MMRF 2004 Annual Report

In 2004, the Multiple Myeloma Research Foundation raised $12.1 million, a 39 percent increase over 2003. MMRF is now funding more than 20 new compounds in pre-clinical testing and Phase I, II and III clinical trials that show promise in treating patients at all stages of the disease.

Celgene temporarily suspends Revlimid trial

Reuters - Celgene Corp. on Wednesday said it expects a suspended trial of its cancer drug Revlimid to resume within weeks, after the trial design is changed to ensure all patients receive aspirin to reduce the chance of developing blood clots.

Celgene confirmed a published report that the Phase III trial, involving patients recently diagnosed with multiple myeloma, had been suspended after some developed blood clots during treatment with Revlimid in combination with a steroid called dexamethasone.

Celgene, whose shares fell nearly 4 percent, said patients with the blood cancer typically develop blood clots after being treated with standard drugs, as well as with the company's experimental Revlimid.

But company spokesman Brian Gill said low incidence of such clots was seen in similar patients taking Revlimid in a smaller Phase II trial conducted by the same Mayo Clinic doctor who has supervised the recently suspended larger trial. In the earlier trial, he said patients received aspirin, and will do so in the revamped Phase III trial to avert risk of blood clots.

"The Mayo Clinic has told us the trial design will be changed to include aspirin for everyone and the information they have given us suggests the trial will be resumed in the next few weeks," Gill said. "Without question, the trial will resume."

Moreover, Gill said Celgene is continuing with plans to seek U.S. approval later this year for use of Revlimid to treat patients with later stages of multiple myeloma.

That application will be based on two large late-stage trials in which Revlimid plus chemotherapy significantly delayed progression of multiple myeloma in such late-stage patients, compared with chemotherapy alone.

Merrill Lynch analyst Eric Ende said the suspended multiple myeloma trial is unlikely to affect either the FDA's upcoming decision on use of the drug for myelodysplastic syndromes, or the company's planned application to use it to treat multiple myeloma.

Kathy Giusti story

It has been nine years since Kathy Giusti was diagnosed with multiple myeloma, an incurable form of blood cancer with one of the lowest five-year survival rates of any cancer.

"My daughter was 1 at the time. My goal was to see her go to kindergarten," Giusti recalled.

This month, she saw her daughter off to sixth grade.

"It's a nice story," said Giusti, a New Canaan resident who since has also given birth to a boy.

Scientists and cancer survivors say more people are alive today because of the work Giusti has done since 1996. The former pharmaceutical executive and her twin sister, Karen Andrews, have started not one but two separate nonprofit organizations dedicated to jump-starting research into multiple myeloma. The Multiple Myeloma Research Foundation has raised $47 million for research, and the Multiple Myeloma Research Consortium has forged a scientific alliance of seven major cancer research institutions and created the first multiple myeloma tissue bank.

"Kathy and her sister Karen have turned adversity into an opportunity for multiple myeloma patients worldwide and gave them hope for a better life," said Dr. Ken Anderson, chief of the division of hematologic neoplasia at the Dana Farber Cancer Institute in Boston. Anderson serves on the boards of both the foundation and consortium.

When Giusti was first diagnosed in 1996, the only treatment options available for the approximately 14,000 people diagnosed with multiple myeloma each year in the United States were chemotherapy and stem cell transplantation, which is designed to replace blood cells destroyed during chemo.

Those treatments often bought patients a reprieve from cancer, but there remains no cure.

"It is hard enough to be diagnosed with a cancer, but it was unbelievable to be diagnosed by one that is uniformly fatal," Guisti said.

She took a survey of research activity at drug companies and academic institutions and found that little work was being done on the disease.

"I told my sister that this looks pretty dismal," she said.

Giusti and Andrews set about to change that outlook. In 1998, they formed the Multiple Myeloma Research Foundation to raise money and promote awareness of the disease. They went a step further and took an active role in promoting the development of promising research at both drug companies and federal regulatory agencies.

The creation of the foundation coincided with the discovery that a notorious drug called thalidomide seemed to halt the progression of blood cancer in many patients. Thalidomide was taken by many pregnant women in the 1960s to ward off morning sickness. After the drug was discovered to cause serious birth defects, it was approved only to treat patients with leprosy. Giusti said the foundation began educating both the public and physicians about the potential benefits of the drug, which is now commonly prescribed for multiple myeloma patients who have had a recurrence.

Thalidomide, however, is not a cure. So the foundation has aggressively backed the development of two new multiple myeloma drugs. Velcade, designed for patients whose cancer has become resistant to treatment, was approved in 2003. Revimid, an immune-system booster, is now in Phase III trials.

"We went from no drugs to three since we started," Giusti said.

One multiple myeloma patient who has benefited from the new treatment options is the Connecticut weather forecaster Mel Goldstein. Like Giusti, he was diagnosed in 1996. He was one of the first patients in the country to be given thalidomide for his cancer.

"I can't speak highly enough [about] progress that has been made in the field. It occurred as the foundation was raising funds and awareness of the disease and getting drug companies to develop new treatments," Goldstein said.

Linking drug companies and academic centers developing promising new treatments was one of Giusti's goals in 2004, when she formed the Multiple Myeloma Research Consortium. One of the consortium's initiatives was to create the first multiple myeloma tissue bank. New drugs under investigation can be tested on tissue from multiple myeloma patients. The hope is that successful tests will prompt pharmaceutical companies to develop the new drug, Giusti said.

She also has announced plans to have scientists map the genome of multiple myeloma, with an aim to identify key genetic markers in the development of the disease and additional drug development targets.

"I never lose my sense of urgency," said Giusti, who, like Goldstein and an estimated 45,000 myeloma patients, still live under a death sentence from the disease. "We run this like a Fortune 100 company. We don't mess around here."

By William Hathaway, Courant Staff Writer

Copyright 2005, Hartford Courant

Obesity linked to greater myeloma risk in women

Case-control and cohort studies have investigated a potential link between excess adiposity and multiple myeloma, but results have been inconsistent, Cindy K. Blair of the University of Minnesota Cancer Center in Minneapolis and her colleagues note. However, laboratory studies suggest at least two mechanisms through which the two could be related.

Adipose tissue synthesizes and secretes interleukin-6 (IL-6), which plays a role in plasma cell proliferation and survival. And insulin-like growth factor, which has been tied to obesity, can trigger proliferation of multiple myeloma cells and block their apoptosis.

Past studies have used different BMI cutoff points to gauge obesity, Blair noted in an interview with Reuters Health. To clarify the relation between multiple myeloma and obesity, she and her colleagues used several anthropometric characteristics to investigate the association, including BMI, weight, waist-to-hip ratio, and individual waist and hip measurements.

In a group of 37,083 post-menopausal women followed for 16 years, Blair and her team found that several of these characteristics conferred greater risk.

Those with a BMI of 30 or greater were 1.5 times more likely to develop multiple myeloma, while weight, waist circumference or hip circumference in the highest tertile all roughly doubled the risk. However, there was no relationship between waist-to-hip ratio and multiple myeloma risk.

A recent study found that people with a certain polymorphism in the IL-6 gene promoter had higher BMI, her team reports in the September issue of Epidemiology. "Investigating this and other gene polymorphisms could shed light on the biologic mechanisms involved in the link between excess adiposity and multiple myeloma carcinogenesis," they conclude.

Epidemiology 2005;16:691-694.

Pomegranate juice may help ward off prostate cancer

Pomegranates are packed with healthy anti-oxidants and anti-inflammatory agents. The juice dramatically slowed down the growth of prostate cancer cells in mice.

Scientists at the University of Wisconsin Medical School tested the juice on human prostate cancer cells in the laboratory. They found that the higher the dose of pomegranate juice, the more tumour cells died.

The team then conducted tests on mice injected with prostate cancer cells taken from humans. 24 mice were divided into three groups. The control group was given water, while the others had water containing 0.1% or 0.2% of pomegranate juice. The doses reflect a person’s typical daily amount of juice consumption.

Cancer progression was significantly slowed in mice receiving the higher amount of pomegranate juice. Their blood showed decreased levels of prostate-specific antigen, which is used to monitor prostate cancer.

Screening of FDA-approved drugs for Myleoma

The MMRF is pleased to award David A. Frank, MD, PhD, Dana-Farber Cancer Institute; Suzanne Lentzsch, MD, PhD, University of Pittsburgh; and Aaron D. Schimmer, MD, PhD, FRCPC, Princess Margaret Hospital each with a $100,000 grant award to support the testing of existing drug libraries against known molecular targets in myeloma. Using advanced screening technologies, researchers will identify compounds from these libraries that interact with known myeloma targets -- an important first step in developing these compounds into viable treatments for patients with myeloma.

Anti-CD40 Monoclonal Antibody Clinical Trial

A Phase 1, Open-label, Dose-escalation Trial of Anti-CD40 Monoclonal Antibody (CHIR-12.12) Administered Intravenously to Subjects With Advanced Multiple Myeloma that is Refractory or Relapsed After Prior Treatment

The primary objective is to determine the safety, pharmacokinetics, and pharmacodynamics of CHIR-12.12 administered intravenously (IV) at escalating multiple doses to subjects with multiple myeloma (MM) that is relapsed or refractory after prior treatment.

The secondary objective is to report the clinical response after various doses of IV CHIR 12.12 in subjects with MM that is refractory or relapsed after prior treatment.

Seattle, WA, Fred Hutchinson Cancer Center
PI: Dr. William Bensinger, Kathy Lilleby, 206-667-5836, klilleby@fhcrc.org

Lonafarnib increases Velcade potency

The identification of signaling pathways critical to myeloma growth and progression has yielded an array of novel agents with clinical activity. Multiple Myeloma (MM) growth is IL-6 dependant, and IK-6 is secreted in an autocrine/paracrine fashion with signaling via the Ras/Raf/MAPK pathway. We hypothesized that combining a Ras pathway inhibitor (lonafarnib, SCH66336) with a proteasome inhibitor (bortezomib, Velcade, PS-341) would enhance myeloma cell killing. Methods: MM cell lines and primary human cells were used to test either single agent bortezomib, lonafarnib, or the combination on MM signaling and apoptosis. Results: Combination therapy induced synergistic tumor cell death in MM cell lines and primary MM plasma cells. Cell death was rapid, and associated with increased caspase 3, 8, and 9 cleavage and concomitant down regulation of p-AKT. Down regulation of p-AKT was seen only in combination therapy, and not seen with either single agent. Cells transfected with constitutively active p-AKT, wild type AKT or Bcl-2 continued to demonstrate synergistic cell death in response to the combination. The order of addition was critically important supporting bortezomib followed by lonafarnib as the optimal schedule. Conclusion: The combination of a proteasome inhibitor and farnesyl transferase inhibitor demonstrates synergistic myeloma cell death, and warrants further pre-clinical and clinical studies.

David E, Sun SY, Waller EK, Chen J, Khuri FR, Lonial S.

Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA.

PMID: 16118318

Revlimid®/Dexamethasone Effective Initial Therapy for Multiple Myeloma

According to a recent article published in the journal Blood, the treatment combination consisting of Revlimid (lenalidomide) and the steroid dexamethasone is an effective option for the treatment of newly diagnosed multiple myeloma.

Revlimid, a derivative of thalidomide, is an investigational new drug that is considered to be an immunomodulatory drug (iMID). Immunomodulatory drugs work by either modifying or regulating the immune system. They appear to have anticancer and anti-inflammatory effects and are the focus of intense study. An immediate benefit of Revlimid is that it is taken orally.

Researchers from the Mayo Clinic recently conducted another clinical trial to further evaluate the treatment combination consisting of Revlimid plus the steroid dexamethasone as therapy for patients with multiple myeloma. This trial included 34 patients and was the first trial to evaluate this treatment combination in patients with newly diagnosed multiple myeloma. Treatment with Revlimid/dexamethasone resulted in high anticancer responses—91% of patients achieved a regression of their cancer. The most common severe side effect associated with treatment regimen was fatigue.

The researchers concluded that Revlimid plus dexamethasone provides high anticancer responses as initial therapy in the treatment of multiple myeloma. Furthermore, this treatment regimen is generally well tolerated in comparison to standard therapies for this disease. Patients with newly diagnosed multiple myeloma may wish to speak with their physician regarding the risks and benefits of participating in a clinical trial further evaluating Revlimid or other promising therapeutic strategies. Two sources of information regarding ongoing clinical trials include the National Cancer Institute (www.cancer.gov) and www.cancerconsultants.com.

Reference: Rajkumar S, Hayman S, Lacy M, et al. Combination therapy with lenalidomide plus dexamethasone (REV/DEX) for newly diagnosed myeloma. Blood. 2005. E-Pub ahead of print. DOI: 10.1182/blood-2005-07-2817

Nobel prize winners research led to Velcade

Avram Hershko and Aaron Ciechanover were the first Israelis to receive the Nobel in the sciences. They received the prize for their discovery of the ubiquitin system of regulated protein degradation, a fundamental process that influences vital cellular events and has been implicated in cancer and many other diseases, including Alzheimer's. This discovery led to the development of Velcade, a drug used to treat multiple myeloma.

Stem cell research: University of Michigan

Where: University of Michigan: Ann Arbor

What: OncoMed Pharmaceuticals is a California biotech company founded by two U-M internal medicine professors to test drugs that target cancer stem cells. It's a new approach in the field. Earlier this month, the company announced it had attracted $14 million in initial stock backing.

Who: Dr. Max Wicha, director of the comprehensive cancer center, and Dr. Michael Clarke, now at Stanford University.

The research: Cancer spreads by stem cells, Wicha and Clarke have found. Stem cells drive the subsequent growth of a tumor, dictating whether it spreads elsewhere. "The stem cells may have an Achilles' heel," Wicha says. "They may be much more fragile. Our theory is, one reason chemotherapy doesn't extend life much for women with advanced disease, is that it may selectively have killed non-stem cells in tumors, not just the stem cells. We've probably targeted the wrong cell population."

In the pipeline: The company hopes to have its first drug, in a class known as monoclonal antibodies, by 2007. It has assembled a large library of these drugs to test in patients with multiple myeloma, breast cancer and colon cancer. The approach, says Clarke, "is a new era of cancer drug development. The discovery and characterization of the cancer stem cells that drive tumor growth will, for the first time, allow us to specifically target these deadly cells." The team has identified as many as 50 targets -- all small molecules -- on cancer stem cells.

Concerns: Finding ways to kill stem cells in cancer without destroying other stem cells the body needs elsewhere, such as in bone marrow and the gut.

Learn more: A company profile and other biotech links are at www.Biospace.com

Copyright © 2005 Detroit Free Press Inc.

Stem cell patients remain healthy

Blood cancer patients who had stem-cell transplants are virtually as healthy as their peers 10 years later, an American study has found. Researchers at Fred Hutchinson Research Cancer Center looked at 137 patients a decade after their operations.

The study showed they were "largely indistinguishable" from the general population, said the report in the Journal of Clinical Oncology. However, there was a higher incidence of some forms of disease.

More than 45,000 people receive stem-cell transplants across the world each year. But the US researchers say there is very little information about long-term progress.

This study looked at patients who had received haematopoietic cell transplants (HCTs) to replace diseased blood-forming cells produced in the bone marrow.

Disease survey All of the patients received their transplants between March 1987 and March 1990. After 10 years, researchers compared their health with that of 137 healthy people, most of whom were siblings of the patients.

They were questioned about 85 diseases and symptoms and asked to indicate whether they had these problems now, whether the diseases or symptoms were ever a problem in the past 10 years or were no longer a problem.

Twenty-seven diseases or conditions emerged as the most prevalent. They ranged from asthma to secondary cancers.

Transplant survivors and the healthy control group were found to have had similar rates of hospitalisation and outpatient medical visits.

They also had similar rates of diseases and conditions such as asthma, diabetes, high blood pressure, high cholesterol, osteoporosis and hypothyroidism, and they had similar psychological health, marital satisfaction and employment.

But the transplant patients did have a higher incidence of musculoskeletal problems, such as stiffness and cramping; poor long-term sexual health and urinary tract problems.

They were also more likely to use antidepressant and anti-anxiety medicines, even though reported rates of depression and anxiety were about the same as that of the healthy group.

The researchers also identified under-diagnosed problems among transplant patients such as osteoporosis and under-active thyroid.

'Good news' Dr Karen Syrjala, who led the study, said: "Ten years after HCT, the 137 survivors were indistinguishable from case-matched controls in many areas of health and psychosocial functioning, although survivors reported a greater number of medical problems and greater limitations in sexuality, insurance and social, emotional and physical roles.

"Some of these problems are known to be associated with HCT, while others have not been recognised previously as concerns." The researchers also found the 10% of transplant survivors who had suffered relapse were in complete remission at the time of the study.

Dr Syrjala said: "The fact that patients can relapse and still have healthy, full lives 10 years later and look like everyone else who has gone through a transplant without relapse is really good news. "In the past, relapse after a transplant was always thought to be a very bad sign for quality of life."

http://news.bbc.co.uk/go/pr/fr/-/2/hi/health/4251972.stm

© BBC MMV

Study of Defibrotide to treat Multiple Myeloma

Gentium S.p.A. Announces Initiation of Independent Phase I/II Study of Defibrotide to treat Multiple Myeloma

Gentium S.p.A. (AMEX:GNT) (the "Company") announced today that its lead product, Defibrotide, will be the subject
of an independent Phase I/II study to treat Multiple Myeloma (MM) in combination with Melphalan, Prednisone, and
Thalidomide (MPT) at approximately 10 cancer centers in Italy. The principal investigator for this study is Dr. Mario
Boccadoro, M.D., Division of Hematology, University of Turin, Italy.

The study is a Phase I/II dose-escalating, multi-center, non-comparative, open label study designed to assess the safety
and the efficacy of Defibrotide with MPT regimen as a salvage treatment in advanced refractory MM patients. 

Dr. Laura Ferro, Chairman and CEO of the Company, said, "We are encouraged by the continued interest from world leading
clinicians to independently test Defibrotide to treat Multiple Myeloma. Preclinical studies conducted at the Jerome Lipper 
Multiple Myeloma Center at Harvard University's Dana Farber Cancer Institute were very promising and suggest that
Defibrotide sensitizes MM cells to anti-MM agents in the bone marrow by preventing the molecular cascade of events triggered
by MM-bone marrow stromal cells contact.  This pre-clinical study provided the framework for this Phase I/II clinical trial of
oral MPT in combination with Defibrotide in the treatment of Multiple  Myeloma."

About Defibrotide

Defibrotide is a single-stranded DNA that protects the vascular endothelial cells, particularly those of small vessels, from damage
and activation. After binding to endothelial cells, Defibrotide decreases cell adhesion and pro-coagulant activity of activated endothelial
cells, and increases the fibrinolytic potential of endothelial cells. Defibrotide's effects are predominately local within the vascular bed,
and there is no significant effect on systemic coagulation. Its extensive beneficial pharmacological effects owe to its
anti-thrombotic, anti-inflammatory and anti-ischemic properties.

Genomics in multiple myeloma: biology and clinical implications

The advent of new techniques, such as interphase fluorescence in situ hybridization, and, more recently, global array-based gene expression profiling, has accelerated genomic research in myeloma. Distinct biologic subtypes, characterized by unique genetic abnormalities with differing clinical outcomes, have been identified. The identification of these primary genetic defects, and the deregulated oncogenes and pathways in myeloma, has allowed for the development of more targeted therapies. This has led to the discovery of an increased number of active agents in the treatment of myeloma. Genetics also have prognostic importance in myeloma. Recent studies have elucidated a genetic prognostic hierarchy, and have enabled improved definition of the prognostic significance of their interactions. The current challenges are to: improve the dissection of the genetic heterogeneity of the disease; better define progression events; improve the risk stratification of patients; more accurately select patients who will respond well to a particular treatment; and develop more rational combinations of treatment. Genomics will have an important role to play in all of these goals.

PMID: 16142997 [PubMed - in process]

Chng WJ, Fonseca R.

Mayo Clinic Scottsdale, Division of Hematology-Oncology, Johnson Research Building, 13400 E Shea Blvd, Scottsdale, AZ 85259, USA. fonseca.rafael@mayo.edu

DNA microarray

Until recently, cancer researchers laboriously studied one gene at a time. But advances in molecular biology and computer science are combining to accelerate cancer exploration. In particular, a new tool called the gene chip, invented by Stanford biochemist Patrick Brown, is now allowing researchers to sort through thousands of genes at a time, doing the work of years in just a few days.

The gene chip, known more technically as a DNA microarray, is a thumbnail-size glass wafer embedded with thousands of genes. Despite its name, the chip has no relation to a microprocessor and involves just a few simple steps to produce and use. In fact, many labs are building their own machines to make the chips. Each gene chip analysis gives a readout of the distinct patterns of genes switched on or off in a cell, effectively letting the researcher peer inside and get a comprehensive snapshot of the cellular dynamics at work. "[It's] the molecular microscope of modern cancer research," says Todd Golub, associate professor of pediatrics at Harvard Medical School and director of cancer genomics at the Whitehead/MIT Center for Genome Research.

Some cancers have been considered simply too complex to decipher at the genetic level, and scientists have chosen not to spend their limited time on them. But molecular profiling might put even those tumors on the radar screen. One example is multiple myeloma, a cancer of the blood that afflicts 15,000 new people a year. Now, using gene chips, John Shaughnessy of the University of Arkansas for Medical Sciences has already begun to make sense of the genetic chaos of multiple myeloma. Indeed, he now believes myeloma is really an umbrella term that describes at least four distinct types of disease. And in a recent study, he has identified several new possible drug targets for these variations. Of course, years of hard work lie ahead to further explore these novel targets and design therapies to strike them. But a huge step has been taken forward. "Instead of walking around in a dark room with a pin light," he says, "we are using a floodlight."

From U.S. News & World Report
http://www.usnews.com/usnews/health/articles/020624/archive_021674.htm

FDA advisory committee recommends REVLIMID for approval for MDS patients

FDA Oncologic Drugs Advisory Committee Recommends REVLIMID(R) for Full Approval

By a 10-5 Vote, ODAC Recommends REVLIMID as Oral Targeted Therapy for Low to Intermediate-1-Risk MDS Patients With Deletion 5q Chromosomal Abnormality

WASHINGTON, Sept 14, 2005 /PRNewswire-FirstCall via COMTEX News Network/ -- Celgene Corporation (Nasdaq: CELG) announced that the Oncologic Drugs Advisory Committee (ODAC) of the U.S. Food and Drug Administration (FDA) recommended full approval of REVLIMID (lenalidomide) for the treatment of patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. The committee based its recommendation on clinical data from an open label Phase II trial, evaluating REVLIMID in the largest trial with MDS patients with deletion 5q chromosomal abnormality to date. The data showed that:

• Approximately two-thirds of patients achieved resolution of chronic refractory anemia resulting in transfusion independence
• Response was associated with meaningful cytogenetic and bone marrow remission
• Responder median hemoglobin increased more than 5.0 grams per deciliter
• After median follow-up of 58 weeks, the median duration of transfusion-independence response had not yet been reached
• The dosing in the study was based on tolerability and additional studies are planned to refine dosing
• The major side effects were cytopenias leading to dose reductions

"We are excited about ODAC's positive recommendation for approval of this NDA. REVLIMID will offer the opportunity to improve the lives of deletion 5q MDS patients with limited therapeutic options beyond blood transfusions," said John W. Jackson, Chairman and Chief Executive Officer, Celgene Corporation.

Broccoli and cauliflower inhibit lung cancer?

A family of compounds found in cruciferous vegetables, such as broccoli, cauliflower, and watercress, blocked lung cancer progression in both animal studies and in tests with human lung cancer cells, report researchers from Georgetown University Medical Center and the Institute for Cancer Prevention.

They say the results, published in a set of papers in the September 15 issue of Cancer Research, suggest that these chemicals — put into a veggie pill of sorts — might some day be used to help current and former smokers ward off development of lung cancer, the leading cause of cancer death in Americans.

“These studies provides significant insight into the mechanisms of lung cancer prevention and suggests ways the process can be slowed down after exposure has already occurred,” said the study’s principal investigator Fung-Lung Chung, Ph.D., Professor of Oncology in the Lombardi Cancer Center at the Georgetown University Medical Center.

Beans beat cancer?

A team of scientists led by Dr Marco Falasca (UCL Sackler Institute for Musculo-skeletal Research) has discovered that a potent anti-cancer compound found in beans, nuts and cereals inhibits a key enzyme – phosphoinositide 3-kinase – involved in tumour growth. The findings, published in the latest issue of ‘Cancer Research’, suggest that a diet enriched in such foods could help prevent cancer, while the inhibitor offers a new tool for anti-cancer therapy.

Inositol pentakisphosphate is a non-toxic, water-soluble compound found in most legumes such as lentils, peas and beans, and in wheat bran and nuts. These properties make the compound a promising therapeutic agent since conventional chemotherapy agents can be toxic to different degrees, whereas in the study, the inositol phosphate agent was found to be non-toxic, even at higher concentrations.

Dr Falasca said: “Our study suggests the importance of a diet enriched in food such as beans, nuts and cereals which could help prevent cancer. Our work will now focus on establishing whether the phosphate inhibitor can be developed into an anti-cancer agent for human therapy. We believe that inositol pentakisphosphate is a promising anti-cancer tool and we hope to bring it to clinical testing soon.”

http://www.ucl.ac.uk/news/news-articles/05091604

GlycoGenesys' drug candidate GCS-100 update

GCS-100 Targets Galectin-3 in Multiple Myeloma Cells In Vitro, Leading to Increased Anti-Tumor Activity When Combined With Dexamethasone

GlycoGenesys, Inc. (NASDAQ:GLGS), today announced the publication of an in-depth article introducing new and exciting in vitro findings about the Company's cancer drug candidate GCS-100. The paper was authored by Dr. Kenneth C. Anderson and researchers at the Dana-Farber Cancer Institute in collaboration with GlycoGenesys employees. It appeared in the American Association of Cancer Researcher's publication Cancer Research, September 15, 2005; Vol. 65, No.18 edition.

To provide the context to understand the potential commercial implications of these new findings, it is important to know that GlycoGenesys' cancer drug candidate GCS-100 has been shown to bind to Galectin-3. Galectin-3 is over-expressed in a variety of cancers including multiple myeloma, as well as solid tumors. Galectin-3 is a protein that protects cancer cells from dying. Notably, GCS-100 is currently in clinical testing for the treatment of multiple myeloma and solid tumors.

With this as a background, this new in vitro data generated at the Dana-Farber Cancer Institute illustrates for the first time that GCS- 100 decreases Galectin-3 expression in multiple myeloma cells when tested in combination with dexamethasone. These findings further showed that decreased Galectin-3 expression correlates with increased anti-tumor activity. This data adds to the understanding of how GCS-100 works in killing multiple myeloma cells.

The following additional findings show that GCS-100 has the potential to selectively kill and inhibit the growth of multiple myeloma cells, including drug-resistant cells, as well as prevent metastasis in patients with multiple myeloma:

-- GCS-100 selectively causes programmed cell death (apoptosis) in multiple myeloma cell lines without killing normal white blood cells;

-- GCS-100 blocks the growth of multiple myeloma cells from patients resistant to Velcade(R), thalidomide, and dexamethasone;

-- GCS-100 inhibited the growth of multiple myeloma cells even when grown in the presence of bone marrow cells. The bone marrow environment protects multiple myeloma cells and provides a survival advantage for growing cells;

-- GCS-100 overcomes the protective effect of several proteins important for drug resistance and growth of multiple myeloma and other cancers, for example Bcl-2, Hsp-27, and NF-kB;

-- GCS-100 was shown to prevent the movement of multiple myeloma cells caused by VEGF, a protein important in angiogenesis and growth of multiple myeloma cells.

The paper concludes that "Collectively, these findings provide the frame work for clinical trials of GCS-100, either alone or in combination with dexamethasone, to enhance clinical efficacy, reduce toxicity, and overcome drug resistance to conventional and Velcade therapy in patients with relapsed/refractory multiple myeloma."

GlycoGenesys has an ongoing Phase I/II dose escalation trial for treatment of multiple myeloma being conducted at Dana-Farber Cancer Institute and the Lucy Curci Cancer Center in Rancho Mirage, California. Additional sites are planned.

About The Trial

The Company is currently enrolling patients in it's Phase I/II dose escalation trial for treatment of multiple myeloma. The primary objective of the study is to evaluate the safety of GCS-100 when given to patients with relapsed or refractory multiple myeloma and to identify the recommended dose for future studies. Secondary objectives are to evaluate the response to GCS-100 as a monotherapy and in combination with dexamethasone and determine the pharmacokinetics of GCS-100 alone and with dexamethasone.

IGF-1 inhibits Multiple Myeloma cells

Emerging evidence suggests the insulin-like growth factor-1 receptor (IGF-1R) to be an important mediator of tumor cell survival and resistance to cytotoxic therapy in multiple myeloma (MM). Recently, members of the cyclolignan family have been shown to selectively inhibit the receptor tyrosine kinase (RTK) activity of the IGF-1R-chain. The effects of the cyclolignan picropodophyllin (PPP) were studied in vitro using a panel of 13 MM cell lines and freshly purified tumor cells from 10 MM patients. PPP clearly inhibited growth in all MM cell lines and primary MM samples cultured in the presence or absence of bone marrow stromal cells. PPP induced a profound accumulation of cells in the G₂/M-phase and an increased apoptosis. Importantly, IGF-1, IGF-2, insulin or IL-6 did not reduce the inhibitory effects of PPP. As demonstrated by in vitro kinase assays, PPP downregulated the IGF-1 RTK activity without inhibiting the insulin RTK activity. This conferred decreased phosphorylation of Erk1/2 and reduced cyclin dependent kinase (CDK1) activity. In addition, the expression of mcl-1 and survivin was reduced. Taken together, we suggest that interfering with the IGF-1 RTK by using the cyclolignan PPP offers a novel and selective therapeutic strategy for MM.

Blood First Edition Paper, prepublished online September 15, 2005; DOI 10.1182/blood-2005-01-0306

Aplidin(R) commences clinical trials

MADRID- Further Steps in the Development of Aplidin(R) in Melanoma in First Line Therapy
PharmaMar announces the initiation of a programme of combination studies with Aplidin(R) (plitidepsin), PharmaMar's novel marine-derived anti-tumour agent, originally isolated from the tunicate Aplidium albicans.
Aplidin in Combination with Carboplatin
The second of these combination studies will assess the safety and tolerability of Aplidin when administered in combination with carboplatin in patients with advanced solid and haematological tumours. The Phase I multicentre, open-label, dose-escalating, clinical and pharmacokinetic study will identify the maximum tolerated dose and recommended dose of Aplidin administered in combination with carboplatin to patients for whom there is no standard therapy.
About Aplidin
Aplidin is a cyclic peptide, originally isolated from the marine tunicate Aplidium albicans, now manufactured synthetically. It induces apoptosis rapidly and consistently, inhibits VEGF secretion and blocks the cell-cycle.
It is currently being evaluated in Phase II trials in solid and haematological malignancies. The clinical programme involves hospitals in Europe, Canada and the US. Approximately 500 patients have been treated to date. In preclinical development, leukemia, myeloma and lymphoma tumour cell lines were shown to be particularly sensitive to Aplidin. There is no evidence of cross-resistance with commonly used therapeutic agents for haematological malignancies.
Aplidin(R) shows no clinical evidence of relevant bone marrow toxicity. Its main side effects, muscular toxicity and liver biochemical alterations, are reversible and manageable. Hair loss and oral ulcers are infrequent.
About PharmaMar
PharmaMar is the world's leading biopharmaceutical companies in advancing cancer care through the discovery and development of innovative marine-derived medicines. PharmaMar's clinical portfolio currently includes: Aplidin(R), in Phase II, designated Orphan Drug for acute lymphoblastic leukaemia by the E.C. in 2003 and by the FDA in 2004, and for multiple myeloma by the FDA and the EC in 2004; as well as Kahalalide F in Phase II, and ES-285 and Zalypsis(R) in Phase I clinical trials.

Yet another Curcumin article

Indian Spice May Ward Off Disease — Turmeric, an Antioxidant, Is Studied for Use in Fight Against Cancer, Alzheimer’s

By Christina S.N. Lewis
30 August 2005
The Wall Street Journal
(Copyright (c) 2005, Dow Jones & Company, Inc.)

New evidence suggests a common Indian spice is a potent antioxidant that can prevent many diseases. The spice, turmeric, a key ingredient of curry, has been used medicinally for hundreds of years. But scientists are starting to systematically explore the sweeping qualities of the bright-yellow powder.

An increasing body of scholarly research indicates that curcumin, the active ingredient in turmeric, could be used to prevent a range of illnesses, from cancer to skin disorders. Faced with a number of promising laboratory studies and animal trials, scientists are rushing to test curcumin’s effectiveness in humans.

The U.S. National Institutes of Health has four clinical trials registered that are recruiting patients to test curcumin for pancreatic cancer, multiple myeloma, Alzheimer’s and colorectal cancer.

Curcumin is “definitely on our radar screen,” said Niles Frantz, a spokesman for the Alzheimer’s Association in the U.S., when asked about a recent Alzheimer’s trial. Curcumin is cheap, widely available and has no known toxicities. Studies have shown that it has anti-inflammatory and cholesterol-lowering properties. And it is a potential Cox-2 inhibitor, the same mechanism targeted by Merck & Co.’s Vioxx painkiller and a promising anticancer sign.

Interest in curcumin was piqued after scientists realized that people living in India had lower rates of certain cancers. Researchers theorized that eating curry, which is liberally spiced with turmeric, could be the explanation. Curcumin isn’t related to cumin, a spice commonly associated with Moroccan cooking.

In India, tradition calls for a bride to cover herself with turmeric to prevent wrinkles; some mothers will mix the powder with milk to ease an upset stomach. Johnson & Johnson sells a turmeric Band-Aid in India because the powder is reputed to help heal wounds.

Interest in curcumin appears to be increasing for several reasons. For one thing, alternative medicine has become more acceptable to mainstream doctors.

Also, in 2002, the NIH’s National Center for Complementary and Alternative Medicine began actively soliciting grant proposals for preliminary trials in natural therapies, making it easier for researchers to find funding.

Consumers also may be ready to try something new. Several negative studies have affected sales of vitamin E, the most well-regarded antioxidant. Its sales declined about 35% in the past year, according to Grant Ferrier, editor in chief of Nutrition Business Journal.

By contrast, sales of turmeric-related dietary supplements increased 35%, Mr. Ferrier said. But curcumin still represents only $15 million of sales in the U.S., a drop in the bucket compared with the $20.3 billion nutritional-supplement industry.

“From the data that I’ve seen in the laboratory, curcumin could be very potent in terms of killing tumor cells,” said Razelle Kurzrock, an investigator at M.D. Anderson Cancer Center in Houston, who studies curcumin and has applied for a patent on an injectable anticancer curcumin compound.

Research activity has exploded. A search of the U.S. National Library of Medicine reveals that 256 curcumin papers were published in the past year, compared with 94 published studies five years ago.

Though curcumin looks promising, it still has to make the leap from promising data to successful clinical trials. “Something can look very good in the laboratory and still not do much for patients,” Dr. Kurzrock said.

Even if science bears out curcumin’s effectiveness, this doesn’t mean eating more curry necessarily will improve your health, since a lot of curcumin is needed to reap anticancer benefits, doctors say. In the Alzheimer’s study at University of California, Los Angeles, for instance, patients were given daily four-gram doses, roughly the equivalent of about 120 curry dinners, according to its lead investigator.

Already, some entrepreneurs are trying to cash in on curcumin’s promise.

Last month Pure Prescriptions Inc., an Encinitas, Calif., online retailer specializing in natural substances, launched a curcumin-based supplement, marketing it as an all-purpose antioxidant.

A biotechnology venture called Curry Pharmaceuticals, in Research Triangle Park, N.C., is seeking funding to develop curcumin compounds and to research a curcumin cream to treat psoriasis and other skin disorders. Madalene Heng, a doctor at the Center for Dermatology Care in Thousand Oaks, Calif., already sells such a cream, called Psoria-Gold. Martin Yarnell, a 41-year-old lawyer from Oak Park, Calif., said the product has nearly eliminated his lifelong psoriasis.

Cellular switch for controlling immune system

A finding by researchers at the La Jolla Institute for Allergy & Immunology (LIAI) has identified a previously unknown cellular mechanism that acts as an off switch for immune system function. The discovery could lead to the future development of new treatments for autoimmune diseases.

In autoimmune diseases, the immune system, which normally wards off invading viruses and bacteria, instead mistakenly attacks normal body tissues, leading to illness. "By understanding this cellular process for turning off immune system activity, we are hopeful this will lead to new treatments that will stop unwanted immune responses, such as those which occur in autoimmune diseases," said LIAI scientist Carl Ware, Ph.D., who co-led the study with LIAI researcher Chris Benedict, Ph.D. The research team also involved scientists from Rush Medical Center and Northwestern University in Chicago and Washington University in St. Louis.

The findings will be published September 13 in the Proceedings of the National Academy of Sciences in a paper entitled, "Evolutionarily Divergent Herpesviruses Modulate T cell activation by Targeting the Herpesvirus Entry Mediator Cosignaling Pathway."

In the study, the team of scientists looked at two members of the herpes family of viruses, cytomegalovirus and herpes simplex virus, because of their ability to lay dormant in the immune system without causing disease. "These viruses teach us how to manipulate the immune system," Dr. Ware said. "We found that these two very different viruses were attacking the same communication pathway in the immune system." By disrupting that pathway, the viruses were keeping T lymphocytes - which are white blood cells that fight disease - from communicating with other cells in the immune system.

Central in the viruses' ability to manipulate immune system communication was a cellular protein called the Herpesvirus Entry Mediator (HVEM), which the scientists found effectively worked as an "off and on switch" for immune responses. Several cellular proteins -- members of the tumor necrosis factor (TNF) family -- interact with HVEM to enable this immune system communication switch. HVEM is part of a larger TNF family of molecules involved in a wide variety of important immune system functions. Drugs targeted at the TNF family are prominent treatments against some autoimmune diseases, including rheumatoid arthritis, psoriasis and Crohn's disease.

The findings also have implications beyond autoimmune disease, including possible application in treatments for infectious diseases and cancer. "An important part of our findings is that HVEM can not only switch off immune system response but it can also switch it on," Dr. Ware said. "This may be valuable in fighting infectious disease, where the body needs a stronger immune response. It also could aid in prompting immune cells to attack cancerous cells."

Source: La Jolla Institute for Allergy and Immunology

Study: Overweight females have increased Myeloma risk

Anthropometric characteristics and risk of multiple myeloma.

Blair CK, Cerhan JR, Folsom AR, Ross JA.

Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.

BACKGROUND: Few studies have examined obesity and risk for multiple myeloma, and the results are inconsistent. Laboratory evidence suggests mechanisms through which obesity could influence carcinogenesis of this hematopoietic malignancy. METHODS: We examined the association between anthropometric characteristics and incident multiple myeloma in a prospective, population-based sample of 37,083 postmenopausal women. In 1986, the women completed a mailed questionnaire that included self-report of height and weight, and friend measurement of waist and hip circumferences. During 16 years of follow up, 95 cases of multiple myeloma were identified through linkage to the Iowa Cancer Registry. RESULTS: In an age-adjusted model, women in the highest category of several anthropometric measurements compared with the lowest category were at increased risk of developing multiple myeloma. For body mass index (kg/m), the rate ratio (95% confidence interval) was 1.5 (0.92-2.6); for weight, 1.9 (1.1-3.4); for waist circumference, 2.0 (1.1-3.5); and for hip circumference, 1.8 (1.0-3.0). CONCLUSION: Greater adiposity may increase the risk of multiple myeloma.

PMID: 16135948 [PubMed - in process]

Myeloma--an ancient curse

Archaeological investigations have been ongoing in the cemetery at Hofstadir in Myvatnssveit since the summer of 1999. To date, the remains of two chapels as well as 78 skeletons have been excavated, dated to between the 11th and 15th century. A skeleton was excavated in the summer of 2003 which showed pathological changes indicative of a malignant disease. Palaeopathological cases of malignancies are very rare, and it is therefore important to report on each case. Skeleton HST-027 was a female, aged 45-50 years at the time of death. Standard osteological methods were used to determine the sex, age and stature. Macroscopic analysis was carried out on the skeleton and all pathological changes on each bone described. The cranium, ribs, left os coxa and all left long bones were then radiographed to aid in the diagnosis. The analysis showed lytic lesions in all the flat bones, as well as the vertebrae, ribs and the proximal end of the left femur, all changes indicative of multiple myeloma. Palaeopathologically myeloma and metastatic cancer (then usually due to breast cancer in the case of women) are often difficult to distinguish. However there is no new bone formation surrounding the lesions, which means that metastatic cancer is unlikely to be the cause. Skeleton HST-027 from Hofstadir is the first published case of malignant disease in Iceland, and one of the clearer cases of myeloma in an archaeological specimen, but to date, approximately twenty cases have been reported world-wide.

PMID: 16135876

[Myeloma in an archaeological skeleton from Hofstadir in Myvatnssveit]

Gestsdottir H, Eyjolfsson GI.

The Icelandic Archaeological Institute, Barugata 3, 101 Reykjavik, Iceland. hildur@instarch.is

Two types of smoldering myeloma

Two variants of smoldering multiple myeloma (SMM) have been recognised: (i) an evolving type, characterised by a progressive increase in the M-protein size and short time to progression to overt multiple myeloma (MM) and (ii) a non-evolving type, with a long-lasting, stable M-protein and longer time to progression. Comparative genomic hybridisation (CGH) analyses in both subtypes of SMM (seven evolving and eight non-evolving SMM) were performed. Evolving SMM showed cytogenetic changes consistent with those found in de novo symptomatic MM (1q gains, chromosome 13 deletions) while the non-evolving variant showed no 1q gains and deletions were uncommon.

British Journal of Haematology; Sep2005, Vol. 130 Issue 5, p729, 4p

The paradox of response and survival in cancer therapeutics

Although most cancer patients respond to therapy, few are cured. Moreover, objective clinical responses to treatment often do not even translate into substantial improvements in overall survival. For example, indolent lymphoma patients who achieved a complete remission with conventional-dose therapies in the pre-rituximab era did not experience a survival advantage over similar patients treated with a "watch and wait" approach. Several studies have also shown that neither the magnitude, nor the kinetics, of clinical response has an impact on survival in multiple myeloma. Recent data suggesting many malignancies arise from a rare population of cells that exclusively maintain the ability to self-renew and sustain the tumor (i.e., "cancer stem cells") may help explain this paradox that response and survival are not always linked. Therapies that successfully eliminate the differentiated cancer cells characterizing the tumor may be ineffective against rare, biologically-distinct cancer stem cells. New methods for assessing treatment efficacy must also be developed, as traditional response criteria measure tumor bulk and may not reflect changes in rare cancer stem cell populations. In this article, we discuss the evidence for cancer stem cells in hematologic malignancies and possible ways to begin targeting these cells and measuring clinical effectiveness of such treatment approaches.

PMID: 16150939 [PubMed - as supplied by publisher]

Blood. 2005 Sep 8; [Epub ahead of print]

The paradox of response and survival in cancer therapeutics.

Huff CA, Matsui W, Smith BD, Jones RJ.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16150939&query_hl=10

Mushrooms boost health

Researchers from Penn State have found that shiitake, oyster and maitake mushrooms as well as more common portabellas and white buttons contain high levels of an antioxidant linked with protection against chronic disease.

White button mushrooms and portabellas were found to contain about 12 times more of the antioxidant ergothioneine than wheat germ and four times more than chicken liver, previous top-rated sources of the compound.

They say exotic mushrooms, including shiitake, oyster, king oyster or maitake, can contain higher levels of the anti-oxidant, about 40 times as much as wheat germ.

Levels of ergothioneine do not decrease when mushrooms are cooked.

Raleigh cancer patient will be there, OSU's treat

His legs hobbled by a rare cancer and his body suffering from a painful attack of shingles, Joe Downing of Raleigh was learning to walk again when the physical therapist asked him what his goals were.

Downing, a 1959 Ohio State graduate and diehard Buckeyes fan, had an immediate answer: to make it to OSU's stadium, the famed Horseshoe, Sept. 10.

Tonight, he'll be there, sitting eight rows above field level with a prime view of the long-awaited meeting of the No. 4 Buckeyes and the No. 2 Texas Longhorns. It's considered one of the toughest tickets ever in Columbus. He thinks he got two because Coach Jim Tressel has made him part of the team almost 50 years after he unsuccessfully tried to walk on to Ohio State's varsity as a tight end.

Downing, 68, suffers from multiple myeloma, a rare bone marrow cancer. Two stem-cell transplants and multiple chemotherapy treatments have driven the disease into remission 2 1/2 years after he was diagnosed.

Tressel, whose brother also needed a stem-cell transplant, learned of how Downing was trying to fight the disease by mapping out a daily game plan based on football terms.

One day last year, the phone rang in Downing's North Raleigh home. The caller said, "Joe, this is Jim Tressel." Downing didn't believe him. Tressel told him how he learned about his game-plan approach to cancer and said, "I just wanted to call you and encourage you and see what I can do for you."

They talked for 45 minutes. The coach told him, "We Buckeyes take care of each other."

Since then, two Ohio State shirts have came from the athletics department with no mention of the sender. Every year, Downing is entitled to two tickets to one OSU home game. This year, he got prime tickets.

Downing, who saw his first OSU games as a boy selling programs, isn't parting with them.

"I had people call from Columbus and say, 'You want to sell your tickets for a thousand bucks?' I said, 'No, I'm 68, and I want to see every game.'"

By NED BARNETT, Staff Writer, The News & Observer, Raleigh, North Carolina

New radioactive-tipped antibodies battle non-Hodgkin's lymphoma

Health Canada has approved two new "smart" drugs to treat low-grade non-Hodgkin's lymphoma, a cancer that kills about 3,000 Canadians a year.

The drugs, Zevalin and Bexxar, are part of a class of medications known as radio-immunotherapy. They harness the body's immune system to attack cancer while zapping the tumour cells with sharply targeted radiation.

Monoclonal antibodies are part of a new generation of "smart" cancer therapies.

Scientists inject human cancer cells in mice, which then produce antibodies against these cells. The antibodies are harvested from the mice and cloned in the lab to produce identical copies. The patient is then infused with the antibodies, stimulating an immune response.

A monoclonal antibody, rituximab, has been used for a number of years to treat non-Hodgkin's lymphoma. Zevalin and Bexxar, however, are tipped with a kind of radioactive warhead, making them doubly effective.

Smart drug combats prostate cancer's helper proteins

Intravenously administered OGX-011 drug, inhibited the production of a gene protein called clusterin, which protects cancer cells.

The "chaperone" protein is targeted for suppression because of its helper role to cancer cells, allowing them to survive the assaults of treatments like chemotherapy and radiation by making tumours resistant to such therapy.

Conventional cancer treatments actually turn on the clusterin gene protein but by inhibiting it, OGX-011 helps boost the effectiveness of radiation, chemotherapy and other standard treatments after surgery.

In the Journal of the National Cancer Institute Wednesday, researchers from the B.C. Cancer Agency and the VGH Prostate Centre reported on the first human trial using OGX-011 in 25 patients.

The $1.4-million experiment was paid for by the U.S. Defence Department, which is sponsoring numerous prostate cancer trials to help thousands of aging war veterans diagnosed with the disease. The U.S. army has doled out hundreds of millions of dollars in grants for prostate cancer research since 1997.

Dr. Martin Gleave, the urologist who led the team that discovered and patented OGX-011, said that while clusterin is helpful in healthy people for its ability to help the body fight off certain stressors like cardiac events or other trauma, in those with cancer, it's nasty since it helps malignancies survive and spread.

Dr. Kim Chi, the BCCA oncologist who led the clinical trial, said the body's other defence mechanisms can step in when clusterin levels are reduced, as they were by about 90 per cent when patients were given the OGX-011 drug.

"Treatment for cancer in the past has involved poisons to kill the cancer cells. But in the next five years you'll be hearing a lot about these kinds of drugs which target cancer cells at the molecular level," Chi said.

Whether the drug actually helps patients live longer will be the subject of Phase 3 clinical trials.

Clusterin is also active in bladder, pancreas and kidney cancers, said Gleave, whose team was the first in the world to develop an anti-clusterin agent.

The OGX-011 drug is licensed to a University of B.C. biotechnology spinoff company.

Video Clip on Thalidomide

For a very interesting video clip on the history and current advances with respect to Thalidomide, refer to http://ir.celgene.com/phoenix.zhtml?c=111960&p=irol-irhome

Check out the video above the heading Horizons - THAL Story, February 12, 2004

Three New Cancer Centers Join MMRF

Emory University's Winship Cancer Institute, University of Chicago and St. Vincent's Comprehensive Cancer Center
of Saint Vincent Catholic Medical Centers of New York -- have joined the MMRC.

Joining forces with founding MMRC Member Institutions -- Dana Farber Cancer Institute, H. Lee Moffitt Cancer Center
& Research Institute, Mayo Clinic Cancer Center and University Health Network (Princess Margaret Hospital) -- researchers
from the new member institutions will conduct innovative research in the most promising areas of myeloma research:
genomics, target and compound validation and clinical trials.

The MMRC also sets itself apart with its state-of-the art tissue bank, the only repository of its kind,
which provides researchers with the critical mass of high-quality myeloma tissue needed to advance research efforts. 
With more than 300 tissue samples accrued to date under stringent Good Laboratory Practices, the MMRC Tissue Bank
serves as an important resource in enabling researchers to initiate strong pre-clinical validation efforts -- a critical step in
developing effective, targeted therapies for myeloma.

Novel Research Projects

The MMRC is now conducting several research efforts that are truly on the cutting edge of scientific
novelty and significance.  These research efforts include a pre-clinical effort to validate key targets in myeloma;
a pre-clinical study, in collaboration with a biotech partner, to validate antibodies that may represent promising
therapeutic options in myeloma; and, a Phase I trial and correlative sciences study, initiated in collaboration with
Chiron Corporation, of an FGFR3 inhibitor.

Effects of PS-341 on the Activity and Composition of Proteasomes in Multiple Myeloma Cells

Multiple myeloma is a B-cell malignancy for which no curative therapies exist to date, despite enormous research efforts. The remarkable activity of the proteasome inhibitor bortezomib (PS-341, Velcade) observed in clinical trials of patients with relapsed refractory myeloma has led to investigations of the role of the ubiquitin-proteasome pathway in the pathogenesis of myeloma. Here we report a biochemical analysis of proteasome activity and composition in myeloma cells exposed to PS-341 in the presence or absence of cytokines present in the bone marrow milieu. We observed that the myeloma cell lines MM1.S, RPMI8226, and U266 contain active immunoproteasomes, the amount of which is enhanced by IFN-gamma and tumor necrosis factor-alpha. Using a radiolabeled active site-directed probe specific for proteasome catalytic subunits, we show that PS-341 targets the beta5 and beta1 subunits in a concentration-dependent manner. Furthermore, PS-341 also targeted the corresponding catalytic subunits of the immunoproteasome, beta5i and beta1i, respectively. These data suggest that PS-341 targets both normal and immunoproteasome species to a similar extent in myeloma cells.

Altun M, Galardy PJ, Shringarpure R, Hideshima T, Leblanc R, Anderson KC, Ploegh HL, Kessler BM.

Department of Pathology, Harvard Medical School

Pre-clinical list of future Myeloma treatments

Here is a list of future potential Myeloma treatments.

http://www.myeloma.org/main.jsp?type=article&tab_id=1&menu_id=0&id=1541

ImmunoGen, Inc. Initiates Clinical Testing of HuN901-DM1

ImmunoGen, Inc. (Nasdaq: IMGN) today announced the initiation of clinical testing with its Tumor-Activated Prodrug (TAP) compound, huN901-DM1, for the treatment of multiple myeloma. This study expands the huN901-DM1 clinical program - the compound also is in two clinical trials for the treatment of small-cell lung cancer.

The huN901-DM1 multiple myeloma study is being conducted at the Jerome Lipper Center for Multiple Myeloma of the Dana-Farber Cancer Institute in Boston, MA. Robert Schlossman, MD, is the Principal Investigator. Co-investigators in the study include Kenneth Anderson, MD, Paul Richardson, MD, and Nikhil Munshi, MD, of the Jerome Lipper Center. Additional clinical centers are expected to be added.

The primary objective of this Phase I study is to evaluate the safety of huN901-DM1 in patients with relapsed or refractory multiple myeloma, and to identify the maximum tolerated dose of the compound in this patient population. The study also will evaluate the anticancer activity of huN901-DM1 in multiple myeloma.

The first dose level to be evaluated in this study will be close to the maximum tolerated dose that was established with the compound as part of the small-cell lung cancer clinical program. Patients will receive huN901-DM1 - as monotherapy - once weekly for two consecutive weeks every three weeks.

Patients need to have multiple myeloma that expresses the CD56 antigen targeted by huN901-DM1. Previous research conducted at the Dana-Farber Cancer Institute confirms that most cases of multiple myeloma express CD56.

In the same preclinical research, conducted in the laboratory of Dr. Munshi, huN901-DM1 was found to selectively target and kill CD56-expressing multiple myeloma cells. The compound was found to have substantial activity even when the multiple myeloma cells were in the presence of bone marrow stromal cells (BMSCs). There is evidence that multiple myeloma cells adhering to BMSCs are able to resist being killed by standard chemotherapeutic agents.

Dr. Schlossman commented, "HuN901-DM1 is a targeted approach to the treatment of multiple myeloma, in contrast to the currently approved agents for this malignancy. The findings from the preclinical multiple myeloma studies are encouraging, and we look forward to assessing this compound clinically."

HuN901-DM1 is in development by ImmunoGen for the treatment of cancers that express the CD56 protein targeted by the compound. CD56-expressing malignancies include multiple myeloma, small-cell lung cancer, and other cancers of neuroendocrine origin. HuN901-DM1 comprises the anti-CD56 antibody, huN901, and the potent cell-killing agent, DM1. The huN901 antibody is used to target the compound specifically to CD56-expressing cancer cells and the DM1 serves to kill these cells.

Stem cell harvesting improved

A study published in the current issue of the journal, Blood, demonstrates that cancer patients who received AMD3100
(MOZOBIL(TM)) plus granulocyte-colony stimulating factor (G-CSF) were able to collect more stem cells in less time
 compared to the standard mobilization regimen, G-CSF alone.

Extra virgin olive oil relieves pain

Extra virgin olive oil relieves pain in the same way as ibuprofen

The oil contains oleocanthal, which suppresses the same pain pathway as non-steroidal anti-inflammatory agents, such as ibuprofen.

Research shows that a 50 gram daily dose of olive oil is equivalent to about 10 per cent of the ibuprofen dose recommended for adult pain relief.

Regular olive oil consumption might confer some of the long-term benefits of ibuprofen, such as reduced cancer risk.

Genasense®/Thalomid®/Dexamethasone Promising for Recurrent Multiple Myeloma

According to an article recently published in the Journal of Clinical Oncology, the treatment combination of Genasense® (oblimersen), Thalomid® (thalidomide) and dexamethasone appears promising in the treatment of recurrent multiple myeloma.

One obstacle to treating recurrent or refractory cancers is that cancer cells often become resistant to the cancer-killing effects of various forms of therapy. One mechanism currently being investigated through which this resistance occurs is Bcl-2 expression. Bcl-2 is a protein that exists in delicate balance with other related proteins. One of its known functions is to prevent cells from apoptosis (death). Through several mechanisms not entirely understood, Bcl-2 proteins protect cancer cells from the lethal effects of therapy. Various types of cancers have higher than normal levels of Bcl2 proteins—this often results in a poorer prognosis than cancers without high levels of Bcl-2.

Genasense is a new agent still being evaluated in clinical trial that utilizes a relatively novel approach to treat cancer: Genasense inhibits or reduces the production of Bcl-2 protein by binding to the specific molecules that are involved in the process of producing Bcl-2 proteins. This binding action stops or reduces production of Bcl-2 proteins within a cell, making the cell sensitive to anti-cancer therapy agents. Previous studies demonstrate that Genasense amplifies the cytotoxicity (ability to kill cancer cells) of many therapeutic agents for a variety of different blood cancers. Studies have also demonstrated that Genasense has anti-cancer activity in various cancers when used as a single agent.

Researchers from the University of Maryland and the National Cancer Institute (NCI) recently conducted a clinical trial evaluating the treatment combination of Genasense, Thalomid and the steroid dexamethasone.

This trial included 33 patients with multiple myeloma—31 who had cancer progression following an autologous stem cell transplant and 15 who had cancer progression following treatment with Thalomid. Following treatment with Genasense/Thalomid/dexamethasone, overall anti-cancer responses were achieved in over half of patients (55 percent).

Reference: Badros AZ, Goloubeva O, Rapoport AP, et al. Phase II study of G3139, a Bcl-2 antisense oligonucleotide, in combination with dexamethasone and thalidomide in relapsed multiple myeloma patients. Journal of Clinical Oncology. 2005;23:4089-4099.

Combination of Farnesyl transferase inhibitor (Lonafarnib) and the proteasome inhibitor (Bortezomib) induces synergistic apoptosis in human myeloma

The identification of signaling pathways critical to myeloma growth and progression has yielded an array of novel agents with clinical activity. Multiple Myeloma (MM) growth is IL-6 dependant, and IK-6 is secreted in an autocrine/paracrine fashion with signaling via the Ras/Raf/MAPK pathway. We hypothesized that combining a Ras pathway inhibitor (lonafarnib, SCH66336) with a proteasome inhibitor (bortezomib, Velcade, PS-341) would enhance myeloma cell killing. Methods: MM cell lines and primary human cells were used to test either single agent bortezomib, lonafarnib, or the combination on MM signaling and apoptosis. Results: Combination therapy induced synergistic tumor cell death in MM cell lines and primary MM plasma cells. Cell death was rapid, and associated with increased caspase 3, 8, and 9 cleavage and concomitant down regulation of p-AKT. Down regulation of p-AKT was seen only in combination therapy, and not seen with either single agent. Cells transfected with constitutively active p-AKT, wild type AKT or Bcl-2 continued to demonstrate synergistic cell death in response to the combination. The order of addition was critically important supporting bortezomib followed by lonafarnib as the optimal schedule. Conclusion: The combination of a proteasome inhibitor and farnesyl transferase inhibitor demonstrates synergistic myeloma cell death, and warrants further pre-clinical and clinical studies.

Celebrex-related drug shows anti-Myeloma activity

A close structural relative of the celebrated COX-2 inhibitor celecoxib (brand name: Celebrex) is a potent tumor fighter, able to wipe out tumor cells that are resistant to conventional chemotherapies, according to an interdisciplinary team of researchers from the University of Southern California.

Led by Axel H. Schsnthal, associate professor of molecular microbiology and immunology at the Keck School of Medicine of USC, the researchers have been studying the effects of an analog of celecoxib that does not have its cousin's celebrated ability to block the activity of cyclooxygenase-2 (COX-2), an enzyme integral to the inflammatory process. Nonetheless, the scientists showed that the analog manages to halt tumor growth even in drug-resistant lines of multiple myeloma cells.

The work was published in the most recent online edition of the journal Blood, and will be appearing in an upcoming print edition of the journal.

Most of the attention celecoxib has received in recent years has been as a result of its anti-inflammatory effects and, most recently, the withdrawal of the two other main COX-2 inhibitors on the market - Vioxx and Bextra - after data unearthed linking them to an increased risk of stroke in some patients. (Celebrex remains on the market, but now carries a "black box" warning about the potential for cardiovascular side effects.)

But the truth is, celecoxib is more than just an anti-inflammatory agent. Over the past couple of years, researchers have begun to recognize that cyclooxygenase-2 can sometimes play a role in cancer; for instance, they've shown that the enzyme is overexpressed by multiple myeloma cells, and that this is a predictor of a poor outcome for the patient. Thus, it seemed clear that a cylooxygenase inhibitor might be able to turn things around.

It did. In several laboratory studies, the COX-2 inhibitor celecoxib showed an ability to target several of the growth pathways; further studies, including some performed by Schsnthal and colleagues, showed that celecoxib's anticancer activity appeared to be independent from its COX-2 inhibition. Schsnthal's team then went on to show that the analog in question-2,5-dimethyl-celecoxib or DMC-retains the ability to stop cancer growth despite the fact that it doesn't inhibit the activity of COX-2.

"Amazingly," the researchers noted in the Blood paper, "these growth-inhibitory effects take place even in cells that otherwise are highly resistant to the inhibitory effects of various anti-cancer drugs that are commonly used in the clinic for the treatment of cancer patients."

The fact that DMC is as potent - or, says Schsnthal, even more potent, even at lower doses - than celecoxib despite having no ability to inhibit COX-2 is important, the researchers say, especially in light of the recently revealed side effects of COX-2 inhibitory drugs. "Bearing in mind that substantially increased daily dosages of these drugs are considered - and probably necessary - for cancer prevention or cancer therapy, the increased risk of cardiovascular failure is of considerable concern," they wrote in the Blood paper. But because the unwanted cardiovascular side effects of celecoxib are connected to its ability to inhibit COX-2, Schsnthal speculates that DMC, which lacks that ability, might not cause similar problems.

Schsnthal notes that his research points to celecoxib in particular as being unique in its ability to slow or stop tumor growth. All the COX-2 inhibitors are able to block the activity of cyclooxygenase-2, he says, but only celecoxib and its analogs seem able to arrest growth and induce cellular suicide (apoptosis), even in cells that don't produce COX-2.

What does all this mean for the treatment of multiple myeloma? It will be important to extend these current results and determine whether these drugs achieve similar anti-tumor effects in myeloma patients, Schsnthal says. "Curing laboratory mice of multiple myeloma isn't good enough," he adds. "But proof of principle has been established with this work, so our next goal will be to evaluate DMC in myeloma patients, perhaps in combination with other drugs.

This work was funded by grants from the James H. Zumberge Faculty Research and Innovation Fund and from the Margaret E. Early Medical Research Trust.