Aeolus Pipeline Initiative: Radioprotection

Third party scientific collaboration with Duke University.
In August 2003, the Company was awarded a $100,000 Small Business Innovation and Research, or SBIR, Phase I grant from the National Cancer Institute, a division of the National Institutes of Health, and in March 2004, Aeolus was awarded a $750,000 SBIR Phase II grant from the NIH. Pursuant to the grants, the Company is studying the anti-tumor and radiation-protective effects of various catalytic antioxidants. The study is collaboration between the Company and the Department of Radiation Oncology at Duke University Medical Center.

A drug to protect normal cells will not be useful if it also protects tumor cells. In a model in which breast cancer cells were transplanted into rats, AEOL 10113 did not protect the tumor cells from radiation. Instead, the anti-tumor effect of radiation was enhanced by administration of the compound. Both AEOL 10113 and AEOL 10150 have shown anti-tumor activity following radiation therapy in RP9 prostate cancer in mice and in human HCT116 colon cancers in athymic mice. Both AEOL 10113 and AEOL 10150 have shown some degree of anti-tumor activity in the absence of radiation therapy in rat models of breast and skin cancers.

Radiation-Induced Brain Injury
Most patients with malignant tumors of the central nervous system (CNS) are treated with a course of cranial radiation. The limiting factor determining the radiation dose is the radiosensitivity of normal CNS tissue. Radioprotectant drugs that can increase the tolerance of normal tissue to the adverse effects of ionizing radiation have been sought for many years. There is considerable evidence that SOD activity modulates the biological effects of ionizing radiation through scavenging of toxic oxygen radicals formed during tissue / cell irradiation. Accordingly, a rational approach for protecting CNS tissue from radiation damage would be to increase the SOD activity of the normal tissue surrounding the tumor.

A high dose (100 Gy) of radiation was used to determine the effects of AEOL 10150 on radiation-induced brain injury (DNA damage, blood brain barrier disruption, and histopathological changes). A low dose irradiations (15 Gy) was used to determine the effect of AEOL 10150 and radiation exposure on the proliferating stem cells in the dentate gyrus. DNA damage was assessed 12 hours after irradiation using TUNEL staining. Effects on stem cell proliferation were assessed 14 days after treatment / irradiation using BrdU immunohistochemistry. Blood brain barrier permeability and histopathology assessments were performed on the same set of animals. BBB was assessed 28 days post-treatment / irradiation using MRI. Histopathology was assessed 50 days post-AEOL 10150 / irradiation. AEOL 10150 was found to be an effective CNS radioprotectant when administered intraventricularly (ICV) within three hours prior to cranial radiation. AEOL 10150 treatment prevented acute radiation induced DNA damage in vitro and in vivo. AEOL 10150 alleviated delayed radiation induced blood brain barrier disruption. AEOL 10150 protected against delayed radiation-induced CNS necrosis.

Radiation-Induced Lung Fibrosis
Similar to the laboratory findings for AEOL 10150, Aeolus’ catalytic antioxidant AEOL 10113 significantly protected the normal lung tissue of rats against damage caused by radiation (Free Radic Biol Med 33: 857, 2002). Fourteen weeks after radiation exposure, breathing rates (an indirect measure of lung restriction) increased 71% in untreated rats compared with only a 42% increase in AEOL 10113 treated rats. Twelve weeks after radiation exposure, plasma TGF-ß levels increased 2.9 fold in untreated rats compared with only a 40% increase in AEOL 10113 treated rats. AEOL 10113 treated rats exposed to radiation had a 37% decrease in compared to radiation alone.

Tumor Suppression / Bone Marrow Transplantation
Cancer can arise in almost any organ and is marked by abnormal cell differentiation and growth. This abnormal growth is uncoordinated and lacks the normal regulatory controls present in healthy cells. Cancer causes damage by competing with healthy tissue for nutrients; because the cancerous cells continue to proliferate, the healthy tissues essentially starve to death.

Cancer often arises as a result of mutations in the DNA, which can potentially be the result of free radicals and ROS activity. Cancer is also known to develop at sites of chronic inflammation, possibly due to the free radicals and ROS produced by that process. Antioxidants and anti-inflammatory substances may play an important role in protecting the body against the formation of cancerous cells.

Combinations of surgery, chemotherapy and radiation treatments are the mainstay of modern cancer therapy. Success is often determined by the ability of patients to tolerate the most aggressive, and most effective, treatment regimens. A compound that would directly inhibit tumor growth and protect against the therapy-limiting side effects of other cancer treatment could enhance the success of therapy. Preclinical studies have found that our catalytic antioxidants, AEOL 10150, inhibits formation of blood vessels required for tumor growth, and protect normal tissues from damage induced by radiation and chemotherapy. We have obtained outside funding for this program in the form of a National Institutes of Health Small Business Innovation Research grant. AEOL 10150 is our lead candidate in the cancer therapy area.