New Strategy
for Treating Bladder Cancers
Highlights
- More
than 90% of all bladder cancers are deficient in an enzyme
Argininosuccinate synthetase 1 (ASS1).
- Bladder
cancer patients with deficient ASS1 expression , had lower survival
rates.>/li>
- Treatment
with arginine-degrading enzyme ADI-PEG 20 arrested tumor cell growth in
ASS1-deficient cells.
In
a new therapeutic approach to bladder cancer, treatment with the
arginine-degrading enzyme ADI-PEG 20 inhibited tumor growth in
Argininosuccinate synthetase 1 or ASS1-deficient cells both in vivo and in
vitro.
Argininosuccinate
synthetase 1 (ASS1) is an enzyme which is necessary for arginine synthesis.
‘Arginine dependency
in bladder cancer may be a useful mechanism to selectively target a subset of
these cancers using arginine-degrading enzyme or ADI-PEG 20.’
Arginine is a
semi-essential amino acid that is synthesized from citrulline in two steps of
the urea cycle. First step involves the conversion of citrulline and aspartate
to argininosuccinate via the enzyme ASS1. The argininosuccinate is then
converted to arginine and fumarate.
Arginase and arginine
deiminase (ADI) are arginine-degrading enzymes. ADI-PEG 20 is a commercial
formulation of arginine deiminase (ADI). It has a longer pharmacokinetic
half-life.
Patients with tumors
having low ASS1 expression have shorter survival. More than 90% of all bladder
cancers are deficient in ASS1 and with few treatment options available to
patients with advanced bladder cancer, researchers are looking for novel
molecular targets.
"There is a
major unmet need to identify additional therapies for bladder cancer patients
that includes agents that can target both conventional urothelial carcinoma and
less common subtypes of bladder cancer. Our findings suggest that arginine
dependency in bladder cancer may be a useful mechanism to selectively target a
subset of these cancers using ADI-PEG 20, although further investigation into
the mediators of this effect and the role of combination therapy, including
chemotherapy, to enhance efficacy is required," explained lead investigator
Donna Hansel, MD, PhD, Professor of Pathology, University of California at San
Diego (CA).
Normal urothelium
demonstrated robust ASS1 expression throughout its full thickness. Researchers
found this using immunohistochemistry on tissue specimens taken from 252
patients who had undergone surgery for muscle-invasive bladder cancer over a
20-year period.
Significant
reductions in ASSI expressions were seen in majority of samples with urothelial
carcinoma, small cell carcinoma, and squamous cell carcinoma.
"This finding suggests that these three major subtypes of bladder cancer, which account for more than 90% of all bladder cancers, may potentially respond to arginine-degrading therapy such as ADI-PEG 20," noted Dr. Hansel.
The researchers found that in comparison to bladder cancer patients with high ASS1 expression, the survival was significantly lower in patients having tumors with low ASS1 expression. The researchers tested the effects of therapy with ADI-PEG 20, on cells that were deficient in ASS1 and in cells that expressed ASS1. They found that ADI-PEG 20 decreased colony formation and reduced cell viability only in cells deficient in ASS1 but had little or no effect on other cells.
In vivo testing, mice were injected with ASS1-deficient cells into subcutaneous tissue in the left flank and ASS1-expressor cells into the right flank, to test the effects of ADI-PEG 20 . The result showed that ADI-PEG 20 arrested tumor growth only in tissue containing ASS1-deficient cells.
"This finding suggests that these three major subtypes of bladder cancer, which account for more than 90% of all bladder cancers, may potentially respond to arginine-degrading therapy such as ADI-PEG 20," noted Dr. Hansel.
The researchers found that in comparison to bladder cancer patients with high ASS1 expression, the survival was significantly lower in patients having tumors with low ASS1 expression. The researchers tested the effects of therapy with ADI-PEG 20, on cells that were deficient in ASS1 and in cells that expressed ASS1. They found that ADI-PEG 20 decreased colony formation and reduced cell viability only in cells deficient in ASS1 but had little or no effect on other cells.
In vivo testing, mice were injected with ASS1-deficient cells into subcutaneous tissue in the left flank and ASS1-expressor cells into the right flank, to test the effects of ADI-PEG 20 . The result showed that ADI-PEG 20 arrested tumor growth only in tissue containing ASS1-deficient cells.
The effect of ADI-PEG
20 is currently being evaluated in a Phase III trial for hepatocellular
carcinoma and is being assessed for other cancers including melanoma and mesothelioma.
"Our results suggest that arginine deprivation may be a useful strategy
for treating bladder cancer and show that ADI-PEG 20 functions through a novel
signaling mechanism that includes the pathway mediated by the general control
nonderepressible 2 kinase that controls autophagy and apoptosis,"
commented Dr. Hansel.
The study is
published in The American Journal of Pathology.
Reference
Reference
- Donna
Hansel et al. Argininosuccinate Synthetase 1 Loss in Invasive Bladder
Cancer Regulates Survival through General Control Nonderepressible 2
Kinase-Mediated Eukaryotic Initiation Factor 2α Activity and Is Targetable
by Pegylated Arginine Deiminase. The American Journal of Pathology;
(2017) DOI: http://dx.doi.org/10.1016/j.ajpath.2016.09.004.
By
Dr. A. Praveena
Assistant Professor
Department of Biochemistry
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