4 / 38
J u n e 1 1 - 1 3 , 2 0 1 8 | D u b l i n , I r e l a n d
allied
academies
Page 22
CANCER STEM CELLS AND
ONCOLOGY RESEARCH
11
th
International Conference on
Journal of Medical Oncology and Therapeutics
|
Volume 3
Kiera Rycaj et al., J Med Oncl Ther 2018, Volume 3
PHAGE DISPLAY LIBRARY SCREENING
IDENTIFIES NOVEL BINDING PEPTIDES
THAT PREFERE NTIALLY TARGET
CASTRATION-RESISTANT PSA-/lo
PROSTATE CANCER STEM CELLS
Kiera Rycaj
1
, John Moore
1
, Xin Liu
1
, Mikhail G Kolonin
2
and
Tang DG
1,3,4
1
Roswell Park Cancer Institute, USA
2
University of Texas Health Science Center at Houston, USA
3
The University of Texas MD Anderson Cancer Center, USA
4
Tongji University School of Medicine, China
A
ndrogen deprivation therapy (ADT) is the mainstay treatment for
patients with advanced prostate cancer (PCa). Despite an initial
response, the majority of patients relapse resulting in castration-resistant
prostate cancer (CRPC). Both untreated advanced PCa and CRPC are
enriched in phenotypically undifferentiated PCa cell populations that
expresses little or no prostate specific antigen (i.e., PSA-/lo). We have
demonstrated that the PSA-/lo PCa cell population harbors self-renewing
prostate cancer stem cells (PCSCs) that are intrinsically resistant to ADT
and can long-term propagate tumors, mediate recurrence, and serve as
a cell-of-origin for CRPC (Cell Stem Cell, 2012; Oncotarget, 2015; Clin
Cancer Res, 2016; Oncotarget 2016). Consequently, it is important to find
therapeutics that can preferentially target these cells. By employing phage
display technology, we screened a combinatorial library for peptides that
preferentially bind to PSA-/lo LNCaP PCa cells. An initial competitive
assay identified the JRM1 peptide that showed slight preferential binding
to the PSA-/lo LNCaP cells. With this knowledge, we carried out another
screen using an indirect subtraction assay to identify the peptide JRM2,
which demonstrated preferential and statistically significant binding to the
PSA-/lo LNCaP cells. Fluorophore-conjugated JRM2 could be internalized
into cells. When conjugated to a pro-apoptotic peptide, JRM2 specifically
inhibited cell proliferation in PSA-/lo PCa cells. Preliminary
in vivo
studies
showed tumor-inhibitory effects of the JRM2-killer peptide conjugates.
Our findings demonstrate the feasibility of utilizing novel ligand-directed
therapeutics to target undifferentiated (AR-)PSA-/lo CRPC cells.
Kiera Rycaj, PhD, is currently Assistant Profes-
sor at the Roswell Park Comprehensive Cancer
Center (RPCCC) in Buffalo, NY, USA. She ob-
tained her PhD from the University of Texas M.D
Anderson Cancer Center (MDACC) in 2012 Her
PhD thesis work focused on the expression and
biological functions of HERV-K (Human Endog-
enous Retrovirus – K) in breast and ovarian can-
cer (OC) cells. Her work has demonstrated that
the HERV-K env protein not only is expressed on
the surface of breast cancer and OC cells but
also can function as TAA (tumor-associated
antigen) to elicit T-cell and antibody respons-
es. She developed HERV-K specific vaccines
and demonstrated their utility in killing autolo-
gous patient cancer cells. She conducted her
postdoc training in Dr. Tang’s laboratory during
2012-2015 and her work focused on elucidat-
ing prostate cancer (PCa) cell heterogeneity
and therapeutically targeting the phenotypically
undifferentiated AR-/lo(PSA-/lo) prostate can-
cer stem cells (PCSCs). Her recent published
study on high-throughput screening shows that
treatment-reprogrammed castration-resistant
PCSCs are AR-PSA- and completely refractory
to antiandrogens but remain partially sensitive
to inhibitors of BCL-2 and certain kinase. She
became a junior faculty in 2015, and her lab
has been focusing on elucidating how primary
tumor microenvironment regulates functional
properties of metastatic PCSCs and on devel-
oping novel immunotherapeutic strategies to
target undifferentiated, therapy-resistant and
metastasis-prone PCa cells.
Kiera.Rycaj@RoswellPark.orgBIOGRAPHY