Posts tagged cancer

A cancer patient has made a full recovery after being injected with billions of his own immune cells in the first case of its kind, doctors have disclosed. The 52-year-old, who was suffering from advanced skin cancer, was free from tumours within eight weeks of undergoing the procedure.

Doctors took cells from the man’s own defence system that were found to attack the cancer cells best, cloned them and injected back into his body, in a process known as “immunotherapy”. After two years he is still free from the disease which had spread to his lymph nodes and one of his lungs. Experts said that the case could mark a landmark in the treatment of cancer.

Researchers have long searched for a novel cancer drug that activates a certain protein to kill tumor cells. But finding a drug that kills the cancer without causing damage to normal cells has stymied researchers.

Now, researchers at the University of Michigan Comprehensive Cancer Center have designed a small molecule that is highly effective in cell cultures at inhibiting the interaction between this protein, called p53, and another protein that inactivates p53 in cancer. The new molecule is ideal for drug development as it can be given orally as a pill and it appears to be safe for use in animals.

“For more than 10 years scientists have searched for ways to block p53 inhibition, but with little success. Our study clearly shows that this can be done,” says study author Shaomeng Wang, Ph.D., Warner-Lambert/Parke-Davis Professor in Medicine at the U-M Medical School and co-director of the molecular therapeutics program at the U-M Comprehensive Cancer Center.

If clinical trials prove out the drug’s promise, it could have potential for treating many different types of cancer. Results of the study appear the week of March 3 in the online edition of the Proceedings of the National Academy of Sciences.

The protein p53, which normally helps suppress tumors, is inactivated in almost all human cancers. About half the time, p53 does not do its job because the gene that holds the protein is mutated or missing altogether. The other half of the time, another protein, called human MDM2, is the culprit. It binds to p53 and inhibits the tumor suppressor function of p53, promoting cancer development.

Using a computer-assisted approach, U-M researchers designed a small molecule, called MI-219, that is highly effective in blocking the interaction of MDM2 and p53. MI-219 specifically kills tumor cells by harnessing the power of p53. In animal models of human cancer, MI-219 completely inhibited tumor growth and appeared to cause no toxicity to animals.

“Many traditional cancer drugs also activate p53 but they do so by causing DNA damage. They kill not only tumor cells but also normal cells, thus having severe side effects. MI-219 is unique in that it is designed to activate p53 without causing DNA damage, specifically killing tumor cells. Indeed, MI-219 is highly effective in inhibiting tumor growth, and even inducing tumor regression, but it has caused no toxicity to animals at efficacious doses,” says Wang, professor of internal medicine and pharmacology at the U-M Medical School and professor of medicinal chemistry at the U-M College of Pharmacy.

In addition to its effectiveness at killing cancer cells without toxic side effects, MI-219 can be developed as a pill that patients could take orally, rather than the traditional chemotherapy drugs that must be given intravenously at a hospital or cancer center.

“While promising in preclinical studies, MI-219 needs to be evaluated in human clinical trials for its safety and efficacy for cancer treatment since it is a brand new drug,” Wang cautions.

“We are very excited about the therapeutic potential of MI-219 for the treatment of many types of human cancer. Ascenta is committed to advancing MI-219, which we have designated AT-219, into human clinical trials,” says study author Dajun Yang, M.D., Ph.D., senior vice president of research and a co-founder of Ascenta Therapeutics, a clinical-stage biopharmaceutical company that has licensed the technology related to MI-219 from U-M and plans to aggressively advance it into human clinical trials.

MI-219 is in preclinical studies and not yet ready for human trials in cancer patients. For questions about currently available cancer treatments, call the U-M Cancer AnswerLine at 800-865-1125 or visit www.mcancer.org.

The lead author on the study was Sanjeev Shangary, Ph.D., research investigator at the U-M Medical School. Other authors were Dongguang Qin, Donna McEachern, Meilan Liu, Rebecca Miller, Su Qiu, Zaneta Nikolovska-Coleska, Ke Ding, Guoping Wang, Jianyong Chen, Denzil Bernard, Jian Zhang, Yipin Lu, Qingyang Gu, Rajal Shah, Kenneth Pienta and Yi Sun, all from the University of Michigan; and Xiaolan Ling, Sanmao Kang, Ming Guo, and Dajun Yang from Ascenta Therapeutics Inc.

Funding for the study is from the National Cancer Institute, a U-M Prostate Cancer SPORE grant, the Leukemia and Lymphoma Society, the Prostate Cancer Foundation, Ascenta Therapeutics Inc. and the U-M Comprehensive Cancer Center.

The University of Michigan has filed a patent application for MI-219 and its related molecules. The technology has been licensed by Ascenta. U-M and Wang have equity in Ascenta. Wang is a scientific founder of Ascenta and serves as its chief scientific adviser and is the principal investigator on a research contract from Ascenta to U-M.

Reference: Proceedings of the NationalAcademy of Sciences, published online week of March 3, 2008

Note: This story has been adapted from a news release issued by the University of Michigan

SAN DIEGO, CA — Green tea is high in the antioxidant EGCG (epigallocatechin-3- gallate) which helps prevent the body’s cells from becoming damaged and prematurely aged. Studies have suggested that the combination of green tea and EGCG may also be beneficial by providing protection against certain types of cancers, including breast cancer. A new study conducted by researchers at the University of Mississippi researchers now finds that consuming EGCG significantly inhibits breast tumor growth in female mice. These results bring us one step closer to better understanding the disease and potentially new and naturally occurring therapies.

The study was conducted by Jian-Wei Gu, Emily Young, Jordan Covington, James Wes Johnson, and Wei Tan, all of the Department of Physiology & Biophysics, University of Mississippi Medical Center, Jackson, MS. Dr. Gu will present his team’s findings, entitled, Oral Administration of EGCG, an Antioxidant Found in Green Tea, Inhibits Tumor Angiogenesis and Growth of Breast Cancer in Female Mice, at the  121^st Annual Meeting of the American Physiological Society (APS; www.the-APS.org/press), part of the Experimental Biology 2008 scientific conference.

The Study

Epidemiological studies suggest that green tea and its major constituent, EGCG, can provide some protection against cancer. Because these studies were very limited, the anti-cancer mechanism of green tea and EGCG was not clear. As a result, the researchers examined whether drinking EGCG (just the antioxidant infused in water) inhibited the following: expression of VEGF (vascular endothelial growth factor, which is found in a variety of breast cancer types); tumor angiogenesis (thought to help tumors expand by supplying them with nutrients); and the growth of breast cancer in female mice.

Seven week old female mice were given EGCG (25 mg/50 ml) in drinking water for five weeks (approximately 50-100 mg/kg/day.) The control mice received regular drinking water. In the second week of the study mouse breast cancer cells were injected in the left fourth mammary glands of the mice. Tumor size was monitored by measuring the tumor cross section area (TCSA). Tumors were eventually isolated and measured for tumor weight, intratumoral microvessel (IM) density (using staining), and VEGF protein levels (using ELISA).

At the end of the five week period the researchers found that oral consumption of EGCG caused significant decreases in TCSA (66%), tumor weight (68%), IM density 155±6 vs.111±20 IM#mm^2) and VEGF protein levels (59.0±3.7 vs. 45.7±1.4 pg/mg) in the breast tumors vs. the control mice, respectively (N=8; P<0.01).  Further, VEGF plasma levels were lower in EGCG mice than in control mice (40.8±3.5 vs. 26.5±3.8 pg/ml P< 0.01).

Dr. Gu, the senior researcher for the study, hypothesized that the reason for the link between EGCG and the reductions in the cancer data was because EGCG directly targets both tumor blood vessels and tumor cells of breast cancer for suppressing the new blood vessels formation in breast tumor, the proliferation and migration of breast cancer cells.

Gu concluded by saying, “In this study we have demonstrated that the frequent ingestion of EGCG significantly inhibits breast tumor growth, VEGF expression and tumor angiogenesis in mice. We believe our findings will help lead to new therapies for the prevention and treatment of breast cancer in women.”

Physiology is the study of how molecules, cells, tissues and organs function to create health or disease. The American Physiological Society (APS; www.The-APS.org/press) has been an integral part of this discovery process since it was established in 1887.

by Dianne C. Witter

Dr. Aggarwal is conducting laboratory studies on the apparent anticancer activity of curcumin, which is the main ingredient of the curry spice turmeric.

Razelle Kurzrock, M.D., rigorously evaluates the laboratory data behind any new pharmaceutical agent she considers moving into clinical trials at M. D. Anderson Cancer Center. As a physician, she is cautious; as a scientist, she’s a skeptic; she wants unbiased, evidence-based information. And that, to her own surprise, is how she became interested in studying curcumin—the primary ingredient of the curry spice turmeric—as a possible anticancer agent in humans.

“Dr. Bharat Aggarwal, chief of the cytokine research laboratory in the Department of Experimental Therapeutics, came to me and said, ‘I want to show you some great results we’ve gotten in the lab with an exciting new agent,’” said Dr. Kurzrock. “But he wouldn’t tell me what the agent was—he wanted me to see the data first.”

Dr. Kurzrock, professor in and chair ad interim of M. D. Anderson’s Department of Investigational Cancer Therapeutics (formerly the Phase I Clinical Trials program), was impressed with the data. “It was clear that this agent was just as potent at killing tumor cells in the lab as any experimental drug I’d seen from pharmaceutical companies,” she said. When Dr. Aggarwal told her this active agent was curcumin, she was intrigued and began designing a clinical study to test curcumin’s efficacy in humans.

Shutting down the master switch

Curcumin’s anti-inflammatory properties have been valued in Eastern medicine for centuries, but its specific mechanism of action has only recently been identified. In 1995, Dr. Aggarwal and colleagues demonstrated that curcumin shuts down nuclear factor kappa B (NF-kB), which is involved in the regulation of inflammation and many other processes.

By blocking the activity of this “master switch,” curcumin appears to interfere with the cancer process at an early point, impeding multiple routes of development: reducing the inflammatory response, inhibiting the proliferation of tumor cells, inducing their self-destruction, and discouraging the growth of blood vessels feeding tumors. These effects can shrink tumors and inhibit metastasis. Furthermore, shutting down NF-kB can enable traditional chemotherapy drugs to destroy cancer cells more effectively.

Hundreds of laboratory studies by Drs. Aggarwal and Kurzrock and others have demonstrated that curcumin is biologically active against many types of cancer cells—melanoma, and breast, bladder, brain, pancreatic, and ovarian carcinomas, to name just a few. “In the lab, we haven’t yet found a type of cancer it doesn’t show activity against,” Dr. Aggarwal said.

While it’s a long road from lab to clinic, Dr. Aggarwal sees promise in curcumin both as a possible preventive agent and as a cancer treatment. As a medicinal agent, its potential extends far beyond cancer. Laboratory studies have demonstrated curcumin’s promise in a number of different diseases that are also affected by inflammation, including arthritis, inflammatory bowel disease, Alzheimer’s disease, diabetes, cardiovascular disease, autoimmune diseases, and others. In light of these findings, the number of clinical studies of curcumin has grown substantially in the past few years and continues to rise.

Studying activity in cancer patients

The clinical research on curcumin in cancer is new but promising. Early studies at M. D. Anderson and elsewhere have shown curcumin to be well tolerated and non-toxic at high oral doses.

Dr. Kurzrock is designing clinical trials of curcumin, based on promising lab results.

Dr. Kurzrock and colleagues recently conducted a trial of curcumin in 49 patients with advanced pancreatic cancer, which is notoriously resistant to treatment. Two of those patients had clinically meaningful responses and remained stable for 8 months and more than 22 months, respectively. Another had a brief but dramatic response (73% reduction in tumor size).

“In advanced pancreatic cancer, the response rate to the Food and Drug Administration-approved treatments is only about 5%, so we were very encouraged that we saw any activity at all in this group,” said Dr. Kurzrock. “That tells us curcumin does have biologic activity in pancreatic cancer—there was a true antitumor effect. It’s too soon to know if it will affect survival rates, but more study is definitely warranted.” The fact that some patients benefited is encouraging, since there were questions about whether therapeutic concentrations could be achieved with oral administration.

To address the issue of absorption, Dr. Kurzrock is leading the development of an intravenous, liposome-encapsulated delivery system for curcumin that she says has so far been “very potent” in the lab. Liposomal curcumin would be given intravenously, thereby circumventing the problem of poor absorption.

“The fact that the curcumin did show some activity in the study even though it was poorly absorbed suggests that if we can develop a more effective method to get it to the tumors, it may well have promise as an anticancer treatment,” said Dr. Kurzrock. She hopes to have the liposome-encapsulated delivery system ready to test in a phase I clinical trial for patients with a variety of cancers in 2008. Whether the intravenous formulation would have more side effects in patients because of the higher blood levels of the agent is not yet known, but preliminary testing in mice has shown no toxicity, even at maximum doses.

Currently under way at M. D. Anderson is a clinical trial of curcumin in multiple myeloma, and researchers are seeking funding for a trial in breast cancer. Trials of curcumin in colorectal cancer and in myelodysplastic syndrome are in progress at other institutions. Curcumin is also in clinical trials as a treatment for non-cancer diseases such as Alzheimer’s disease, arthritis, and psoriasis.

Food for thought

Dr. Aggarwal, for one, is not surprised at the evidence that curcumin may have efficacy in treating cancer. He feels curcumin has the potential to one day be an inexpensive and nontoxic alternative to harsher oncology drugs; a chemopreventive agent; and an adjunct to chemotherapy. But he notes that progress in developing curcumin for medical use is likely to be much slower than for pharmaceutical agents because curcumin can’t be patented on a broad scale and therefore is unlikely to attract the interest and the funding of pharmaceutical companies.

For his part, Dr. Aggarwal takes a curcumin tablet every day, and he offers this food for thought: “The combined rate of the four most common cancers in the United States—lung, prostate, breast, and colon—is at least 10 times lower in India, where curry is a staple in the diet.”

For more information, call Dr. Aggarwal at 713-794-1817 or Dr. Kurzrock at 713-794-1226.

Scientists at Dana-Farber Cancer Institute have identified a previously undetected trigger point on a naturally occurring “death protein” that helps the body get rid of unwanted or diseased cells. They say it may be possible to exploit the newly found trigger as a target for designer drugs that would treat cancer by forcing malignant cells to commit suicide.

Loren Walensky, MD, PhD, pediatric oncologist and chemical biologist at Dana-Farber and Children’s Hospital Boston, and colleagues report in the Oct. 23 issue of the journal Nature that they directly activated this trigger on the “executioner” protein BAX, killing laboratory cells by setting in motion their self-destruct mechanism.

The researchers fashioned a peptide (a protein subunit) that precisely matched the shape of the newly found trigger site on the killer protein, which lies dormant in the cell’s interior until activated by cellular stress. When the peptide docked into the binding site, BAX was spurred into assassin mode. The activated BAX proteins flocked to the cell’s power plants, the mitochondria, where they poked holes in the mitochondria’s membranes, killing the cells. This process is called apoptosis, or programmed cell death.

“We identified a switch that turns BAX on, and we believe this discovery can be used to develop drugs that turn on or turn off cell death in human disease by targeting BAX,” said Walensky, who is also an assistant professor of pediatrics at Harvard Medical School.

BAX is one of about two dozen proteins known collectively as the BCL-2 family. The proteins interact in various combinations leading to either the survival of a cell or its programmed self-destruction. Cancer cells have an imbalance of BCL-2 family signals that drives them to survive instead of dying on command.

The late Stanley Korsmeyer, MD, an apoptosis research pioneer and Walensky’s Dana-Farber mentor, had suggested that killer proteins like BAX could be activated directly by “death domains,” termed BH3, contained within a subset of BCL-2 family proteins. He hypothesized that this activating interaction was a fleeting “hit-and-run” event, making it especially challenging for scientists to study the phenomenon.

As suspected, the proposed BAX-activating interactions could not be captured by traditional methods. “When you tried to measure binding of the BH3 subunits to BAX, you couldn’t detect the interaction,” explained Walensky. He recognized, however, that the BH3 peptides being used in the laboratory didn’t retain the coiled shape of the natural BH3 domains that participate in BCL-2 family protein interactions. Walensky and his colleagues pioneered the design of “stapled” BH3 peptides, which contain a chemical crosslink that locks the peptides into their natural coiled shape. With biologically active shape restored, the stapled BH3 peptides bound directly to BAX and triggered its killer activity.

Defining how the activating peptides docked on BAX remained a formidable catch-22. In order to solve the structure of an interaction complex, it needed to be stable enough for analysis. In this case, the BH3 binding event itself triggers BAX to change its shape and self-associate to perform its killer function, rendering the activating interaction unstable by definition.

What if, Walensky proposed, you could set up the interaction of BH3 and BAX under laboratory conditions that caused it to be more stable or proceed in slow motion? The plan was to adjust the potency of the stapled BH3 peptide so that, according to Walensky, “it was good enough to bind BAX, yet activate it just a bit more slowly so that we could actually study the interaction.” The researchers would then look for any detectable shift in the three-dimensional structure of the BAX protein to help point them to the docking site.

The researchers used nuclear magnetic resonance (NMR) spectroscopy to monitor the arrangement of atoms in the protein. First authors of the Nature paper Evripidis Gavathiotis, PhD, of Walensky’s laboratory and Motoshi Suzuki, PhD, of Nico Tjandra, PhD,’s laboratory at the National Institutes of Health, succeeded in generating pure BAX protein that could be put into solution with the stapled BH3 peptide — the latter in increasing concentrations until it initiated a BH3-BAX interaction. Gavathiotis and Suzuki used the NMR technique to spot a group of BAX amino acids, the building blocks of proteins, which were affected by the addition of the stapled BH3 peptide.

“The discrete subset of amino acids that shifted upon exposure to the stapled BH3 peptide mapped to a completely unanticipated location on BAX,” said Walensky. The long-elusive binding site on BAX that initiates its killer activity was revealed. “Because BAX lies at the crossroads of the cell’s decision to live or die, drugs that directly activate BAX could kill diseased cells like in cancer and BAX-blocking drugs could potentially prevent unwanted cell death, such as in heart attack, stroke, and neurodegeneration,” said Walensky.

Additional authors include Marguerite Davis, Kenneth Pitter, Gregory Bird, PhD, and Samuel Katz, MD, PhD, of Dana-Farber, and Ho-Chou Tu, Hyungjin Kim, and Emily H.-Y. Cheng, MD, PhD, of Washington University School of Medicine, St. Louis.