MISSION

among men exposed to cigarette smoke. Dr. Foster and colleagues hypothesize that cigarette smoke
impairs the production of selenium containing proteins—called selenoproteins. The aim of their research is
to characterize pathways that regulate selenoprotein production. Perhaps by augmenting selenoprotein
production efficiency or by enhancing the stability of selenoprotein messenger RNAs it will be possible to
increase the selenoprotein content of cells and afford protection against cellular sources of oxidative stress
and toxins such as cigarette smoke. To characterize cellular signaling pathways regulating selenoprotein
production and stability, their laboratory has developed two novel reporter assays. One reporter measures
how efficiently the amino acid selenocysteine is incorporated into an artificial selenoprotein. The other
reporter measures the stability of an artificial selenoprotein. Using these reporters, they have gained preliminary
data that selenoprotein production efficiency is regulated by the phosphoinositide-3 kinase -protein
kinase B (PI3K-AKT pathway). In the presence of selenium, inducers of the PI3K pathway, such as the
cytokine IL-13, enhance L-seryl-tRNA (SEC) incorporation efficiency, increase the level of the antioxidant
selenoprotein glutathione peroxidase 1, and protect HEK293 cells against hydrogen peroxide or cigarette
smoke induced cell death. It is known that under selenium-limiting conditions that some selenoprotein
messenger RNAs (mRNAs) are degraded by a cellular surveillance pathway called nonsense-mediated decay
(NMD). To characterize the mechanisms by which GPX1 mRNA avoids NMD in the presence, but not in
the absence of selenium, Dr. Foster and colleagues are using the second reporter to characterize signaling
pathways that promote the degradation of selenoprotein mRNAs under conditions of selenium deficiency.
In contrast to HEK293 cells, supplemental selenium does not afford PCa cells enhanced protection against
inducers of oxidative stress. They will use their reporter assays and knowledge of the signaling pathways
that regulate selenoprotein production to further characterize the mechanisms by which cigarette smoke
contributes to PCa and to define whether selenoprotein production pathways are impaired in PCa cell
lines.
SMALL PEPTIDE THERAPY ON METASTATIC PROSTATE CANCER
Jer-Tsong Hsieh, PhD; University of Texas Southwestern; CIA 2008
Prostate cancer (PCa) is the most common type of cancer found in American men, other than skin cancer.
Although smoking was unrelated to overall PCa incidence, a prospective study indicates that current
smokers and recent quitters were at higher risk for distant metastatic PCa and fatal PCa. Currently, androgen
ablation is the most effective regimen for distant metastatic PCa, over a period of time, the progression
to life threatening androgen independent (AI) status is inevitable. For the AI disease, there are not
many treatment options currently available with curative outcomes. Therefore, there is an immediate need
to develop a new course of therapy that may hold significant promise for a better cancer control and
improve the life qualities of patients with advanced diseases.
The ultimate goal of this project is to design a combination molecular therapy.
By employing biochemical techniques, Dr. Hsieh and colleagues intend to analyze the underlying mechanism
of CPP specific uptake by PCa. In addition, they will further improve the stability of CPP by changing
its chemical structure. Based on key functional motifs of several prominent tumor suppressor proteins,
they will synthesize small peptides corresponding to these motifs and examine their effect using several preclinical
animal models.
The small peptide is considered much safer than synthetic chemicals. Moreover, the response of tumor
can be detected by non-invasive molecular imaging techniques in a real-time manner. Thus, the outcome
of this study has an immediate clinical application because the goal of this project is to combine new concept
and state-of-art biotechnology to develop a comprehensive therapeutic regimen for AIPCa patients.
INHIBITION OF HEDGEHOG SIGNALING BY CYCLOPAMINE PRODRUG FOR PROSTATE CANCER
Anirban Maitra, MBBS; The Johns Hopkins University; CIA 2007
Dr. Maitra assumed this project from Saeed R. Khan, PhD. The hedgehog (Hh) pathway plays a critical
role in the development of prostate cancer. The Hh signaling pathway specifies patterns of cell growth and
differentiation during embryogenesis in a wide range of tissues. A role for the Hh signaling in oncogenesis
was first reported in subsets of brain tumors (medulloblastomas) and cutaneous basal cell carcinomas arising
in the context of Gorlin’s syndrome, wherein inactivating mutations in the tumor suppressor gene
PTCH result in constitutive activation of the pathway. Most recently Beachy et al described a new paradigm
of Hh pathway activation in endoderm-derived tumors. It has been demonstrated that inhibition of
Hh signaling by smoothened antagonist, cyclopamine suppresses Hh signaling, down-regulates cell invasiveness,
and induces apoptosis. Thus, targeted inhibition of Hh signaling may have significant implications
of prostate cancer (PCa) therapeutics. Currently there is no curative treatment for men with metastatic
1 3 2 P A G E