EH, Lu H, Flanagan J, Mallick AI, Gariépy J.
(2012) A focused immune response targeting the homotypic binding domain
of the carcinoembryonic antigen blocks the establishment of tumor foci in
vivo. Int J Cancer. 131(12):2839-2851.