[tt] New Oral Angiogenesis Inhibitor Offers Potential Nontoxic Therapy For A Wide Range Of Cancers

[Brian Atkins]

http://www.sciencedaily.com/releases/2008/06/080630114209.htm

ScienceDaily (June 30, 2008) — The first oral, broad-spectrum angiogenesis 
inhibitor, specially formulated through nanotechnology, shows promising 
anticancer results in mice, report researchers from Children’s Hospital Boston.

Findings were published online on June 29 by the journal Nature Biotechnology.

Because it is nontoxic and can be taken orally, the drug, called 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. 
Lodamin 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. 
Trials were suspended in the 1990s because of neurologic side effects that 
occasionally occurred at high doses, but it remains one of the broadest-spectrum 
angiogenesis inhibitors known.

Lodamin appears to retain TNP-470’s potency and broad spectrum of activity, but 
with no detectable neurotoxicity and greatly enhanced oral availability. While a 
number of angiogenesis inhibitors, such as Avastin, are now commercially 
available, most target only single angiogenic factors, such as VEGF, and they 
are approved only for a small number of specific cancers.  In contrast, Lodamin 
prevented capillary growth in response to every angiogenic stimulus tested. 
Moreover, in mouse models, Lodamin reduced liver metastases, a fatal 
complication of many cancers for which there is no good treatment.

“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.

TNP-470 was first reformulated several years ago by Ronit Satchi-Fainaro, PhD, a 
postdoctoral fellow in Folkman’s lab, who attached a large polymer to prevent it 
from crossing the blood-brain barrier (Cancer Cell, March 2005). That 
formulation, Caplostatin, has no neurotoxicity and is being developed for 
clinical trials. However, it must be given intravenously.

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, Lodamin 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.”

TNP-470 itself has an interesting history. It was derived from fumagillin, a 
mold with strong anti-angiogenic effects that Ingber discovered accidentally 
while culturing endothelial cells (the cells that line blood vessels). Ingber 
noticed that in certain dishes -- those contaminated with the mold -- the cells 
changed their shape by rounding, a behavior that inhibits capillary cell growth. 
Ingber cultured the fungus, disregarding lab policy, which called for 
contaminated culture to be discarded immediately. He and Folkman later developed 
TNP-470, a synthetic analog of fumagillin, with the help of Takeda Chemical 
Industries in Japan (Nature, December 1990). It has shown activity against 
dozens of tumor types, though its mechanism of action is only partly known.

“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.

Folkman, the Lodamin paper’s senior author, died unexpectedly in January, just 
days after Benny submitted the paper for publication. The paper, a part of his 
legacy, is dedicated to his memory.

The study was supported in part by the U.S. Department of Defense.

-- 
Brian Atkins
Singularity Institute for Artificial Intelligence
http://www.singinst.org/