MELBOURNE, AUSTRALIA--(Marketwire - June 18, 2009) - Antisense Therapeutics Ltd. (ASX: ANP)
is pleased to report further positive results from its collaborative
preclinical research studies on the therapeutic potential of ATL1101 in
prostate cancer. In experimental models, ATL1101 treatment significantly
enhanced the tumor-suppressive effect of the cancer drug Paclitaxel.
Paclitaxel is one of a class of drugs known as taxanes. Along with
androgen (a male hormone) blockade, taxane chemotherapy is an important
treatment option in the most dangerous form of the disease,
castration-resistant prostate cancer (CRPC).
Illustrating the positive effects of the drug in this mouse model of
prostate cancer, prostate tumor volume was halved after 5 weeks of
Paclitaxel/ATL1101 combination treatment, compared with control Paclitaxel
In cell culture experiments, the amount of Paclitaxel required to induce
tumor cell apoptosis (cell death) was significantly reduced when used in
combination with ATL1101. This ability to 'sensitize' tumor cells to the
cytotoxic effects of Paclitaxel affirms ATL1101's potential as a
chemo-sensitizing agent to be used in combination with existing prostate
treatments to improve the outcomes for patients.
ATL1101 is a second generation antisense inhibitor of the insulin-like
growth factor-I receptor (IGF-IR) which as reported previously suppressed
the growth of human prostate tumors in an animal model of prostate cancer,
and slowed down transition to CRPC when used as a single agent. Drugs
targeting IGF-IR are being developed by a number of the major
pharmaceutical companies for a variety of cancer indications, indicating
the importance of the IGF-IR target in cancer.
ANP's research collaborator in the study is Prof. Martin Gleave, a leader
in prostate cancer treatment and drug development. Martin Gleave, a
professor at the Department of Urological Sciences, University of British
Columbia and Director of The Prostate Centre at Vancouver General Hospital
commented, "Resistance of tumor cells to the effects of existing treatment
is a major challenge in the management of prostate cancer. Tumor cells
build resistance to chemotherapy treatment via survival mechanisms that
include IGF-I signaling. In our prostate cancer model we have shown that
ATL1101, which is an IGF-I receptor blocker, can inhibit this mechanism and
restore sensitivity to chemotherapy."
ANP is in dialogue with various parties regarding the continued development
of ATL1101 in prostate cancer, aiming to build on ATL1101's robust
pre-clinical pharmacology data package, completed mouse toxicology study,
established drug manufacturing process and strong intellectual property
Further details on study design and outcomes follow.
ATL1101 combination study with Paclitaxel in prostate cancer laboratory
models -- design and outcomes
-- In vitro experiment Human androgen-independent prostate tumor cell
line PC3 was transfected with ATL1101 or mismatch control oligonucleotide
ISIS 306064 at concentrations ranging from 12.5 nM to 50 nM. After 2nd
transfection, cultured cells were treated with Paclitaxel at concentrations
ranging up to 50 nM, then the number of viable cells remaining after a
further 72 hrs was counted.
-- In vivo experiment PC3 cells (2 x 10(6) cells) were xenografted by
subcutaneous injection into recipient 6-8 week-old athymic nude (nu/nu)
mice. When tumors reached 200 mm(3), mice were randomly assigned to one of
two treatment groups: IGF-IR antisense drug ATL1101 or mismatched
oligonucleotide ISIS 306064.
Treatment was with 15 mg/kg ATL1101 or ISIS 306064 once daily for 5 days
and three times per week thereafter by intraperitoneal injection. At days
7, 9, 11 and 21, 23, 25, 0.5 mg of micellar Paclitaxel was administrated
intravenously once daily. Each experimental group consisted of 10 mice.
Mean tumor volume (+/- standard error of the mean) was assessed in each
group (ATL1101 or ISIS 306064) every week for up to 8 weeks.
Representative outcomes of the study include the following:
-- In cultured PC3 cells, cell viability decreased as expected with
increasing concentrations of Paclitaxel. Transfection with ATL1101 further
reduced viable cell count at a given Paclitaxel concentration, and reduced
the concentration of Paclitaxel required to give the same viable cell
-- For example, at 0.1 nM Paclitaxel, the viable cell count for PC3 cells
was only reduced by approximately 5%, compared with transfection reagent
alone and no paclitaxel. Cells treated with both 0.1 nM Paclitaxel and
mismatch control oligonucleotide ISIS 306064 at 12.5 nM also had
approximately 5% reduced viability. In contrast, cells treated with 0.1 nM
Paclitaxel and ATL1101 at 12.5 nM had approximately 45% reduced viability.
-- In another example, PC3 cell count could be controlled with reduced
concentrations of Paclitaxel when ATL1101 was also present: cells treated
with 1 nM paclitaxel and 25 nM ATL1101 had similar viability to cells
treated with a 10-fold higher Paclitaxel concentration (10 nM) and 25 nM
mismatch control oligonucleotide ISIS 306064.
-- In PC3 mice, after 5 weeks of treatment, mean tumor size in mice
treated with Paclitaxel and mismatch control oligonucleotide ISIS 306064
was 326 +/- 40.9 mm(3) compared with 175 +/- 20.1 mm(3) in mice treated
with Paclitaxel and ATL1101, or 53.7% of control (p < 0.01).
-- After 8 weeks of treatment, mean tumor size in mice treated with
Paclitaxel and mismatch control oligonucleotide ISIS 306064 was 1417 +/-
222 mm(3) compared with 507 +/- 79.3 mm(3) in mice treated with Paclitaxel
and ATL1101, or a further reduction to only 35.8% of control (p < 0.01).
About Prostate cancer: Prostate cancer is the second most frequently
diagnosed cancer in men after skin cancer. It is estimated there will be
218,890 new cases diagnosed in the U.S. this year. Around 1 in 6 men will
develop prostate cancer, a third to a half of whom will recur after local
treatment and risk progression to metastatic prostate cancer. Metastatic
disease invariably progresses to hormone refractory or castrate resistant
prostate cancer (CRPC) if given enough time. Prostate tumors are initially
androgen (male sex hormone) dependent, and can be treated with androgen
ablation therapy (the term "castration" can be used to describe removal of
the source of androgen), however once the disease progresses to its most
dangerous and aggressive form, CRPC, treatment options are limited and
prognosis is poor. Treatment options depend on disease severity and include
radiation and chemotherapy, which are designed to induce programmed cell
death (apoptosis) of tumor cells. There is a pressing need for the
development of new treatment options.
About ATL1101: ATL1101 is an antisense inhibitor of IGF-IR, which has
shown potent activity in laboratory studies, including in human cancer
cells. IGFIR is one of the best known of a family of cell signaling
molecules that are referred to as "anti-apoptotic." These molecules prolong
cell survival by inhibiting programmed cell death (apoptosis). The
connection between IGF-IR activity and prostate cell tumorigenicity has
been studied for many years. Drugs targeting IGF-IR are designed to slow
down tumor growth and make tumor cells more susceptible to cell death.
Inhibition of IGF-IR is also designed to make tumor cells more susceptible
to killing by cytotoxic treatments like radiation therapy and chemotherapy.
Such therapeutic approaches are under investigation in several large
pharmaceutical companies, lending support to our own antisense-based
strategy against the same target. Designed to block IGF-IR synthesis,
ATL1101 offers potential advantages over other therapies targeting IGF-IR
due to its highly differentiated pharmacokinetics and unique antisense mode
ATL1101 was a product of a discovery collaboration between ANP and Isis
Pharmaceuticals (NASDAQ: ISIS) and utilizes second-generation antisense
technology, licensed from Isis. Several antisense drugs with the same
chemical modifications and design as ATL1101 are advancing in cancer
clinical trials, strengthening support for second generation drugs as
targeted cancer therapeutics. For example OGX-011, developed by OncoGenex
and Isis, is currently being evaluated in Phase II clinical trials in
prostate, lung and breast cancer.
About Antisense Therapeutics Limited: Antisense Therapeutics Limited (ASX: ANP) is an Australian publicly listed biopharmaceutical drug discovery and
development company. Its mission is to create, develop and commercialize
antisense pharmaceuticals for large unmet markets. ANP has two drugs in
development and two drugs in pre-clinical research. ATL1102 (injection) is
in the advanced stages of a Phase IIa trial as a potential treatment of
multiple sclerosis. ATL1103 is a second-generation antisense drug designed
to lower blood IGF-I levels and is entering preclinical development as a
potential treatment for acromegaly and vision disorders. ATL1102 (inhaled)
is at the pre-clinical research stage as a potential treatment for asthma.
ATL1101 is a second-generation antisense drug at the pre-clinical research
stage being investigated as a potential treatment for prostate cancer.
ATL1102 has been licensed to Teva Pharmaceutical Industries Ltd.