Healthcare Tips

Antisense Therapeutics Drug ATL1101 Enhances Effect Of Existing Chemotherapy Treatment On Prostate Tumors

April 16, 2017

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 treated mice.

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 protection.

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 count.

-- 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 of action.

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.

Antisense Therapeutics Limited