A new formulation could bring a promising drug back to the clinic.

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Special delivery: This blood-vessel cell–the same type of cell that feeds spreading tumors–has absorbed a newly formulated cancer drug. In this fluorescence image, the cell’s structural elements are labeled red, the nucleus is labeled blue, and a cancer drug encased in a polymer envelope is labeled green.
Credit: Ofra Benny, Children’s Hospital Boston

By Katherine Bourzac, July 11, 2008, MIT Technology Review – In the 1990s, a cancer drug called TNP-470 dramatically increased life span for some patients and led to complete cancer regression in others. But when neurotoxicity was detected in some patients, clinical trials were halted. This is a common problem: many drugs that show great promise in the lab fail in clinical trials due to unforeseen toxicity. Nanomedicine, however, promises a way to make safer, more effective versions of such drugs. Researchers at Children’s Hospital Boston have created and tested in mice a safer version of TNP-470.

“This is one of the first examples of nanotechnology resurrecting older drugs that we’re aware of,” says Piotr Grodzinski, director of the National Cancer Institute’s nanotechnology programs.

The resurrected drug, which has not yet reentered clinical trials, is well proven to be one of the most potent inhibitors of a process key to the spread of cancer. Most cancer deaths are caused by tumors that spread throughout the body, not by the original tumor. In order for these secondary tumors, which start with a single wandering cancer cell, to become entrenched and grow large enough to become deadly, they must first establish a network of blood vessels in a process called angiogenesis. If angiogenesis can be stopped, then a patient’s cancer won’t be able to spread. And compared with traditional chemotherapy and radiation, angiogenesis inhibitors have few side effects. The Children’s Hospital drug, called Lodamin in its nanoformulation, is “the most generic and potent angiogenesis inhibitor ever seen,” says Don Ingber, a professor of vascular biology at Harvard Medical School.

Ingber discovered the drug by accident in 1985, when he was a postdoc in the lab of Children’s Hospital researcher Judah Folkman. Ingber noticed that lab-grown blood-vessel cells accidentally contaminated with a fungus weren’t growing very well; an analog of the responsible fungal compound, TNP-470, was made by Takeda Pharmaceutical Company and extensively tested in animals. These studies suggested that it would prevent blood-vessel growth in a wide range of tumor types. Early-stage clinical trials of the compound were promising. In patients with lung cancer, says Ingber, the drug led to a 50 percent increase in life expectancy. But in some patients, the drug was a neurotoxin, causing confusion and dizziness and, in a few cases, more-serious problems. Just as TNP-470 was about to enter late-stage clinical trials, the company faced a lawsuit and stopped testing the drug.

But Folkman’s lab didn’t forget about TNP-470, even after another anti-angiogenesis drug, called Avastin, became a blockbuster. Avastin stops only one of the triggers of blood-vessel formation; TNP-470 works through an unknown mechanism but appears to target multiple parts of the process and, in animal studies, works in more tumor types. This broad activity suggests that it may work in more people, and that it should be difficult for tumors to become resistant to the drug. A few years ago, Folkman’s group modified TNP-470 to prevent neurotoxicity by attaching a large polymer that prevents the compound from crossing the blood-brain barrier. This version, however, must be given intravenously–a patient would have to return to the hospital again and again for treatments to prevent cancer recurrence.

Folkman, who died in January, encouraged another researcher in his lab, Ofra Benny, to develop a version of TNP-470 that could be taken orally. Benny encased the drug in a micelle, a spherical polymer coating that resembles the fluff on a dandelion. The micelle, which is about 10 nanometers in diameter, is made up of two polymers that are both already FDA approved. Benny tested the new formulation, called Lodamin, in mouse models of melanoma and lung cancer. Her results, recently published in Nature Biotechnology, show that Lodamin is as effective as TNP-470–without having its toxicity. Hidden in the micelle, the drug is absorbed by the intestine into the bloodstream. First, it reaches the liver–a common site of secondary tumor growth–and then selectively accumulates in tumors throughout the body, inhibiting their growth.

The National Cancer Institute’s Grodzinski says that the potential for Lodamin to be taken orally is significant. “If it’s successful, that simplifies the treatment: you don’t have to come to the clinic to take it,” he says. The use of micelles for this purpose is novel, says Ingber, and could be applied to a range of other small-molecule drugs. Simple treatments with fewer side effects that keep small tumors from becoming dangerous are “the future for angiogenesis inhibitors,” he says, and will help cancer therapies keep pace with cancer diagnostics. “Early diagnosis is getting better, but we have nothing to offer these people.”

The group at Children’s Hospital is also developing Lodamin for other blood-vessel diseases, including some forms of blindness and arthritic pain caused by the invasion of capillaries into cartilage. Biotechnology company SynDevRx, based in Cambridge, MA, has optioned Lodamin for clinical development and is trying to bring it to clinical trials, says Ingber.

A new study asks why some people stay healthy into old age.

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Healthy aging: Jeanne Calment of France, shown here at age 119, died in 1997 at age 122 years and 164 days. Scientists hope a large project to sequence genes in healthy old people will reveal how, like Calment, they live so long.
Credit: NVP

By Emily Singer, July 17, 2008, MIT Technology Review – An ambitious plan to sequence 100 genes in 1,000 healthy old people could shed light on genetic variations that insulate some people from the ailments of aging, including heart disease, cancer, and diabetes, allowing them to live a healthy life into their eighties and beyond. Rather than focusing on genetic variations that increase risk for disease, scientists plan to focus on genes that have previously been linked to health and longevity.

In recent years, advances in genetic screening technologies have allowed scientists to start searching the genome for clues to healthy aging and a lengthy life span. That work has revealed that the genomes of healthy old people are not blemish free. “These people have genetic susceptibility markers for many serious diseases, including cardiovascular disease, stroke, and diabetes, but they don’t get any of these diseases,” says Eric Topol, a cardiologist and head of the Genomic Medicine Program at the Scripps Translational Science Institute, in La Jolla, CA, who is leading the project. “What is the explanation? What might account for their insulation from these diseases?”

To answer that question, researchers are collecting blood samples from 1,000 people age 80 or older who have never suffered any serious illnesses and do not take medication. They plan to sequence 100 genes, known from animal research and other studies to influence health and aging. “We are especially interested in major housekeeping, master-control genes like [those involved in] DNA repair or insulin growth factor-1,” a protein hormone involved in cell growth, says Topol. Enzymes involved in DNA repair are of interest in longevity research because cells often accumulate mistakes in their DNA sequence with age, and defects in some mouse and human DNArepairgenes trigger what looks like premature aging. The receptor for insulin growth factor-1 (IGF1) has been shown to affect aging in mice, nematodes, and flies.

Most previous studies have sequenced only a small number of genes or used gene microarrays, which can quickly detect common genetic variations throughout the genome. But recent research suggests that a number of rarer variations in different genes play a role in health and disease. Sequencing allows researchers to determine if healthy older people are more likely to carry variations that either make protective factors function more efficiently or hinder the activity of harmful factors.

Topol and his collaborators will compare the gene sequences from the healthy volunteers with DNA samples collected from people who died from age-related diseases before they reached their eighties. The scientists have already found that the healthy people had only a slightly lower probability of carrying disease-linked variations. That supports the idea that protective genes are playing a major role in people’s successful aging.

Scientists hope that identifying the molecular basis for this protective effect will enable them to mimic it with drugs. “We believe longevity genes are protecting against several age-related diseases rather than just one,” says Nir Barzilai, head of the Longevity Genes Project at Albert Einstein College of Medicine, in New York, who is not involved in the Scripps study. “From a pharmaceutical perspective, it would be more cost effective to target these pathways, and it would really imitate exceptional longevity rather than just treating the diseases themselves.”

Barzilai has already identified a couple of candidates for longevity genes. In an ongoing study of people of Ashkenazi Jewish descent age 95 or older, Barzilai and his colleagues showed that the elderly group was more likely to carry a gene variant that changes the way that people process cholesterol. More recently, the scientists sequenced the genes for IGF1 and its receptor and found mutations unique to female centenarians.

While Barzilai is taking a different approach to the gene hunt–using microarrays–he says that each group looks forward to learning what the other finds. Having two large studies of the genetics of healthy aging will allow each to confirm its findings in a second population–a crucial test of the validity of large-scale genomic studies.