The Academy: May 2007

August 12, 2010
OBTN, May 2007, Volume 1, Issue 4

The Academy delivers the latest news on biotech and oncology research, providing a link between the clinical world of cancer care and the university researchers who are pushing the envelope of knowledge and discovery. In this issue: 1) Northwestern University: Anti-Cancer Flavonoids Synthesized 2) University of Wisconsin-Madison: Turning the Body�s Immune System on Cancer 3) The Institute of Cancer Research, Surrey, England: New Class of Anti-cancer Drugs 4) University of Utah School of Medicine: Advance Against Sarcoma 5) Duke University: Towards an Optical Biopsy 6) University of Southern California, Harvard Medical School, and National Institutes of Health: Genetic Variants Point to Prostate Cancer Risk

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â–º Northwestern University

Anti-Cancer Flavonoids Synthesized

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hemists at Northwestern University have devised a straightforward method to synthesize flavonoids that have anti-cancer properties. The new method, which utilizes only one simple catalyst, could pave the way for the development of new cancer therapies.

Flavonoids are a family of compounds made of more than 2,000 compounds with different chemical structures that are found

abundantly in nature in things such as red wine, dark chocolate and soy. For years, organic chemists have been looking for an

effective way to make flavanones, a type of flavonoid, in the lab. They haven’t been successful because of an inherent complexity of the compounds: flavanones are chiral molecules, which come in two different arrangements that are mirror images of one other, each with very different effects. This is why most therapeutics molecules today that are chiral are made to be either “right-handed” or “left-handed.” A mixture of the two could be potentially dangerous. But so far, it had been hard to synthesize flavanones that were one-handed.

“[Our] work provides for the first time a reliable method for the synthesis of bioactive flavanones in the correct form,” Karl

Scheidt, assistant professor of chemistry who led the work told Oncology & Biotech News. “Previous approaches did not solve

the issues of chirality of these molecules. Since these compounds in the correct handedness have broad anti-tumor activity,

we have provided an important tool in the discovery of new chemotherapies.”

To make their synthetic flavanones, Scheidt’s research team chose to imitate the chemical structures of flavanones in milk thistle, soy, grapefruit, and kosam—a root used in traditional Korean medicine. All of these flavanones are known to be anti-cancerous. The researchers adopted a trial and error process to find a suitable catalyst. After six months of testing more

than 30 different catalysts in different conditions, they discovered that a catalyst derived from quinine, when added to other

simple materials, created a one-handed molecule like the flavonoids found in nature. The researchers have synthesized 10

different kinds of flavanones; they outline their process in the April 4 issue of the Journal of the American Chemical Society.

Scheidt’s goal is to synthesize molecules that will fight prostate cancer. Some of the synthetic flavanones inhibit the ability of

prostate cancer cells to move independently. By selectively modifying the molecules and adding specificity to them, he hopes to

create better prostate cancer therapies. “A naturally occurring flavonoid may not have all the characteristics you want—it may not

be potent enough, for example—but with chemistry you can go in and modify that structure, imbuing the molecule with more

desirable traits, such as binding more effectively to a protein of interest or being less toxic to normal cells,” Scheidt said.

“Many of the new medicines for the 21st century will undoubtedly be a direct result of combining the inspiration from natural

products with the enabling power of synthetic organic chemistry.”

â–º University of Wisconsin - Madison

Turning the Body's Immune System on Cancer

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y harnessing the body’s natural antibodies and immune responses, researchers at the University of Wisconsin-Madison have developed a way to effectively target and kill cancer cells. In cell-based experiments, the researchers’ system found and killed only the cells that had high levels of receptors known as integrins. Integrins are found on the surfaces of cancer cells and tumor vasculature and are important targets in cancer research. Compared to other tumor-homing agents, the new method did not kill healthy cells that did not express integrins.

A popular method to find tumor cells in the human body is to use cell-binding agents such as monoclonal antibodies, which are attracted to certain receptors found only on tumor cells and not on normal cells. Once the antibody finds the tumor cell, though, it binds strongly to the cell surface. This is not the way things work naturally in the body, said Laura Kiessling, a chemistry professor at UW-Madison, who led the work presented at the annual national American Chemical Society meeting

on March 25. In the body, binding agents attach themselves weakly to target receptors. They only stick fast when several receptors are present on the cell surface simultaneously. This helps to reduce false positives, because if the agent mistakenly

finds and adheres to a healthy cell, it can be easily displaced.

So the researchers modified a natural immune response system present in the human body. The human body contains an

antibody known as anti-Gal, which binds to a carbohydrate called alpha-Gal that is found in large quantities on bacterial cells.

When bacterial cells enter the human body, anti-Gal targets them and triggers an immune response. But this immune response occurs only when large quantities of alpha-Gal are present on the bacterial cells.

Kiessling’s research team created a new molecular system by coupling alpha-Gal molecules with an agent that is known to

bind strongly with integrin. When they introduced this new molecule system into cell samples that had high levels of integrin,

the agent bound to the integrin, so that the cell surfaces displayed high levels of alpha-Gal. Then, in human serum samples,

the anti-Gal molecule initiated an immune response. In cells with low concentrations of integrin, the new molecule system still

attached, but the resulting levels of alpha-Gal were low enough not to trigger an immune response.

“This study suggests that the cell recognition mode we used can direct an endogenous immune response to destroy cancer

cells selectively,” Kiessling said. “We think this could lead to a new class of therapeutic agents not only for cancer but also for

seases inv

other diolving harmful cells.”

â–º The Institute of Cancer Research, Surrey, England

New Class of Anti-cancer Drugs

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es

earchers at The Institute of Cancer Research in Surrey, England, have outlined the biological properties of a class of synthetic anti-cancer drugs that have shown promise as treatments for different kinds of cancer.

The compounds belong to a new group of inhibitor proteins known as Heat Schock Protein 90 (HSP90) inhibitors. HSP90 is an important cellular protein, and its inhibition leads to the breakdown of several cancer-causing proteins. This makes HSP90 an appealing target for anti-cancer drugs. In the past, research has shown that HSp90 inhibitors could be developed into effecive treatments for a range of cancers, including breast, colon, ovarian, prostate, and skin.

Researchers at the Center for Cancer Therapeutics at The Institute of Cancer Research, led by Paul Workman, the center’s director, have discovered a new class of HSP90 inhibitors. Their study, published in the journal Cancer Research, gives a detailed description of this new HSP90 inhibitor class. The inhibitor’s lead compound, CCT018159, works by binding to a region of the HSP90 protein in place of an adenosine triphosphate (ATP) molecule. Inhibition of ATP activity results in the depletion of kinases that are involved in the growth and spread of cancer cells. “We show that CCT018159 inhibits the HSP90 target in cancer cells, leading to inhibition of the cell growth, induction of cell cycle arrest and killing of the tumor cells,” Workman told Oncology & Biotech News. “The inhibitor also blocks cancer spread and inhibits the formation of new blood vessels needed by tumors to survive and grow.”

These results confirm the promise of the “exciting” new class of HSP90 inhibitors as potential anti-cancer drugs, Workman said. “Of special significance is that the new inhibitors are very water soluble, and are not affected by drug metabolizing enzymes and membrane pumps that cause problems with the natural product inhibitors,” he said. “They therefore show considerable promise.”

The researchers are now working towards improving the properties of the new inhibitors and making them more potent,

selective, and suitable for use in animals and humans. They are also trying to understand precisely how the inhibitors work in

cancer cells.

â–º University of Utah School of Medicine

Advance Against Sarcoma

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ynovialsarcoma, a type of soft-tissue sarcoma, was once thought to develop in the membrane that lines joints like the elbow. Scientists had later realized that was not true, but until now, they have not known where the cancer first develops. Now, by genetically engineering mice that can develop synovial sarcoma, geneticists at the University of Utah have pinpointed

the cells in which the cancer arises.

In the April issue of the journal Cancer Cell, Mario Capecchi, co-chair of human genetics at the University of Utah School of

Medicine, and his colleagues show that the cancer develops in muscle cell precursors known as myoblasts. This mouse model is an important step toward developing treatments for synovial sarcoma, an aggressive cancer that is most often fatal to teenagers and young adults.

Synovial sarcoma usually develops in the arms or legs, typically near the knees or ankles. Like other soft-tissue sarcomas,

synovial sarcoma predominantly occurs in younger people and there are no effective therapies to treat the cancers yet. Five-year survival rates are as low as 25%, according to Capecchi. Many synovial sarcomas have already spread to the lungs, lymph nodes, and bone marrow by the time they are diagnosed, and about 80% of patients die.

To find out where synovial sarcomas originate, the researchers genetically engineered mice in which they could activate

a certain fusion gene in muscle cells or their precursors. This fusion gene is found only in synovial sarcomas, and not in other

types of sarcomas. Then the researchers used an enzyme to activate the fusion gene in the muscle and precursor cells.

They found that when the gene was activated in less mature precursors, it disrupted normal embryo development and the

mice died. In mature muscle cells, the gene did not cause cancer, but there was muscle damage. But when the gene was activated in myoblasts, the researchers found that the cells became cancerous 100% of the time. While the study would be difficult to replicate in humans, Capecchi said there is enough evidence showing that myoblasts are the likely source of synovial sarcoma in humans. The tumors in mice with the fusion gene “strongly resemble human synovial sarcoma” in appearance, and they also express the same set of genes, he said.

This study shows a basic research advance and treatments based on the findings would take years to develop, but the

researchers believe that this is an important step in the right direction. “The only way to develop a therapy that is specific for

this cancer is to understand how it works, and the mouse gives you that possibility,” Capecchi said.

â–º University of Southern California, Harvard Medical School, National Institutes of Health

Genetic Variants Point to Prostate Cancer Risk; Could Improve Screening and Treatment

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hree separate studies have identified several new genetic variants, all clustered on the same chromosome, that are associated with an increased risk of prostate cancer in diverse male populations—white men in the US of north European

descent, African American men, and Icelandic men. The studies were published online on April 1 in Nature Genetics. By

helping doctors to identify men at high risk of prostate cancer, the findings could lead to improvements in prostate cancer

screening and treatment. In addition, the results might explain the high occurrence of prostate cancer in African American

men.

Last year, researchers at deCODE Genetics, a biopharmaceutical company based in Reykjavik, Iceland had discovered a genetic variant on chromosome 8 that was associated with an increased prostate cancer risk. The three groups who have published the new studies looked at this same area on chromosome 8 and have found additional variants that contribute to prostate cancer risk.

Kari Stefansson and his colleagues at de-CODE Genetics have found that a second variant on chromosome 8 is associated

with the disease in several different populations. They found that while the variant is uncommon in men of European descent,

it is pretty common in African Americans. This could account for the known higher rate of prostate cancer in African American

men compared with other US populations.

In another study, researchers at the University of Southern California (USC) and Harvard Medical School identified the same

variant that the Icelandic scientists found. In addition, the researchers found five new variants in populations that represented

five different ethnic backgrounds. All of these variants were present in the same region of chromosome 8 and strongly predicted a man’s probability of developing prostate cancer. “The study has identified combinations of genetic variants that predict more than a fivefold range of risk for prostate cancer,” said David Reich, assistant professor in Harvard Medical School’s genetics department, who led the Harvard-USC study. Combinations of these variants could be responsible for up to two-thirds of prostate cancer cases in African Americans and up to a third of cases in American men of European descent, according to Reich.

The third study, led by Stephen Chanock, a senior investigator at the National Institutes of Health, showed that one of the variants reported by the Harvard-USC researchers was associated with elevated risk of prostate cancer in five different

populations.

“Clinical testing of these genetic variants may help us identify men who should be prioritized for early prostate cancer screening

and prevention efforts,” Reich said.