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.”
This is great. I wonder why the original drug had the neurological side effects but this one does not? Is it in a lower dosage? I’m surprised that this works as good as it does. Do any doctors on here know if these drugs targeting angiogenesis affect healing and normal blood vessal growth, and if so, to what extent?
What what is the future of genomic and personalized medicine? In this panel organized by Helix Health, five experts discuss what new developments in pmed advances in breast and ovarian cancer management, what they means for patients, doctors, and the health industry, and how these treads apply to all health care.
“This [genomics] revolution is akin to the discovery that bacteria cause disease.” begins Dr. Steven Murphy, an expert in genomic medicine. Yet, “how did medicine advance so technologically, yet fail to keep us informed? … I’m amazed how difficult it is to translate this wealth of technology into truly effective patient care.”
And “we are in the beginning of an enormous tsunami of new [genomic] information that’s just beginning to hit,” says author David Duncan, who has subjected himself to “The Experimental Man” project to take every test to learn what can be learned about one’s body. These tests are expensive today, the BRCA breast cancer gene test costs upwards of $2500, but like microchips “technology is making these tests cheaper and easier —even including full genome sequencing.”
But who in the medical community needs to learn this information? “Everyone, so everyone is liable.” says Gary Marchant, J.D. By the “loss of chance doctrine,” simply by not discussing all the new genomic information to patients, “today, it’s any doctor who is potentially liable, from the general physician to the family physician to any kind of specialist.”
Yet, “such a small amount of physicians who are genetically knowledgeable,” says Steve, “there are less than 100 trained adult genetics specialists.” And while genomic education is truly empowerment to practice better health, medical students experience what Steve dubs “genomic knowledge erosion:” students know less about genomics after medical school than before and even less after residency. Gary adds, “Most doctors practicing today probably didn’t have genetics in medical school. If you’re an older doctor practicing in some rural community, this issue is all foreign to you.”
“Those doctors should then retire,” rebukes patient advocate Jessica Quller. “Perhaps fear of litigation will force doctors on a national level to become educated in their field and force them to present these options to patients.” Jessica’s mother died of preventable ovarian cancer, prompting Jessica to take the BRCA breast cancer gene test. Testing positive, she underwent a prophylactic mastectomy and oophorectomy. “The year is now 2004: no doctor had ever mentioned that I should be tested, and my sister and I essentially lived in NYU hospital with my mom for two years during her illness… Only my high school friend mentioned the [BRCA test] to me.”
“For 2004, I certainly would have hoped that in New York City, somebody would have talked to you about genetic testing in light of your mom’s illness.” exclaims Dr. Barbara Ward, a surgical oncologist. While “about 7% to 8% of [breast cancer] is inherited… we do believe that [the BRCA 1 & 2] genes reflect most of the inherited breast cancers… as high as 87% of women carrying the BRCA 1&2 gene will develop breast cancer. I look forward to the day that we’ll look back and we’ll say ‘can you actually believe we did prophylactic mastectomy for gene carriers?’ But at this point in time it’s the best we can offer.” But will insurance companies pay for tests like this including breast MRIs? “We definitely struggle… it’s VERY frustrating. Sitting in my desk right now I have a chart of a lady who’s HAD breast cancer, has had a mastectomy, and her insurance company is refusing to screen her with a breast MRI… So, it is frustrating to realize that there’s a test that’s available and realize that you may not be able to get it.”
Thank you to the panelists and Helix Health for conducting this excellent session about genomic medicine and breast cancer management.
A synthetic chemical based on a compound found in cocoa beans slowed growth and accelerated destruction of human tumors in laboratory studies, and should be tested further for cancer chemoprevention or even treatment, say researchers at Georgetown University Medical Center.
“We have all heard that eating chocolate is good for you; this study suggests one reason why that might be true,” says the study’s lead author Min Kim, Ph.D., a research scientist in the Department of Oncology at Lombardi Comprehensive Cancer Center.
Published online today in Cell Cycle, the researchers describe how four different human tumor cells lines out of 16 tested were sensitive to the chemical, known as GECGC. The strongest response was seen in two different colon cancers; growth was cut in half and most of the tumor cells were damaged.
Normal cells were not affected by GECGC, which makes the chemical a candidate for cancer chemoprevention, says Kim.
“This chemical seems to be safe, which makes sense because it has a structure similar to a natural product in cocoa beans - the same beans that are used to make chocolate,” he says.
The researchers have long studied the beneficial effects of flavanols, which are molecules in vegetables and fruits that exhibit potent anti-oxidant and, potentially, anti-tumor properties. As part of these studies, investigators have been testing a new synthetic version of natural procyanidins, a class of flavanols, created and patented by the confectionery company, Mars Incorporated. (The company provided GECGC as a gift, and this project was funded in part by Mars Incorporated.)
In these studies, the scientists tested the effects of three different doses of GECGC on the cancer cell lines - the first time that a synthetic cocoa derivative has been used to screen human cancer cell lines. None of the doses tested were extreme, Kim points out. “The effective concentrations were considered similar to what a person might eat or use,” he says.
They found sensitivity to GECGC in both colon cancer cell lines they tested, in cervical cancer cells and in one line of leukemia, tumor cells. Other cell lines were resistant, including ovarian and prostate cancer cells.
Overall, GECGC showed the most effect in treating cancer cells that are normally fast growing, Kim says. And the fact that it demonstrated the most killing power in colon cancer suggests the chemical “could serve as a promising therapeutic for colon cancer,” he says. “So far, these data are very convincing.”
The researchers do not yet clearly understand the mechanism by which GECGC disrupts tumor growth, but they think it inhibits the physical connections between cancer cells and blocks internal cell signaling pathways.
Kim says that animal studies testing the anticancer power of GECGC are currently underway. “While this work is indeed promising, we have much more study to do before we can say with authority that GECGC has anticancer properties.”
A team of scientists at the Genome Institute of Singapore (GIS), a research institute of the Asian city-state’s Agency for Science, Technology and Research (A*STAR), and the University of California at San Francisco have developed a pharmacological approach to kill colon cancer cells.
Genetic and epigenetic defects in the signaling of a protein called Wnt/β-catenin, which is often found to be abnormally activated in human malignance, play important roles in colorectal cancer development. The team of scientists identified a gene, called DACT3, whose function is to inhibit Wnt/β-catenin, is often lost (or transcriptionally silenced) in colorectal cancer.
Apart from the findings on DACT3, they have also developed a pharmacological approach to restore the expression of DACT3, which results in the effective inhibition of Wnt/β-catenin massive death of colon ancer cells. Their discovery was published in Cancer Cell on June 9, 2008.
GIS Group Leader, Yu Qiang, Ph.D., said, “This work identifies a significant new regulator of the Wnt/β-catenin avenue for future colorectal cancer research.”
Edison Liu, M.D., Executive Director of GIS, added, “This is indeed a very significant discovery. It suggests a novel therapy for colorectal cancer, an important step towards clinical treatment for the disease, which is one of the leading causes of death from tumors.”
The team is now working with other A*STAR research institutes and industry partners for the development of potential drug candidates based on this technology.
In a new study in PLoS Medicine, Samir Hanash and colleagues from Fred Hutchinson Cancer Research Center in Seattle report the identification of proteins that appear in increased numbers at an early stage of pancreatic tumor development in a mouse model and may be a useful tool in detecting early tumors in humans.
Using a well-characterized mouse model of pancreatic cancer the researchers identified a panel of five proteins selected on the basis of their increased level at an early stage of tumor development in the mouse and tested them in a blinded study in 26 humans from the CARET (Carotene and Retinol Efficacy Trial) cohort. The panel of proteins discriminated pancreatic cancer cases from matched controls in blood specimens obtained between 7 and 13 months prior to the development of symptoms and clinical diagnosis of pancreatic cancer.
Although further validation will be needed, these results indicate that mouse models of cancer, in combination with in-depth proteomic analysis, could help identify candidate markers in human cancer and potentially be used for early detection, say the researchers
Tobacco smokers who eat three servings of fruits and vegetables per day and drink green or black tea may be protecting themselves from lung cancer, according to a first-of-its-kind study by UCLA cancer researchers.
UCLA researchers found that smokers who ingested high levels of natural chemicals called flavonoids in their diet had a lower risk of developing lung cancer, an important finding since more than 90 percent of lung cancers are caused by tobacco smoking.
The study was published this month in the journal CANCER.
“What we found was extremely interesting, that several types of flavonoids are associated with a reduced risk of lung cancer among smokers,” said Dr. Zuo-Feng Zhang, a researcher at UCLA’s Jonsson Cancer Center and a professor of public health and epidemiology. “The findings were especially interesting because tobacco smoking is the major risk factor for lung cancer.”
Flavonoids are water-soluble plant pigments that have antioxidant and anti-inflammatory properties, both of which can counteract damage to tissues. For the UCLA study, researchers looked at 558 people with lung cancer and 837 people who did not have lung cancer and analyzed their dietary history.
Researchers found that study participants who ate foods containing certain flavonoids seemed to be protected from developing lung cancer. Zhang said the flavonoids that appeared to be the most protective included catechin, found in strawberries and green and black teas, kaempferol, found in Brussels sprouts and apples, and quercetin, found in beans, onions and apples.
So should smokers run out and stock up on the teas, apples, beans and strawberries? Quitting smoking is the best course of action, Zhang said, but eating more fruits and vegetables and drinking more black and green teas won’t hurt.
“Since this study is the first of its type, I would usually be hesitant to make any recommendations to people about their diet,” Zhang said. “We really need to have several larger studies with similar results to confirm our finding. However, it’s not a bad idea for everyone to eat more fruits and vegetables and drink more tea.”
Zhang said flavonoids protect against lung cancer by blocking the formation of blood vessels that tumors develop so they can grow and spread, a process called angiogenesis. They also stop cancer cells from growing, allowing for naturally programmed cell death, or apoptosis, to occur.
The antioxidant properties found in the flavonoids also may work to counteract the DNA damaging effects of tobacco smoking, Zhang said, explaining why they affected the development of lung cancer in smokers but not in non-smokers.
“The naturally occurring chemicals may be working to reduce the damage caused by smoking,” Zhang said.
The next step, Zhang said, are laboratory-based studies of flavonoids on cell lines and animal models to determine how they are protecting smokers from developing lung cancer. And in addition to larger studies to confirm these findings, other studies need to be done to see if the protective effects of flavonoids extend to other smoking-related cancers, such as bladder, head and neck and kidney cancers.
Zhang and his team also plan to study which types of fruits and vegetables have the highest levels of the flavonoids found to be helpful in this study and what the optimal number of servings per day might be to provide the greatest protection.
I unfortunately can’t find the paper, as there are a lot of journals called “Cancer” and the paper may or may not actually be available yet. This is just yet another study that demonstrates how good for you flavinoids are. I remember another study that said flavinoids cause an immune response, which may be why they’re helpful for preventing disease.
New research suggests that the form of tomato product one eats could be the key to unlocking its prostate cancer-fighting potential, according to a report in the June 1 issue of Cancer Research, a journal of the American Association for Cancer Research.
“Processing of many edible plants through heating, grinding, mixing or drying dramatically increases their nutrition value, including their cancer prevention potential. It appears that the greatest protective effect from tomatoes comes by rehydrating tomato powder into tomato paste,” said Valeri V. Mossine, Ph.D., research assistant professor of biochemistry at the University of Missouri.
The protective effect of tomato products against prostate cancer has been suggested in many studies, but researchers remain uncertain about the exact mechanisms. Mossine and colleagues demonstrated that FruHis, an organic carbohydrate present in dehydrated tomato products, exerts a strong protective effect.
Researchers divided rats into groups of 20 and fed them a control diet or a diet that included tomato paste, tomato powder or tomato paste plus additional FruHis. All animals were then injected with prostate cancer-causing chemicals.
Animals fed the tomato paste plus FruHis diet had the longest survival from cancer at 51 weeks compared with 50 weeks in the tomato powder group, 45 weeks in the tomato paste alone group and 40 weeks in the control group.
On post-mortem exam, prostate tumors were found in 10 percent of the rats that had been given a combination of tomato paste and FruHis, compared with 30 percent of animals in the tomato powder group, 25 percent in the tomato paste alone group and 60 percent in the control group.
Mossine said the protective effect of tomato-based products was restricted to prostate tumors, which is consistent with other research on tomatoes and cancer. Incidence of other tumors was too small to examine.
In vitro, Mossine and colleagues evaluated the anti-cancer properties of FruHis and 14 other D-fructose amino acids and found that FruHis in a concentrated form protected against DNA damage known to lead to prostate cancer. When combined with lycopene, FruHis stopped cancerous cell growth more than 98 percent of the time.
“Before this study, researchers attributed the protective effect of tomatoes to ascorbic acid, carotenoids, or phenolic compounds,” Mossine said. “FruHis may represent a novel type of potential dietary antioxidant. Experiments like these suggest that a combination of FruHis and lycopene should be investigated as a potential therapeutic anti-tumor agent, not just a prevention strategy.”
Although Mossine cautioned against drawing broad conclusions from this animal study, he said, “the result may introduce an additional intrigue into an ongoing dispute over the beneficial effects of dietary lycopene and tomato products in lowering the risk of prostate cancer. Human trials are certainly warranted.”
The paper is not currently available. I wonder how long it will take for FruHis to be available as a supplement or added to multivitamins. It certainly should be easy enough to mass produce.
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.
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