Cancer Research

Cancer Research UK's Drug Development Office has launched a clinical trial to test an experimental drug in patients with advanced (Stage IV) pancreatic cancer - one of the most difficult cancers to treat.

A NEW survey released today (Wednesday 1 September) reveals almost half of Brits (46 per cent) got sunburnt this year. Of those who got burnt, a third (32 per cent) admitted their motivation was to get a tan. And half of those who burnt whilst trying to get a tan would risk burning again next year.

Deep in the ocean, sponges of the Agelas family, or bacteria living within the sponges, emit chemicals believed to help them defend their territory. Those chemicals, called agelastatins, have also shown the ability to kill cancer cells. For that reason, chemists have been trying to find ways to synthesize agelastatins in the laboratory since the chemicals were discovered in 1993.

Chemists at MIT, led by Associate Professor Mohammad Movassaghi, recently discovered the shortest and most productive way to synthesize all six of the known agelastatins. The team, which also includes graduate students Dustin Siegel and Sunkyu Han, described the new method in the Aug. 16 online edition of the journal Chemical Science.

“Movassaghi's very elegant synthesis demonstrates a nicely scalable, multi-gram preparation of all the known agelastatins,” says Tadeusz Molinski, the chemist who first isolated agelastatins C and D, the third and fourth agelastatins discovered, in 1998. Molinski, a professor of chemistry at the University of California at San Diego, says the new synthesis will allow researchers to produce enough of the compounds to test them as cancer drugs.

Agelastatins have been shown to inhibit cancer-cell proliferation by interfering with cell division. They also repress an enzyme known as glycogen synthase kinase-3, a potential target for treating Alzheimer’s disease and bipolar disorder.

“They have a very broad range of biological activity,” says Movassaghi. “The sponges are not interested in treating cancer or Alzheimer’s, but the agelastatins are potently active against them.”

Scientists speculate that sponges, or bacteria that live in symbiosis with them, release agelastatins into their watery environment to warn other sponge species not to colonize the area.

Copying nature

Agelas sponges, which have been found in the Coral Sea and Indian Ocean, are difficult to obtain, so researchers have had trouble generating enough agelastatin to do large-scale experiments in cancer cells. Since they were first discovered, chemists have reported about a dozen ways to produce one or more of the compounds, but none of the chemists have been able to produce all six. The MIT team can do so, and in relatively large quantities — a gram per reaction batch.

The reaction begins with a commonly available starting material, aspartic acid. The synthesis requires seven steps to produce agelastatin A, the first discovered and most potent of the compounds. Agelastatin A can then be converted to agelastatins B, C or E. The synthesis can also be altered slightly to produce D, which can then be converted to F.

In designing their synthesis, Movassaghi, Siegel and Han tried to mimic the way they believe the sponges naturally produce agelastatins.

Each agelastatin contains four rings, known as A, B, C and D, and most chemists have used syntheses in which the C ring forms before the B ring. The MIT team formed the B ring first, and the C ring last. The C ring is the only ring made solely of carbon atoms (all of the others contain at least one nitrogen atom), and it is where all four of the molecule’s stereocenters are found. (Stereocenters are atoms around which the molecule can take different three-dimensional orientations.)

Other chemists had theorized that the biological synthesis of agelastatins would use precursors with an electron-deficient carbon atom in the fourth carbon position and a carbon atom that wants to share its electrons in the eighth position. Movassaghi switched those features.

To show whether sponges do the same series of steps, more experiments are needed. Researchers could label the precursors with isotope tags, give them to the sponges and follow where the isotopic labels end up. Although some of the steps of Movassaghi’s synthesis require high temperatures or acidic conditions, those same reactions could occur under biological conditions if catalyzed by enzymes.

Movassaghi’s lab is now collaborating with researchers in academia and industry to test the biological activity of the compounds, with an emphasis on their anti-cancer activity. Using the new synthesis, the researchers should be able to easily produce variants not found in nature that might have even more powerful effects, says Movassaghi. The synthesis should also provide a good starting point for possible future large-scale production, should there be a need, he says.

Oesophageal cancer rates in men have risen by 50 per cent over the last 25 years, according to new figures published by Cancer Research UK today.

An experimental drug designed to treat cancers with a particular genetic fault has shown promising results in a small clinical trial.

The National Institute for Health and Clinical Excellence (NICE) has released draft guidance which recommends the drugs bortezomib and thalidomide as first-line therapies for some patients with multiple myeloma, a type of cancer that affects cells in the bone marrow.

A new study suggests that tobacco companies may be using online video portals, such as YouTube, to get around advertising restrictions and market their products to young people.

CANCER RESEARCH TECHNOLOGY has signed an agreement with Bayer Schering Pharma AG, Germany to evaluate new leptin antagonist peptides as potential experimental treatments initially in the area of gynaecological diseases, including cancer.

The National Institute for Health and Clinical Excellence (NICE) has released draft guidance for cancer drug bevacizumab (Avastin).

UK scientists at the University of Oxford have discovered that vitamin D can affect the activity of more than 200 genes of cells grown in the lab. Some of these genes are known from previous studies to be involved in diseases like diabetes and cancer.

A US study, published in the Journal of the National Cancer Institute, has confirmed suggestions that certain types of breast cancer are more common among women who regularly drink alcohol.

Introducing palliative care at an early stage of treatment for advanced lung cancer could help patients to live for longer, as well as improving their mood and quality of life.

NHS Stop Smoking Services helped 373,954 people to quit smoking during 2009-10 - a higher number than ever before.

The number of 16 and 17 year old smokers has dropped since it became illegal to sell cigarettes to under 18s according to new research published in Addiction today (Wednesday).

Two Cancer Research UK scientists were recently awarded prestigious Royal Society Awards, while a number of Cancer Research UK scientists were elected fellows of the Royal Society and the Academy of Medical Sciences.

An experimental drug called olaparib has been shown to shrink tumours in women whose advanced cancers were caused by faults in their BRCA genes.

Clinical trials using patients’ own immune cells to target tumors have yielded promising results. However, this approach usually works only if the patients also receive large doses of drugs designed to help immune cells multiply rapidly, and those drugs have life-threatening side effects.

Now a team of MIT engineers has devised a way to deliver the necessary drugs by smuggling them on the backs of the cells sent in to fight the tumor. That way, the drugs reach only their intended targets, greatly reducing the risk to the patient.

The new approach could dramatically improve the success rate of immune-cell therapies, which hold promise for treating many types of cancer, says Darrell Irvine, senior author of a paper describing the technique in the Aug. 15 issue of Nature Medicine.

“What we’re looking for is the extra nudge that could take immune-cell therapy from working in a subset of people to working in nearly all patients, and to take us closer to cures of disease rather than slowing progression,” says Irvine, associate professor of biological engineering and materials science and engineering and a member of MIT’s David H. Koch Institute for Integrative Cancer Research.

The new method could also be used to deliver other types of cancer drugs or to promote blood-cell maturation in bone-marrow transplant recipients, according to the researchers.

T-cell therapy

To perform immune-cell therapy, doctors remove a type of immune cells called T cells from the patient, engineer them to target the tumor, and inject them back into the patient. Those T cells then hunt down and destroy tumor cells. Clinical trials are under way for ovarian and prostate cancers, as well as melanoma.

Immune-cell therapy is a very promising approach to treating cancer, says Glenn Dranoff, associate professor of medicine at Harvard Medical School. However, getting it to work has proved challenging. “The major limitation right now is getting enough of the T cells that are specific to the cancer cell,” says Dranoff, who was not involved in this study. “Another problem is getting T cells to function properly in the patient.” 

To overcome those obstacles, researchers have tried injecting patients with adjuvant drugs that stimulate T-cell growth and proliferation. One class of drugs that has been tested in clinical trials is interleukins — naturally occurring chemicals that help promote T-cell growth but have severe side effects, including heart and lung failure, when given in large doses. 

Irvine and his colleagues took a new approach: To avoid toxic side effects, they designed drug-carrying pouches made of fatty membranes that can be attached to sulfur-containing molecules normally found on the T-cell surface.

In the Nature Medicine study, the researchers injected T cells, each carrying about 100 pouches loaded with the interleukins IL-15 and IL-21, into mice with lung and bone marrow tumors. Once the cells reached the tumors, the pouches gradually degraded and released the drug over a weeklong period. The drug molecules attached themselves to receptors on the surface of the same cells that carried them, stimulating them to grow and divide.

Within 16 days, all of the tumors in the mice treated with T cells carrying the drugs disappeared. Those mice survived until the end of the 100-day experiment, while mice that received no treatment died within 25 days, and mice that received either T cells alone or T cells with injections of interleukins died within 75 days.

The study was funded by the National Institutes of Health, the National Science Foundation, the National Cancer Institute and a gift to the Koch Institute from Curtis ’63 and Kathy Marble.

‘A much simpler procedure’

Irvine’s approach to delivering the adjuvant drugs is both simple and innovative, says Dranoff. “The idea of modifying T cells in the lab to make them work better is something many people are exploring through more complicated approaches such as gene modification,” he says. “But here, the possibility of just attaching a carefully engineered nanoparticle to the surface of cells could be a much simpler procedure.”

While he is now focusing on immune-cell therapy, Irvine believes his cell pouches could be useful for other applications, including targeted delivery of chemotherapy agents. “There are lots of people studying nanoparticles for drug delivery, especially in cancer therapy, but the vast majority of nanoparticles injected intravenously go into the liver or the spleen. Less than 5 percent reach the tumor,” says Irvine, who is also a Howard Hughes Medical Institute Investigator.

With a new way to carry drugs specifically to tumors, scientists may be able to resurrect promising drugs that failed in clinical trials because they were cleared from the bloodstream before they could reach their intended targets, or had to be given in doses so high they had toxic side effects.

Irvine and his colleagues also demonstrated that they could attach their pouches to the surface of immature blood cells found in the bone marrow, which are commonly used to treat leukemia. Patients who receive bone-marrow transplants must have their own bone marrow destroyed with radiation or chemotherapy before the transplant, which leaves them vulnerable to infection for about six months while the new bone marrow produces blood cells.

Delivering drugs that accelerate blood-cell production along with the bone-marrow transplant could shorten the period of immunosuppression, making the process safer for patients, says Irvine. In the Nature Medicine paper, his team reports successfully enhancing blood-cell maturation in mice by delivering one such drug along with the cells.

Irvine is now starting to work on making sure the manufacturing process will yield nanoparticles safe to test in humans. Once that is done, he hopes the particles could be used in clinical trials in cancer patients, possibly within the next two or three years.

A US study has found that a daily dose of aspirin may reduce the risk of prostate cancer, but Cancer Research UK has noted that regular use of aspirin can cause serious side-effects and should not be undertaken unless recommended by a doctor.

A LINK between the level of active DNA repair genes in melanoma tumours and the effectiveness of chemotherapy for skin cancer patients has been established for the first time by a team of scientists.

CANCER RESEARCH TECHNOLOGY has signed a deal to provide biotech company ValiRx plc with the global rights to develop a promising compound to treat hormone-resistant prostate cancer.