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Journal of Medical Oncology and Therapeutics | Volume: 3
July 23-25, 2018 | Moscow, Russia
12th World Cancer Congress
Targeting the WASF3 regulatory complex to suppress Metastasis
John K Cowell, Yong Teng, Ali S Arbab and Eileen J Kennedy
The Georgia Cancer Center, USA
The WASF3 gene is involved in actin cytoskeletal
reorganization in response to external stimuli from growth
factors and cytokines. It is expressed at high levels in metastatic
cancers and was part of the gene expression signature defining
the claudin-low subgroup of breast cancers. Cells that do not
express WASF3 do not metastasize and knock down of WASF3
in metastatic breast cancer cells leads to suppression of
invasion in vitro and invasion in vivo. Re-expression of WASF3
in non-metastatic cells increase cell motility and invasion. This
strict requirement for WASF3 function in metastatic breast
cancer cells suggested targeting this function may provide a
means to suppress metastasis. There are currently no small
molecule inhibitors of WASF3 function and so we decided to
target protein-protein interactions essential for its function.
In resting cells, WASF3 is maintained in an auto-inhibited
conformation through interaction with a protein complex
referred to as the WASF3 regulatory complex (WRC). NCKAP1
and CYFIP1 are important components of the WRC and genetic
knockdown of these proteins in metastatic breast cancer cells
leads to destabilization of the WASF3 complex. Stimulation
of quiescent cells with growth factors activate RAC1/2 which
binds to NCKAP1 and relaxes the protein complex to allow
phosphoactivation of WASF3. To target theWRC, we developed
stapled peptides against alpha helical interaction sites between
WASF3 and CYFIP1. Stapled peptides are a new class of
therapeutic peptides which show increased stability, resistance
to protease degradation, non-immunogenic and are actively
transported into cells. Targeting theWASF3-CYFIP1 complex led
to loss of phosphoactivation of WASF3 and reduced invasion
in vitro. As shown in the crystal structure of the WRC, NCKAP1
does not interact directly with WASF3 but rather binds to
CYFIP1. Targeting the CYFIP1-NCKAP1 interaction using stapled
peptides led to destabilization of the WRC and loss of invasion
of breast cancer cells in vitro. When the two classes of stapled
peptides were used in in vivo xenograft studies of MDA231
metastatic cells, compared with vehicle treated animals,
metastasis to the lungs and liver was significantly suppressed.
Biodistribution studies showed uptake in liver and stomach in
early stages and over 72 hours concentrated in tumors. The
half-life of the peptides in peripheral blood was ~30 minutes.
These studies demonstrate the proof-of-principle that targeting
the WRC in breast cancer cell can suppress the metastatic
phenotype. Current efforts involve modification of stapled
peptides to increase potency, increase retention times in the
blood and to increase solubility in formulations that can be
delivered intravenously.
Speaker Biography
John K Cowell is Interim Director of the Georgia Cancer Center, Associate Director
for basic science and a Professor of Pathology. Prior leadership roles include
Director of the Center for Molecular Genetics at the Cleveland Clinic and Chair of
the Department of Cancer Genetics at the Rowell Park Cancer Institute in Buffalo,
New York. He investigates the molecular genetics of cancer particularly the genetic
basis of metastasis in breast and prostate cancer. He is also developing novel
therapeutic approaches to the treatment of stem cell leukaemia. His research
has been continuously funded by the National Cancer Institute for over 20 years.
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