Study to test anti-tumor effects of AEOL 10150 initiated

Nov 18 2009

Aeolus Pharmaceuticals, Inc. (OTC Bulletin Board: AOLS) announced today the initiation of a study to test the anti-tumor effects of AEOL 10150 when combined with radiation and chemotherapy in nude mice bearing human non-small cell lung cancer (NSCLC) xenografts. This study, led by Zeljko Vujaskovic, M.D. Ph.D. of Duke University, is designed to build on the growing body of pre-clinical data that shows that AEOL 10150 protects healthy tissue from radiation damage, while not interfering with the effectiveness of radiotherapy in killing tumors. AEOL 10150 has also been shown to be an effective treatment for damage to the lungs due to exposure to radiation.

While previous studies have shown that AEOL 10150 synthetic can suppress both acute and late normal tissue radiation injury, it is not known what effect this compound might have on tumor chemoresponsivness or responsiveness to combination chemo/radiation therapy. There is convincing evidence in the literature to support the hypothesis that Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS) are capable of promoting tumor vascular angiogenesis and that antioxidants have antiangiogenic activity. Additional data suggests that antiangiogenic compounds act synergistically with radiotherapy by increasing radiation damage to the vasculature, leading to secondary tumor cell kill, thus raising the possibility that AEOL 10150 may improve chemotherapeutic and/or radiotherapeutic control of tumors through an antivascular mechanism.

“This study will provide important insight into AEOL 10150’s ability to protect healthy tissue from combination chemo and radiation therapy, while either enhancing or not hindering the effect of this therapy on the tumor cells,” stated John L. McManus, President and Chief Executive Officer of Aeolus Pharmaceuticals, Inc. “Successful completion of this study will allow us to amend our IND with the US FDA, so that we can run phase 1 and phase 2 studies in non-small cell lung cancer patients to support our cancer radiation therapy as well as provide further safety data to support our program for the compound as a countermeasure for Pulmonary Acute Radiation Syndrome.”

Animal Model and Design

In this experiment, nude mice will be injected with human NSCLC tumor cells. Animals will be irradiated using a clinically relevant fractionated radiation schedule, and the chemotherapy group will be receiving paclitaxel intraperitonealy once a week for a total of three weeks. Tumor size will be measured twice weekly, and statistical analysis will be performed on data collected from the tumor growth assay. Tumor growth delay experiments will be conducted to test the efficacy of each treatment regimen, and the endpoint used is the number of days to reach 5 times the original tumor volume. At the time of sacrifice, tumors will be harvested for tissue homogenization and molecular analysis or immunohistochemical analysis. Endpoints to be assessed include HIF-1 alpha, a pro-angiogenic transcription factor, and its downstream gene product, vascular endothelial growth factor (VEGF), which regulates vessel sprouting and tubal formation. The endothelial cell marker CD31 will be used to evaluate overall microvessel density and a ratio of immature vasculature versus total vascularization will be measured by positive CD105 expression against CD31.

Non-Small Cell Lung Cancer is one of the most common cancers in the United States, with more than 170,000 cases diagnosed each year. About 30% of these cancer cases will present without metastases but with locally advanced or medically inoperable disease. For these patients radiation therapy has been the treatment of choice. However, results using conventional radiotherapy (60 Gy over 6 weeks) have been poor, with 5 year survival rates in the range of 5-10%. The combination of radiation and chemotherapy has slightly improved these results but randomized trials have not consistently demonstrated a survival advantage over that achieved with radiation therapy alone. Despite the high frequency of distant metastases in patients with unresectable NSCLC, local failure remains a significant clinical problem and the importance of local control has been clearly recognized. Several studies have demonstrated that achievement of local tumor control was translated to an increase in survival. Both local control as well as survival in NSCLC patients is related to the total radiation dose delivered to the tumor. However, normal tissue toxicity is a dose-limiting barrier. Thus, increasing the overall anti-tumor effect of radiation and/or chemotherapy while preferentially protecting normal tissue from radiation-induced injury, as proposed in this study with AEOL 10150, would be useful approaches in an effort to improve survival in locally advanced NSCLC.

AEOL 10150 has been shown to be safe and well tolerated in two phase 1 safety studies, and in animal studies it has been proven to be efficacious in protecting the lungs from radiation damage and increasing survival at doses in the range of 5 to 30 mg/kg given daily up to 24 hrs after irradiation and administered for as long as 10 weeks. The compound mitigated functional lung injury in rats and led to a statistically significant survival advantage in mice. In rodents and humans, radiation of the lungs can cause reduced breathing capacity, pneumonitis, fibrosis, weight loss and death and is characterized by oxidative stress, inflammation and elevated macrophage counts. AEOL 10150 has proven to be an effective countermeasure to radiation exposure of the lungs in mice and rats.