Nontoxic Therapy for a Wide Range of Cancers

Because it is nontoxic and can be taken orally, Lodamin may be useful as a preventive therapy for patients at high risk for cancer or as a chronic maintenance therapy for a variety of cancers, preventing tumors from forming or recurring by blocking the growth of blood vessels to feed them. It may also be useful in other diseases that involve aberrant blood-vessel growth, such as age-related macular degeneration and arthritis.

Developed by Ofra Benny, PhD, in the Children’s laboratory of the late Judah Folkman, MD, Lodamin is a novel slow-release reformulation of TNP-470, a drug developed nearly two decades ago by Donald Ingber, MD, PhD, then a fellow in Folkman’s lab, and one of the first angiogenesis inhibitors to undergo clinical testing. In clinical trials, TNP-470 suppressed a surprisingly wide range of cancers, including metastatic cancers, and produced a few complete remissions.

“The success of TNP-470 in Phase I and II clinical trials opened up anti-angiogenesis as an entirely new modality of cancer therapy, along with conventional chemotherapy, radiotherapy and surgical approaches,” says Ingber, now co-interim director of the Vascular Biology Program at Children’s.

Benny took another approach, attaching two short polymers (PEG and PLA) to TNP-470. Experimenting with polymers of different lengths, she found a combination that formed stable, “pom-pom”-shaped nanoparticles known as polymeric micelles, with TNP-470 at the core. The polymers (both FDA-approved and widely used commercially) protect TNP-470 from the stomach’s acidic environment, allowing it to be absorbed intact when taken orally. The micelles reach the tumor, react with water and break down, slowly releasing the drug.

Tested in mice, it had a significantly increased half-life, selectively accumulated in tumor tissue, blocked angiogenesis, and significantly inhibited primary tumor growth in mouse models of melanoma and lung cancer, with no apparent side effects when used at effective doses. Subsequent tests suggest that Lodamin retains TNP-470’s unusually broad spectrum of activity. “I had never expected such a strong effect on these aggressive tumor models,” Benny says.

Notably, Lodamin accumulated in the liver without causing toxicity, preventing liver metastases and prolonging survival. “This was one of the most surprising things I saw,” says Benny. “When I looked at the livers of the mice, the treated group was almost clean. In the control group you couldn’t recognize the livers -- they were a mass of tumors.”

“It’s been an evolution,” says Benny, “from fumagillin to TNP-470 to Caplostatin to Lodamin.”

Lodamin and Caplostatin have been optioned for clinical development by SynDevRx, Inc., a Cambridge, Mass.-based biotechnology company. Benny, who is from Israel, coined the name Lodamin from Hebrew. (“Lo dam” means “no blood.”) She continues to study Lodamin’s effects in other animal models of cancer, and in macular degeneration with Robert D’Amato, MD, PhD, in the Vascular Biology program.; Source: Children's Hospital Boston