Influence of acoustic cluster therapy and Methotrexate on human prostate xenograft growth
Acoustic cluster therapy (ACT) can be used to improve localized pathologies responses to therapeutic agents. This therapy uses diagnostics ultrasound for treatment of through stimulating local uptake of systemic administered drugs.
Ectopic pregnancy is a serious condition with a prevalence rate in the Western world as high as 1-2% of all pregnancies. Estimated number of cases/year in the EU/US is 100.000. The Standard of Care (SoC) for removal of the ectopic embryo is treatment with chemotherapy (methotrexate) in two, biweekly cycles. Unfortunately, the success rate of this SoC is only approx. 60% after one treatment and less than 80% after the second cycle. Further treatments with methotrexate is not indicated due to potentially serious side effects. The remaining, more than 20%, of these patients typically develops serious conditions (rupture and bleeding) with ensuing surgery, often with loss of fertility. In the non-western world, ectopic pregnancy is estimated to be the cause of 5 to 15% of maternal deaths. Improved treatment of ectopic pregnancy hence represents a significant unmet clinical need.
In a series of pre-clinical studies, ACT has been shown to significantly increase the therapeutic effect of a range of chemotherapies for treatment of a variety of cancerous. Unfortunately, there exists no pre-clinical models for ectopic pregnancy. However, cancerous models should be a reasonable mimic for the condition (rapidly dividing cells) and, in discussions with regulatory bodies, it has been indicated that showing synergistic effects between ACT and methotrexate in e.g. a prostate cancer model, in combination with clinical Proof of Concept for the ACT concept in an ongoing clinical trial for treatment of hepatic metastases from colon cancer (NCT04021277), will be sufficient to warrant a clinical trial with ACT/methotrexate for treatment of ectopic pregnancy. The described study will hence be instrumental in getting regulatory approval for a clinical trial on this disease.
Also, simulation studies were performed, however, it is not possible to mimic the complex vascular system of human tumors in simulations and phantom studies to predict its behavior in patients.
This study is designed to test if ACT will get the same or better improved of Methotrexate (MTX) efficacy. PC3 tumor bearing mice will be injected with Methotrexate and treated with ACT. At the start of this study, the tumors are 50-200 mm3 and will not have given the mice pain or any other discomfort.
40 mice will undergo treatments (ones a week for 3 weeks). The doses of MTX will be below the MTD and is expect to reduce tumor growth but will not cure the mice. Former studies have proven that ACT has no effect on the heath of the mice. The treatment should not cause any serious side effects. Also humane endpoints and the use of anesthesia will prevent any major stress, however, some weight loss and moderate distress might be expected. Monitoring weight and tumor size will be done by normal scale and caliper measurements, respectively, which is done without any anesthesia, it is just gentle handling of animal without any stress.
Ectopic pregnancy is a serious condition with a prevalence rate in the Western world as high as 1-2% of all pregnancies. Estimated number of cases/year in the EU/US is 100.000. The Standard of Care (SoC) for removal of the ectopic embryo is treatment with chemotherapy (methotrexate) in two, biweekly cycles. Unfortunately, the success rate of this SoC is only approx. 60% after one treatment and less than 80% after the second cycle. Further treatments with methotrexate is not indicated due to potentially serious side effects. The remaining, more than 20%, of these patients typically develops serious conditions (rupture and bleeding) with ensuing surgery, often with loss of fertility. In the non-western world, ectopic pregnancy is estimated to be the cause of 5 to 15% of maternal deaths. Improved treatment of ectopic pregnancy hence represents a significant unmet clinical need.
In a series of pre-clinical studies, ACT has been shown to significantly increase the therapeutic effect of a range of chemotherapies for treatment of a variety of cancerous. Unfortunately, there exists no pre-clinical models for ectopic pregnancy. However, cancerous models should be a reasonable mimic for the condition (rapidly dividing cells) and, in discussions with regulatory bodies, it has been indicated that showing synergistic effects between ACT and methotrexate in e.g. a prostate cancer model, in combination with clinical Proof of Concept for the ACT concept in an ongoing clinical trial for treatment of hepatic metastases from colon cancer (NCT04021277), will be sufficient to warrant a clinical trial with ACT/methotrexate for treatment of ectopic pregnancy. The described study will hence be instrumental in getting regulatory approval for a clinical trial on this disease.
Also, simulation studies were performed, however, it is not possible to mimic the complex vascular system of human tumors in simulations and phantom studies to predict its behavior in patients.
This study is designed to test if ACT will get the same or better improved of Methotrexate (MTX) efficacy. PC3 tumor bearing mice will be injected with Methotrexate and treated with ACT. At the start of this study, the tumors are 50-200 mm3 and will not have given the mice pain or any other discomfort.
40 mice will undergo treatments (ones a week for 3 weeks). The doses of MTX will be below the MTD and is expect to reduce tumor growth but will not cure the mice. Former studies have proven that ACT has no effect on the heath of the mice. The treatment should not cause any serious side effects. Also humane endpoints and the use of anesthesia will prevent any major stress, however, some weight loss and moderate distress might be expected. Monitoring weight and tumor size will be done by normal scale and caliper measurements, respectively, which is done without any anesthesia, it is just gentle handling of animal without any stress.