Monday, September 29, 2008

EUropean trial of free LIght chain removal by exTEnded haemodialysis

Renal failure is a frequent complication of multiple myeloma and when severe is associated with a greatly increased morbidity and mortality. The principal cause of severe renal failure in this setting is cast nephropathy, a direct consequence of high concentrations of monoclonal free light chains (FLCs) in the patient's serum.

FLC removal by extended haemodialysis, using a high cut-off dialyser, has recently been described as a novel therapeutic option in this setting.

Methods: The EUropean trial of free LIght chain removal by exTEnded haemodialysis in cast nephropathy (EuLITE) trial is a prospective, randomised, multicentre, open label clinical trial to investigate the clinical benefit of FLC removal haemodialysis in patients with cast nephropathy, dialysis dependent acute renal failure and de novo multiple myeloma. Recruitment commenced in May 2008, in total 90 patients will be recruited. Participants will be randomised, centrally, upon enrolment, to either trial chemotherapy and FLC removal haemodialysis or trial chemotherapy and standard high flux haemodialysis. Trial chemotherapy is a modified PAD regime, consisting of bortezomib, doxorubicin and dexamethasone. FLC removal haemodialysis is undertaken using two Gambro HCO 1100 dialysers in series, over an intensive treatment schedule. The primary outcome for the study is independence of dialysis at 3 months. Secondary outcomes are: duration of dialysis, reduction in serum FLC concentrations; myeloma response and survival.

Hypothesis: FLC removal haemodialysis will increase the rate of renal recovery in patients with severe renal failure secondary to cast nephropathy and de novo multiple myeloma.

Trial Registration: ISRCTN45967602

Author: Colin A Hutchison, Mark Cook, Nils Heyne, Kataja Weisel, Lucinda Billingham, Arthur R Bradwell and Paul Cockwell

Friday, September 19, 2008

Economist Article: The root of all evil?

Cancer may be caused by stem cells gone bad. If that proves to be correct, it should revolutionise treatment.

MUCH of medical research is a hard slog for small reward. But, just occasionally, a finding revolutionises the field and cracks open a whole range of diseases. The discovery in the 19th century that many illnesses are caused by bacteria was one such. The unravelling of Mendelian genetics was another. It now seems likely that medical science is on the brink of a finding of equal significance. The underlying biology of that scourge of modern humanity, cancer, looks as though it is about to yield its main secret. If it does, it is possible that the headline-writer’s cliché, “a cure for cancer”, will come true over the years, just as the antibiotics that followed from the discovery of bacteria swept away previously lethal infectious diseases.

The discovery—or, rather, the hypothesis that is now being tested—is that cancers grow from stem cells in the way that healthy organs do. A stem cell is one that, when it divides, produces two unequal daughters. One remains a stem cell while the other multiplies into the sorts of cells required by its organ. This matters for cancer because, at the moment, all the cells of a tumour are seen as more or less equivalent. Therapies designed to kill them do not distinguish between them. Success is defined as eliminating as many of them as possible, so those therapies have been refined to do just that. However, if all that the therapies are doing is killing the descendants of the non-stem-cell daughters, the problem has not been eliminated. Instead of attacking the many, you have to attack the few. That means aiming at the stem cells themselves.

Not all investigators support the cancer-stem-cell hypothesis, but the share who do so is growing rapidly. A mere five years ago, few research papers on the subject were presented at big academic meetings. This year there were hundreds at one such meeting alone. Moreover, data from clinical trials based on the hypothesis suggest that it has real value for patients. As a result, drug companies have taken notice and are trying to develop substances that will kill cancer stem cells.

The virtues of self-restraint

The root cause of both cancer and stem cells is multicellularity. In the distant past, when all living things had only one cell, that cell’s reproduction was at a premium. In the body of an animal, however, most cells have taken a vow of self-denial. Reproduction is delegated to the sex cells. The rest, called somatic cells, are merely supporting actors, specialised for the tasks needed to give the sex cells a chance to get into the next generation. For this to happen required the evolution of genes that were able to curb several billion years’ worth of instinct to proliferate without killing that instinct entirely. Only then could somatic cells do their job, and be present in appropriate numbers.

The standard model of tumour formation was based on the fact that somatic cells slowly accumulate mutations. Sometimes these disable the anti-proliferation genes. If enough of the brakes come off in a somatic cell, so the theory went, it will recover its ancestral vigour and start growing into a tumour. Cancer, then, is an inevitable cost of being multicellular.

The discovery of stem cells changed this picture subtly, but importantly. Blood stem cells were found a long time ago, but only recently has it become apparent that all tissues have stem cells. The instincts of stem cells lie halfway between those of sex cells and ordinary body cells. They never stop reproducing, but they cannot look forward to making the generational leap. When the body dies, so do they. However, they are few in number, and because at cell division only one daughter continues to be a stem cell, that number does not grow.

This division of labour may even be another type of anti-cancer mechanism. It allows stringent locks to be put on somatic cells (which, for example, strictly limit the number of times they can divide), yet it permits tissue to be renewed. Without stem cells, such tissue-renewal would be the province of any and every somatic cell—a recipe, as the traditional model observes, for tumorous disaster. The obverse of this, however, is that if a stem cell does mutate into something bad, it is likely to be very bad indeed. That, in essence, is the stem-cell hypothesis of cancer.

One obvious prediction of this hypothesis is that tumours will have at least two sorts of cell in them: a dominant population of daughter cells and a minority one of stem cells. The first person to show that to be true was John Dick, a molecular biologist at the University of Toronto. In 1997 he isolated what looked like stem cells from a blood cancer called acute myeloid leukaemia (AML). Blood cancers are easier to deal with in this context than solid tumours because their cells do not have to be separated from one another before they are examined. One characteristic of AML cells is that they have two sorts of a protein, called CD34 and CD38, on their surfaces. Dr Dick thus used two sets of special antibodies for his experiment. One sort stuck only to the CD34 molecule, the other only to CD38. Each sort was also attached to a fluorescent tag.

By mixing the AML cells from his patients with the two antibodies and running them through a machine that sorted them according to how they fluoresced, he showed that most were positive for both proteins. However, a small fraction (as low as 0.2%) were positive only for CD34. These, he suspected, were the stem cells.

He was able to confirm this by injecting the minority cells into mice. The resulting tumours had the same mix of cells as those from human patients. However, when he injected mice with samples from the majority cells, with both sorts of the protein, no tumours resulted. The CD34-only cells thus acted as cancer stem cells.

Moreover, this phenomenon was not confined to leukaemia. In 2003 a group of researchers at the University of Michigan in Ann Arbor, led by Max Wicha and Michael Clarke, used a similar trick on breast-cancer cells. In this case the surface proteins were known as CD24 and CD44, and the minority were those positive only for CD44. As with AML, these minority cells produced cancers in mice, whereas the majority cells did not.

Since these two pieces of work, the list of cancer stem cells has multiplied. It now includes tumours of the breast, brain, prostate, colon, pancreas, ovary, lung, bladder, head and neck, as well as melanoma, sarcoma, AML, chronic myelogenous leukaemia, Hodgkin’s lymphoma and myeloma.

That is quite a list. The question is, what can be done with it? Jeremy Rich, a neurologist at Duke University in Durham, North Carolina, has one idea. He created mice that had human glioblastoma tumours, a form of brain cancer, growing in them. Then he treated these mice with radiation (the standard therapy for such cancer in people). He found that the cancer stem cells were more likely to survive this treatment than the other cells in the tumour. That turned out to be because, although all the tumour cells suffered equal amounts of DNA damage from the radiation, the stem cells were better able to repair this damage. When he treated the mice simultaneously with radiation and with a drug that interferes with DNA repair, however, the stem cells no longer had an advantage. They were killed by the radiation along with the other cells.

If that result applies to people as well as rodents, it opens up a whole avenue of possibility. In fact, Dr Rich is now in negotiations with several companies, with a view to testing the idea in humans. That “if” is a real one, though. A mouse is not a human being.

Indeed, the stem-cell hypothesis is often criticised for its reliance on animal models of disease. Some researchers worry that the experiments used to identify putative cancer stem cells are too far removed from reality—human tumour cells do not naturally need to survive in mice—and thus may not reflect human cancer biology at all.

Proponents of the hypothesis are alive to that concern, but they think that the same pattern has been seen so often in so many different cancers that it is unlikely to be completely wrong. The practical test, though, will be whether the hypothesis and ideas that emanate from it, such as Dr Rich’s combination therapy, actually help patients survive.

Searching for the suspects

As a step towards discovering whether they do, William Matsui, an oncologist at Johns Hopkins University School of Medicine in Baltimore, looked for cancer stem cells in pancreatic-tumour samples taken from nearly 300 patients. His team found that patients whose tumours did contain such stem cells survived for an average of 14 months. Those whose tumours lacked them survived for 18 months.

That finding is consistent with the idea that cancer stem cells contribute to the most aggressive forms of the disease, though it does not prove they cause tumours in the first place. And although the absence of detectable stem cells in some tumours may be seen as casting doubt on the whole idea, it may instead be that they are too rare to be easily detected. If the stem-cell idea is confirmed, it may help doctors and patients choose how to treat different tumours. Those with detectable stem cells might be candidates for aggressive chemical and radiation therapies, while those without might best be treated with the surgeon’s knife alone.

Breast-cancer researchers are also testing the stem-cell hypothesis in the clinic. Jenny Chang’s group at Baylor College of Medicine, in Texas, took samples of tumours from women before and after standard chemotherapy. When they counted the cells in the tissue they found that the proportion of stem cells in a tumour increased after treatment. That suggests the chemotherapy was killing the non-stem tumour cells and leaving the stem cells behind. When the group repeated the experiment using a modern drug called Tykerb that blocks what is known as the HER2 pathway, they got a different result. HER2 is a gene which encodes a protein that acts as a receptor for molecules called growth factors which, as their name suggests, encourage cell growth and proliferation. After the HER2-blocking treatment, cancer stem cells formed the same proportion of the residual tumour as beforehand. That suggests they, too, were being clobbered by the new treatment. It is probably no coincidence that another drug, Herceptin, which also goes after HER2, is one of the few medicines that is able to prolong the lives of people with advanced cancer.

The stem-cell hypothesis has also changed the way people do basic research. For example, over the past few years cancer researchers have been grinding up pieces of tumour and using what are known as gene-expression microarrays to work out which genes are active in them. However, if the hypothesis is correct, this approach will probably yield the wrong result, because the crucial cells make up but a small part of a tumour’s bulk and the activity of their genes will be swamped by that of the genes of the more common non-stem cells. The answer is to isolate the stem cells before the grinding starts.

This approach has already yielded one important finding. When Dr Chang used microarrays to study gene expression in the CD44-positive cells from breast tumours, she noticed that they did not look like those of the epithelial cells that make up the bulk of such a tumour. Epithelial cells are immobile, grow in “cobblestone” patterns and produce proteins that help them stick together. The gene expression of the putative stem cells, however, resembled that of a mesenchymal cell. Mesenchymal cells rarely stick together. Indeed, they are mobile and are able to slip through the matrix of proteins that holds epithelial cells together.

That finding is important because mobile cells are more likely to escape from a tumour and form secondary cancers elsewhere in the body. Once such secondaries are established, successful treatment is much harder. And the CD44-positive cells also expressed genes that are important for stem-cell self-renewal, particularly one called Notch that controls the flow of chemical signals within a cell.

Researchers at OSI Pharmaceuticals, a firm that makes a drug called Tarceva, found a similar pattern in lung cancer. Several years ago, they started looking for gene-expression patterns that correlated with response to Tarceva. They found that tumours with a pattern that resembled epithelial cells were sensitive to the drug. By contrast, those that had a mesenchymal pattern were not. They hypothesised that as tumours develop, some of their cells actually switch from a sticky, epithelial state to a mobile, mesenchymal one. This epithelial-to-mesenchymal transition, or EMT, is well known to biologists who study embryonic development, but OSI’s results, and those of other researchers, suggest that cancers may have hijacked it for their own use.

Robert Weinberg, a molecular biologist at the Massachusetts Institute of Technology, and his colleagues have come to the same conclusion but they have taken the hypothesis one step further. They think that tumour cells which have undergone EMT have acquired many of the characteristics of cancer stem cells. Experiments in his laboratory, employing a variety of animal models of breast cancer, suggest that communication between tumour cells and surrounding non-cancerous support cells can lead some of the cancer cells to undergo EMT.

That is intriguing. If this transition really can be induced in tumour cells, then any of them might be able to become a cancer stem cell. So it may be that the fundamentalist version of the stem-cell hypothesis is wrong, and the stem cells are a result of a cancer, rather than its cause. That could be another reason why Dr Matsui found that pancreatic cancers do not always seem to contain stem cells.

Dr Weinberg is sensitive to this point, and is cautious when talking about these experiments. He refers to the cells that have undergone EMT as “having the qualities of stem cells” but avoids actually calling them cancer stem cells. If his idea is correct, though, it means that finding drugs which block the signals that induce EMT could reduce the stem-cell population and prolong the survival of the patient. It also means that both the epithelial cells and the mesenchymal ones will have to be attacked. And OSI is now testing a drug that does just that.

Notch up a victory?

Breast-cancer researchers, too, are testing drugs that hit molecular targets highlighted by cancer-stem-cell studies. Merck, for example, has turned to a drug it originally developed to treat Alzheimer’s disease. Although this drug, code-named MK0752, did not slow that disease, it does block activity of Notch, the stem-cell self-renewal gene, and might thus be an appropriate weapon against breast-cancer stem cells. Dr Chang and Dr Wicha have started a clinical trial which uses MK0752 in combination with standard chemotherapy. By the end of the year they hope to have some idea of whether the combination kills cancer cells in human tumours.

Attacking Notch is a high-risk approach, because this gene is used by healthy stem cells as well as cancerous ones; healthy organs as well as tumours could be damaged. Some researchers are therefore taking a different tack and looking for drugs that hit only the unhealthy stem cells. Craig Jordan, a biologist at the University of Rochester Medical Centre, in New York state, is one such. He has discovered that a chemical called parthenolide, found in feverfew, a medicinal plant, kills AML stem cells. Normal stem cells, however, seem to be able to tolerate the drug without difficulty. The reason is that the leukaemia cells are reliant on a biochemical pathway that parthenolide blocks, whereas normal stem cells are not. If all goes well, a trial to test the safety of a modified form of parthenolide will start in a few months.

If the safety issues can be dealt with—and most researchers think they can—then attacking cancer stem cells really could help patients survive. If, that is, the stem-cell hypothesis is correct.

At the moment, scientists being scientists, few are willing to be anything other than cautious. They have seen too many past cures for cancer vanish in a puff of smoke. The proof needs to come from patients—preferably with them living longer. But if the stem-cell hypothesis is indeed shown to be correct, it will have the great virtue of unifying and simplifying the understanding of what cancer is.

And that alone is reason for hope.

Source: http://www.economist.com/science/displaystory.cfm?story_id=12202589

Thursday, September 18, 2008

Denosumab Osteoporosis Trial Results

Amgen (NASDAQ:AMGN) announced full data results from a non-pivotal Phase 3 head-to-head, double-blind trial comparing bone mineral density (BMD) gains in postmenopausal women with low bone mass who transitioned from weekly oral alendronate (Fosamax(R)) to denosumab versus those who continued alendronate therapy.

Additional Data From Separate Head-to-Head Trial Showed More Than 75 Percent of Patients Prefer the Administration and Frequency of Twice-Yearly Subcutaneous Injection Compared to Weekly Oral Pill.

Data presented from the bisphosphonate transition study, also known as the STAND (Study of Transitioning from AleNdronate to Denosumab) trial, demonstrated that subcutaneous injections of denosumab every six months achieved significantly greater increases in BMD versus those achieved with alendronate at all sites measured. For the primary endpoint, denosumab resulted in significant increases in BMD at the total hip compared with alendronate (1.9 percent vs. 1.05 percent, p less than 0.0001). Treatment with denosumab also resulted in significant increases in BMD compared with continued alendronate treatment at all secondary endpoints including the lumbar spine, femoral neck, hip trochanter and 1/3 radius. Top-line results of this trial were previously released in May 2008.

The incidence and types of adverse events observed in the study, including neoplasm and infection, were well-balanced between the denosumab and alendronate treatment groups. The most common adverse events across both treatment arms were back pain, arthralgia, and nasal pharyngitis.

About the 234 Bisphosphonate Transition Study (STAND)

The 234 bisphosphonate transition Phase 3 study was a randomized, double-blind, active controlled, parallel group study. Eligible patients had T-scores of less than -2.0 and greater than -4.0 at the lumbar spine or total hip, and had previously been treated with alendronate. A total of 504 women with low BMD participated in the study, with approximately 250 patients in each arm.
The study's primary endpoint was to evaluate the effect of denosumab treatment (twice-yearly 60 mg) on total hip BMD in women with low bone mass compared to patients continuing alendronate therapy (weekly 70 mg) at 12-months. The secondary endpoints included evaluation of the effects of transitioning to denosumab compared to continuing treatment with alendronate on percent change from baseline in BMD at the lumbar spine, hip trochanter, femoral neck, and 1/3 radius.

About the 141 Head-to-Head Study (DECIDE)

In this Phase 3 double-blind, double-dummy, active controlled study, 1,189 healthy postmenopausal women (T-score less than or equal to -2.0 total hip or spine), were randomized 1:1 to receive either denosumab injection (subcutaneous 60 mg, Q6M) plus placebo tablet (oral weekly), or placebo injection and oral alendronate (70 mg weekly). Patients were followed for one year to assess changes in BMD at the total hip compared to alendronate. Secondary endpoints were to evaluate the effect of denosumab on percent change from baseline in BMD at the lumbar spine, hip trochanter, femoral neck, and 1/3 radius compared to alendronate. Preference and satisfaction were assessed after 12-months of treatment, with patients being asked to complete a 34-item questionnaire to rate their preference and satisfaction with each mode and frequency of administration.

About Denosumab
Denosumab is the first fully human monoclonal antibody in late stage clinical development that specifically targets RANK Ligand, an essential regulator of osteoclasts (the cells that break down bone). Denosumab is being investigated for its potential to inhibit all stages of osteoclast activity through a targeted mechanism. Denosumab is being studied in a range of bone loss conditions including postmenopausal osteoporosis, rheumatoid arthritis, and cancer treatment-induced bone loss (in breast cancer and prostate cancer patients), as well as for its potential to delay bone metastases and inhibit and treat bone destruction across many stages of cancer.

Source: http://www.amgen.com/media/media_pr_detail.jsp?year=2008&releaseID=1197250

Thursday, September 11, 2008

IT impact on DNA sequencing

The mystery behind why some have a genetic disposition to a certain disease, or why a medicine works for some and not for others, might be revealed sooner than many had anticipated. Several significant breakthroughs in DNA sequencing technology have been made, giving hope that the coveted $1,000 genome is just around the corner.

Since the completion of the Human Genome Project in 2003, which took over a decade and cost over $300 million, the idea of personalized medicine and using genetic testing for medical procedures has become much more of a reality. Decoding a human genome is far too costly, and, as a result, several companies are in a race to develop the next-generation DNA sequencer that will drive down the costs of sequencing a person's genome to $1,000, and to win the $10 million Archon X Prize, which is awarded to the company that successfully sequences 100 human genomes in 10 days for $10,000 per genome.

In February 2008, Illumina claimed to sequence a human genome in four weeks for $100,000, only to be outdone five weeks later by its competitor, Applied Biosystems (ABI), which announced the sequencing of a whole human genome for less than $60,000. ABI also mentioned that its next-generation DNA sequencer is capable of generating up to nine gigabases per run, which is the highest throughput reported to date.

Also in February 2008, Pacific Biosciences (PacBio) presented a revolutionary technology which, within five years, could produce a three-minute raw sequence, and a complete, high-quality sequence in 15 minutes - all for under $1,000. PacBio plans to introduce a sequencing machine in 2010, but an instrument capable of performing the $1,000 whole genome sequencing will not be available until 2013.

The rapid advancement of next-generation DNA sequencers has been possible due to vast improvements in computer technology, specifically in speed and size. These new systems produce enormous amounts of data - one run could generate close to one terabyte of data - and bioinformatics and data management tools have to play catch-up to handle the analysis and storage of this data.

The $1,000 genome has the potential to bring the genomic age to the physician's office. At this price tag, DNA sequencing could become common for certain medical procedures - such as testing for cancer and developing treatments specifically for the patient and, one day, routine decoding at birth could provide parents with a genetic instruction guide to their children's future ailments.

However, this concept of genome sequencing as a standard medical procedure raises several privacy issues, as there is nothing more personal than genetic code. Important questions raised will include who should have access to this information, and how easily attainable would this data be for others? For example, should only the patient and physician share this knowledge, or should health insurance companies be privy to this valuable genome report?

Technology vendors will have to work with the healthcare and medical industries to establish the answers to these questions and then develop the appropriate security protocols. Healthcare and life science IT vendors should utilize the expertise of other industries, such as the banking and credit card industry, which also require high levels of security in their day-to-day workflow to aid in the development of software to ensure patient privacy.

Phase II clinical trial of Trail receptor antibody HGS-ETR1 in combination with bortezomib

Human Genome Sciences has reported initial topline results from an ongoing randomized Phase II clinical trial of its Trail receptor antibody HGS-ETR1 in combination with bortezomib in patients with advanced multiple myeloma.

The initial data from the multiple myeloma study show that HGS-ETR1 was well tolerated and suggest that disease response was comparable for this combination versus bortezomib alone. The trial in advanced multiple myeloma is a randomized, multi-center, open-label Phase II study to evaluate the efficacy and safety of HGS-ETR1 (mapatumumab) in combination with bortezomib in these patients.

Approximately 104 patients are being treated in the study, which is being conducted in the US, Canada, Australia and India. Patients were randomized into three treatment groups, with one group receiving bortezomib alone and two groups receiving bortezomib in combination with mapatumumab (10mg/kg or 20mg/kg). Approximately 43% (15/35) of the patients in the group receiving bortezomib alone were randomized contemporaneously with randomization of the group receiving a combination of bortezomib and mapatumumab at 10mg/kg.

The remaining 57% (20/35) of the patients in the group receiving bortezomib alone were randomized contemporaneously with randomization of the group receiving a combination of bortezomib and mapatumumab at 20mg/kg. The primary objective of the study is to evaluate disease response to mapatumumab in combination with bortezomib, versus bortezomib alone, in patients with relapsed or refractory multiple myeloma.

Patients participating in the study had received a median of two previous cancer treatment regimens. At baseline, 17.1% (6/35) of patients in the treatment group receiving bortezomib alone had stage 3 disease, versus 40.6% (13/33) in the group receiving the combination of bortezomib and mapatumumab at 10mg/kg, and 19.4% (7/36) in the group receiving the combination of bortezomib and mapatumumab at 20mg/kg.

The initial data show that mapatumumab was well tolerated and could be administered safely and repetitively in combination with bortezomib, with no evidence of increased toxicity in patients receiving the combination of bortezomib and mapatumumab, versus patients receiving bortezomib alone.

Monday, September 08, 2008

VELCADE for multiple myeloma receives front-line approval in Canada

VELCADE* (bortezomib) for Injection has received Health Canada approval for front-line (first) treatment of multiple myeloma. As part of combination therapy, VELCADE is indicated for the treatment of patients with previously untreated multiple myeloma who are unsuitable for stem cell transplantation. With this new approval, patients with multiple myeloma can now receive VELCADE earlier following initial disease diagnosis, which may help to slow, reverse or halt disease progression.

VELCADE’s front-line approval is based on the phase III VISTA (VELCADE as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone) trial, recently published in the New England Journal of Medicine.

VELCADE Approved Across all Disease Stages

Janssen-Cilag / Ortho Biotech, today announced the European Commission's approval of VELCADE in combination with melphalan and prednisone for the treatment of patients with previously untreated multiple myeloma (MM) who are not eligible for high-dose chemotherapy with bone marrow transplant.

In more than 87 countries worldwide, VELCADE monotherapy had already been approved for the treatment of relapsed and / or refractory MM in patients who have received at least one prior therapy.
"VELCADE has already made an important contribution for patients with multiple myeloma at first relapse," said Professor Jesus San Miguel, M.D., University of Salamanca in Spain, the principal investigator for the VISTA trial. "The marketing authorisation from the EMEA is encouraging as it suggests that more patients may benefit from earlier treatment."

The frontline approval is based on phase III results from the VISTA trial, recently published in the New England Journal of Medicine, which demonstrated statistically superior results across all efficacy endpoints compared to melphalan and prednisone. In particular, complete response (CR) rates were similar to those that have been achieved in the transplant setting. VISTA stands for: VELCADE as Initial Standard Therapy in Multiple Myeloma.

Friday, September 05, 2008

Myeloma Research Web Portal at Dana Farber

Researchers can view genetic information from multiple databases with a specially designed Web portal.

The Dana-Farber Cancer Institute in Boston is harnessing the dual power of business intelligence and Web 2.0-based scientific search tools to gather complex, scattered data to better treat patients and work toward a cure for this formidable disease.

Dana-Farber physicians and researchers regularly slog through complex calculations to find connections between data gleaned from tumor biopsies and other clinical samples and the vast genetic research housed within the organization or spread among three massive public-domain databases.

Dana-Farber officials are using data warehousing capabilities with Web-based data- collection tools, since vital connections between patient samples and analytical data will almost certainly prove the crux of both effective patient treatment and any potential breakthroughs tied to the disease, according to researchers.

Not only is data on multiple myeloma and other diseases often far-flung and fiercely guarded, it is also incredibly complex, says Joseph White, a senior research scientist at Dana-Farber. "A single gene may be represented by several different name sequences," he explains. "To gather all of the information on any one particular gene, a researcher must look at many sources and different expressions for the gene."

"You can't engineer serendipity," says White. "You want to be able to ask questions such as 'How do I cure cancer?' and not be limited to questions that are too specific, such as 'Does eating beets have a correlation to curing cancer?'"

Wednesday, September 03, 2008

Drug research: Cyproheptadine

Xinliang Mao1, Sheng-ben Liang1, Rose Hurren1, Marcela Gronda1, Sue Chow1, G. Wei Xu1, Xiaoming Wang1, Reza Beheshti Zavareh1, Nazir Jamal1, Hans Messner1, David W. Hedley1, Alessandro Datti2, Jeff L. Wrana2, Yuanxiao Zhu3, Chang-xin Shi3, Kyle Lee1, Rodger Tiedemann3, Suzanne Trudel1, A. Keith Stewart3, and Aaron D. Schimmer1

1 Princess Margaret Hospital and the Ontario Cancer Institute, Toronto, ON; 2 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON; and 3 Mayo Clinic, Scottsdale, AZ

D-cyclins are regulators of cell division that act in a complex with cyclin-dependent kinases to commit cells to a program of DNA replication. D-cyclins are overexpressed in many tumors, including multiple myeloma and leukemia, and contribute to disease progression and chemoresistance. To better understand the role and impact of D-cyclins in hematologic malignancies, we conducted a high throughput screen for inhibitors of the cyclin D2 promoter and identified the drug cyproheptadine. In myeloma and leukemia cells, cyproheptadine decreased expression of cyclins D1, D2, and D3 and arrested these cells in the G0/G1 phase. After D-cyclin suppression, cyproheptadine induced apoptosis in myeloma and leukemia cell lines and primary patient samples preferentially over normal hematopoietic cells. In mouse models of myeloma and leukemia, cyproheptadine inhibited tumor growth without significant toxicity. Cyproheptadine-induced apoptosis was preceded by activation of the mitochondrial pathway of caspase activation and was independent of the drug's known activity as an H1 histamine and serotonin receptor antagonist.

Thus, cyproheptadine represents a lead for a novel therapeutic agent for the treatment of malignancy. Because the drug is well tolerated and already approved in multiple countries for clinical use as an antihistamine and appetite stimulant, it could be moved directly into clinical trials for cancer.
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