Mayo Clinic Researchers Use Measles Virus to Treat Cancer

Researchers at Mayo Clinic in Rochester are working to give the measles vaccine a whole new purpose -- fighting cancer. Instead of serving only as a vaccine for keeping away measles, researchers have proven the vaccine can be effective in destroying cancer cells. Three recent studies demonstrated that the virus may be effective in treating such cancers as multiple myeloma, recurrent ovarian cancer, non-Hodgkin's Lymphoma and various tumors.

"With the measles vaccine, we have good starting material," said Stephen J. Russell, M.D., Ph.D. "However, we are now working to engineer the vaccine so that it kills cancer cells."

Support Multiple Myeloma Research

Support the MMRF's Spring Annual Appeal. Donations made today will be immediately applied to the world's most promising myeloma research. With your donation, you are providing hope to tens of thousands of myeloma patients worldwide. Your donation is an investment in the fight to find a cure for myeloma.

Visit http://www.multiplemyeloma.org to make a donation.

Mcl-1 is overexpressed in multiple myeloma

We and others have shown that Mcl-1 was essential for the survival of human myeloma cells in vitro. Furthermore, this antiapoptotic protein is upregulated by interleukin-6, which plays a critical role in multiple myeloma (MM). For these reasons, we have evaluated the expression of Mcl-1 in vivo in normal, reactive and malignant plasma cells (PC), that is, myeloma cells from 51 patients with MM and 21 human myeloma cell lines (HMCL) using flow cytometry. We show that Mcl-1 is overexpressed in MM in comparison with normal bone marrow PC. In total, 52% of patients with MM at diagnosis (P=0.017) and 81% at relapse (P=0.014 for comparison with diagnosis) overexpress Mcl-1. Of note, only HMCL but not reactive plasmacytoses have abnormal Mcl-1 expression, although both PC expansions share similar high proliferation rates. Of interest, Bcl-2 as opposed to Mcl-1, does not discriminate malignant from normal PC. Finally, the level of Mcl-1 expression is related to disease severity, the highest values at diagnosis being associated with the shortest event-free survival (P=0.002). In conclusion, Mcl-1, which has been shown to be essential for the survival of human myeloma cells in vitro, is overexpressed in vivo in MM in relation with relapse and shorter survival.

Mcl-1 represents a potential therapeutical target in MM.

Leukemia advance online publication, 5 May 2005; doi:10.1038/sj.leu.2403784.

Single autograft with high-dose melphalan: single-center study

451 myeloma patients, 51% previously untreated, underwent elective single autotransplantation after 200 mg/m(2) melphalan between 1985 and 2001 at the Royal Marsden Hospital. The therapy sequence was: Induction (vincristine, doxorubicin, methylprednisolone+/-cyclophosphamide), marrow or filgrastim-mobilized blood stem cell harvest, autograft, and interferon-alpha2b maintenance. A total of 27 (6%) died of transplant-related toxicity, all within 3 months. Complete or near-complete remission was seen in 59% with an overall response rate of 91%. Subsequent disease progression was seen in 285, and 17 died of unrelated causes. In all, 206 patients were alive at the last follow-up, 6 months to 17.7 years post-transplant (median 65 months); 122 without disease progression at 6 months to 17.7 years (median 58 months). The median overall (OS) and event-free (EFS) survivals were 5.9 and 2.4 years, with 10-year OS and EFS probabilities of 31.4 and 16.5%, respectively.

In Cox analysis, it was seen that significantly longer OS occurred for patients who had beta-2-microglobulin <3.5 p="0.001)">/=35 g/l (P=0.009). EFS was also longer if beta-2-microglobulin was <3.5 mg/l (P=0.0056) and patients were <60 years of age (P=0.033).

We conclude that with a single planned autograft, patients with myeloma have an excellent outcome.

Bone Marrow Transplantation advance online publication, 16 May 2005

Azaspirane - Dana-Farber Cancer Institute Announcement

From the Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; and Callisto Pharmaceuticals Inc, New York, NY.

Azaspirane (N-N-diethyl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine; trade name, Atiprimod) is an orally bioavailable cationic amphiphilic compound that significantly inhibits production of interleukin 6 (IL-6) and inflammation in rat arthritis and autoimmune animal models. We here characterize the effect of atiprimod on human multiple myeloma (MM) cells. Azaspirane significantly inhibited growth and induced caspase-mediated apoptosis in drug-sensitive and drug-resistant MM cell lines, as well as patient MM cells. IL-6, insulin-like growth factor 1 (IGF-1), or adherence of MM cells to bone marrow stromal cells (BMSCs) did not protect against atiprimod-induced apoptosis. Both conventional (dexamethasone, doxorubicin, melphalan) and novel (arsenic trioxide) agents augment apoptosis induced by atiprimod. Azaspirane inhibits signal transducer activator of transcription 3 (STAT3) and a PI3-K (phosphatidylinositol 3-kinase) target (Akt), but not extracellular signal-regulated kinase 1 and 2 (ERK1/2), inhibits phosphorylation triggered by IL-6, and also inhibits inhibitorB (IB) and nuclear factor B (NFB) p65 phosphorylation triggered by tumor necrosis factor (TNF-). Of importance, azaspirane inhibits both IL-6 and vascular endothelial growth factor (VEGF) secretion in BMSCs triggered by MM cell binding and also inhibits angiogenesis on human umbilical vein cells (HUVECs). Finally, azaspirane demonstrates in vivo antitumor activity against human MM cell growth in severe combined immunodeficient (SCID) mice. These results, therefore, show that azaspirane both induces MM cell apoptosis and inhibits cytokine secretion in the BM milieu, providing the framework for clinical trials to improve patient outcome in MM.

Myeloma and Hair Dyes #2

How much is "not very high?" See the bottom line.
***
(Newsday) An analysis of nearly four decades' worth of research on health and hair dyes suggests that today's coloring agents pose only a nominal, if any, risk of cancer.

Hair dye risks have been long linked to a family of chemicals called aromatic amines, which are carcinogenic, most of which have been removed. But a team of Spanish and Canadian scientists, which pooled results from 80 studies, found that certain cancer-causing compounds are no longer used, lowering health risks.

"In the 1970s, dye makers were using more toxic chemicals, such as 2,4-diaminotoluene and 2,4-diaminoanisole, which are no longer used," said Mahyar Etminan, an epidemiologist at Royal Victoria Hospital in Quebec, whose work helped deem the dyes safer than thought.

"Hair dye is something a lot of people are using, and if dye caused cancer, this would be a significant public health concern," Etminan said. While his findings offer a degree of assurance, he acknowledged that additional research is needed.

In today's Journal of the American Medical Association, Etminan and Dr. Bahi Takkouche of the University of Santiago de Compostela in Spain reported that in North America and Europe, about 33 percent of women and 10 percent of men use hair dyes.

Hair coloring agents have been linked to breast, skin and bladder cancers, leukemia and lymphoma. Contrarians to the new risk-free message abound. Among them is Dr. Tongzhang Zheng of Yale University, who last year conducted one of the largest studies on cancer risk and hair dyes.

"Studies like these," Zheng said of Etminan's research, "prove nothing." He called the analysis deeply flawed. Because the research was observational and did not involve patients, Zheng said Etminan and colleagues could not gauge patients' susceptibility to dyes or the amount of dye any individual used. Zheng found that long-term use of dark-colored permanent dyes doubles a person's risk of certain cancers, particularly lymphoma. The new research did not specify dye types or colors. Zheng's study was one of 80 examined by Etminan's team.

"When we analyzed all of the studies, we found a slight increase in cancers of the blood," Etminan said. "But that risk was not very high."

Copyright 2005 Newsday Inc.

Genmab Announces Multiple Myeloma Antibody Program

Genmab announced today its new HuMax®-CD38 program for the treatment of multiple myeloma. HuMax-CD38 is a human IgG1,k antibody selected from a large panel of antibodies based on its ability to bind and to kill multiple myeloma tumor cells. The HuMax-CD38 antibody targets the CD38 molecule which is very highly expressed on the surface of multiple myeloma cells.

In preclinical studies, HuMax-CD38 was effective in killing primary multiple myeloma tumor cells and a range of tumor cell lines by triggering two immune system killing mechanisms: Antibody-Dependent Cellular Cytotoxicity (ADCC) and Complement Dependent Cytotoxicity (CDC). In animal models using sensitive bioluminescence imaging, treatment with HuMax-CD38 slowed tumor growth in both preventive and therapeutic settings in SCID mice. These are mice with a deficient immune system, in which human tumor cells can grow.

Myeloma and Hair Dyes #1

There's no strong link between the use of permanent hair dyes and an increased risk of cancer, says a major study to be published today in the prestigious Journal of the American Medical Association.

The authors, including Canadian pharmacy researcher Mahyar Etminan, undertook what is called a meta-analysis. Rather than do a new trial, they systematically searched the scientific literature for studies on possible links between hair dye and cancer, pooling data from 79 studies published between 1966 and January of this year.

The studies looked at risks for people who have their hair dyed, but not the professionals who did the dying. The same research team plans to conduct a future meta-analysis to see if people working in hair salons are at greater risk of developing cancers than their clients.

They concluded that "globally, there is no effect of personal hair dye use on the risk of breast and bladder cancer."

There was a "borderline" effect for the hematopoietic cancers or blood cancers such as multiple myeloma and leukemia.

"However, the evidence of a causal link effect is too weak to represent a major public health concern," the study concluded.

There was also a borderline effect for brain tumours and ovarian cancer, but the results were based on only two studies for each type of cancer. The researchers urged more study in these areas.

Some previous studies have found increased cancer risk related to permanent dyes, especially darker colours.

"An association between hair dyes and cancer would be an important public health concern since about one-third of women in Europe and North America, along with 10 per cent of men older than 40 years, use some type of hair dye. Permanent dyes, the most aggressive type, represent 70 per cent of the market share -- even more in Asia," said the study.

So far, research into the risks posed by hair dyes has been inconclusive, said Heather Logan, director of cancer control policy for the Canadian Cancer Society.

"This study is valuable because it looks at a large number of studies, she said. "Certainly, this is very reassuring."

© The Edmonton Journal 2005

Vitamin D research turning sunscreen wisdom on head

Controversy: Who to believe?
***

Scientists are excited about a vitamin again. But unlike fads that sizzled and fizzled, the evidence this time is strong and keeps growing.

If it bears out, it will challenge one of medicine's most fundamental beliefs: that people need to coat themselves with sunscreen whenever they're in the sun. Doing that may actually contribute to far more cancer deaths than it prevents, some researchers think.

The vitamin is D, nicknamed the "sunshine vitamin" because the skin makes it from ultraviolet rays. Because sunscreen blocks vitamin D's production, some scientists are questioning the long-standing advice to always use it.

The reason is that vitamin D increasingly seems important for preventing and even treating many types of cancer. In the past three months alone, four separate studies found it helped protect against lymphoma and cancers of the prostate, lung and, ironically, the skin. The strongest evidence is for colon cancer.

Many people aren't getting enough vitamin D, and it's hard to get from food and fortified milk; supplements are problematic.

So the thinking is this: Even if too much sun leads to skin cancer, which is rarely deadly, too little sun may be worse.

No one is suggesting that people fry on a beach, but many scientists believe that "safe sun" - 15 minutes a few times a week without sunscreen - is a healthy thing to do.

One is Dr. Edward Giovannucci, a Harvard University professor of medicine and nutrition who laid out his case in a recent lecture at a major cancer research meeting.

His research suggests that vitamin D might help prevent 30 deaths for each one caused by skin cancer.

"I would challenge anyone to find an area or nutrient or any factor that has such consistent anti-cancer benefits as vitamin D," Giovannucci told the cancer scientists. "The data are really quite remarkable."

The talk so impressed the American Cancer Society's chief epidemiologist, Dr. Michael Thun, that the society is reviewing its sun protection guidelines. "There is now intriguing evidence that vitamin D may have a role in the prevention as well as treatment of certain cancers," Thun said.

Even some dermatologists may be coming around. "I find the evidence to be mounting and increasingly compelling," said Dr. Allan Halpern, dermatology chief at Memorial Sloan-Kettering Cancer Center in New York, who advises several cancer groups.

The dilemma, he said, is a lack of consensus on how much vitamin D is needed or the best way to get it. Even if sunshine were to be recommended, the amount needed would depend on the season, time of day, where a person lives, skin color and other factors. Thun and others worry that folks might overdo it.

"People tend to go overboard with even a hint of encouragement to get more sun exposure," Thun said, adding that he'd prefer people get more of the nutrient from food or pills.

But this is difficult. Vitamin D occurs naturally in salmon, tuna and other oily fish, and is routinely added to milk, but diet accounts for very little of the vitamin D circulating in blood, Giovannucci said.

Most supplements use an old form, D-2, that is far less potent than the more desirable D-3. Multivitamins typically contain only small amounts of D-2 and include vitamin A, which offsets many of D's benefits.

As a result, pills might not raise vitamin D levels much at all.

How vitamin D may do this is still under study, but there are lots of reasons to think it can:

• Several studies of large groups of people found that those with higher vitamin D levels also had lower rates of cancer. Even so, these studies aren't the gold standard of medical research - a comparison over many years of a large group of people who were given the vitamin with a large group that didn't take it. In the past, the best research has deflated health claims involving other nutrients, including vitamin E and beta carotene.
• Lab and animal studies show that vitamin D stifles abnormal cell growth, helps cells die when they are supposed to, and curbs formation of blood vessels that feed tumors.
• Cancer is more common in the elderly, and the skin makes less vitamin D as people age.
• Blacks have higher rates of cancer than whites and more pigment in their skin, which prevents them from making much vitamin D.
• Vitamin D gets trapped in fat, so obese people have lower blood levels of D. They also have higher rates of cancer.
• People in the northeastern United States and northerly regions of the globe like Scandinavia have higher cancer rates than those who get more sunshine year round.
  

During short winter days, the sun's rays come in at too low an angle to spur the skin to make vitamin D. That is why nutrition experts think vitamin D-3 may be especially helpful during winter, and for dark-skinned people all the time.

But too much of the pill variety can cause a dangerous buildup of calcium in the body. The government says 2,000 IUs is the upper daily limit.

On the other hand, it's almost impossible to overdose when getting vitamin D from sunshine.

However, it is possible to get skin cancer. And this is where the dermatology establishment and Dr. Michael Holick part company.

Thirty years ago, Holick helped make the landmark discovery of how vitamin D works. Until last year, he was chief of endocrinology, nutrition and diabetes and a professor of dermatology at Boston University. Then he published a book, The UV Advantage, urging people to get enough sunlight to make vitamin D.

Skin cancer is rarely fatal, he notes. The most deadly form, melanoma, will account for only 7,770 of the 570,280 U.S. cancer deaths expected this year.

Repeated sunburns - especially in childhood and among very fair-skinned people - have been linked to melanoma, but there is no credible evidence that moderate sun exposure causes it, Holick contends.

"The problem has been that the American Academy of Dermatology has been unchallenged for 20 years," he says. "They have brainwashed the public at every level."

The head of Holick's department, Dr. Barbara Gilchrest, called his book an embarrassment and stripped him of his dermatology professorship, although he kept his other posts.

Earlier this month, the dermatology academy launched a "Don't Seek the Sun" campaign, calling any advice to get sun "irresponsible." It quoted Dr. Vincent DeLeo, a Columbia University dermatologist, as saying: "Under no circumstances should anyone be misled into thinking that natural sunlight or tanning beds are better sources of vitamin D than foods or nutritional supplements."

That opinion is hardly unanimous, though, even among dermatologists.

"The statement that 'no sun exposure is good' I don't think is correct anymore," said Dr. Henry Lim, chairman of dermatology at Henry Ford Health System in Detroit and an academy vice president.

© Associated Press 2005

Home remedy test brings rewards to science students

EDMONTON -- Sixteen-year-old Julia Grochowski calls it a year of seconds.

She and Andrew Guardamano, 18, placed second at a regional competition with their project "Lobitonin in Cancer Treatment." They fared as well at the Aventis Biotech Challenge and at the Intel International Science and Engineer Fair.

Recently, the pair brought home yet another silver medal, this time from the International Science and Engineering Fair in Phoenix, Ariz.

The Alberta ScienceFair Foundation financed their $10,000, week-long trip, making them the first students to be sponsored by the foundation.

"We are very pleased just having provided both students with this experience," said Kay J. Jauch, executive director of the Alberta ScienceFair Foundation.

"We hope that the experiences of our national, and now international participants, will encourage other young

Albertans, their teachers and their parents to get involved."

Guardamano and Grochowski didn't let the foundation down. In an event where more than 1,200 students from four dozen countries competed, they took home second prize in the medicine and health category.

"The whole experience was just really amazing," said Guardamano. "We were thinking of just going for the experience. We didn't expect to win anything. Of course, we were going to do our best."

Guardamano, who attends Archbishop McDonald, and Grochowski, an Old Scona Academic student, spent three years studying an Asian fruit and its relationship to cancer. The initial idea for their project stems back to Guardamano's grandmother, Flora Lacson.

Four decades ago, she was diagnosed with breast cancer. It was in its final stages, it was the 1960s and medicine was doing little for her.

It was then when Lacson, a resident of the Philippines, remembered a local fruit known to cure bumps and bruises without causing side-effects. With nothing to lose, she applied it for several months.

It might have been a coincidence, it might have been a misdiagnosis. But a trip to the doctor a few months later revealed the cancer was gone.

"That's where we got the initiative to investigate this fruit and see if it had any anti-cancer properties," Grochow-ski said.

As they discovered, it did.

After exposing the fruit compound to three types of the disease -- leukemia, pancreatic and glioma -- it wasn't long before the pair's hypothesis turned into a definite conclusion. The more fruit extract they added, the more cancer cells they killed.

In 24 hours, it destroyed 85 per cent of leukemia cells.

Guardamano was "quite ecstatic" with the results. He encourages all students to participate in science fairs.

"It allows us to experience science in a way kids our age never thought was possible," he said.

The two cannot disclose which fruit they based their project on because they're applying for a patent.

"It's kind of a big secret right now," Guardamano said.

In time, though, the whole world might know the secret to their success.

© The Edmonton Journal 2005

REVLIMID plus Dex better than Dex Alone

"The North American and International Multiple Myeloma Phase III trials reported a significant clinical benefit for patients treated with REVLIMID plus dexamethasone. In multiple myeloma patients with resistant disease, REVLIMID plus dexamethasone more than doubled the response rate compared with placebo plus dexamethasone confirming that REVLIMID has the potential to be an important new agent for multiple myeloma patients," explained Donna Weber, M.D., Associate Professor, Lymphoma/Myeloma of The University of Texas MD Anderson Cancer Center.

At the ASCO Scientific Symposium, Dr. Weber presented the results of the North American and International Multiple Myeloma Phase III trials. Dr. Weber led the North American Phase III trial ( MM-009 ), a randomized, double-blinded, placebo-controlled trial, using REVLIMID plus dexamethasone, versus placebo plus dexamethasone in pretreated relapsed or refractory multiple myeloma patients. This study enrolled 354 patients from 47 clinical sites throughout North American with data available from 171 patients randomized to REVLIMID plus dexamethasone and 171 patients randomized to placebo plus dexamethasone. The median patient age was 64 years in the REVLIMID plus dexamethasone arm, compared to 62 years in the placebo plus dexamethasone arm of the trial. An Independent Data Monitoring Committee reviewed the planned interim analysis of clinical data and determined that the North American Phase III trial overwhelmingly exceeded the pre-specified efficacy stopping rule of p <0.0015 for the primary endpoint, time-to-disease progression. Consistent with the findings of the interim analysis, available as of March 31, showed best response rates of 61.2% in patients treated with REVLIMID( R ) plus dexamethasone, compared to 22.8% of patients treated with placebo plus dexamethasone.

"Multiple myeloma is an illness with a discouraging outcome, but today, with advances such as REVLIMID, there is a prospect for myeloma to become a chronic illness for the majority of patients worldwide," explained Meletios Dimopoulos, M.D., Professor of Therapeutics at The University of Athens School of Medicine, Greece.

Dr. Dimopoulos led the International Phase III trial ( MM-010 ), a randomized, double-blinded, placebo-controlled trial, using REVLIMID plus dexamethasone, versus placebo plus dexamethasone in previously treated relapsed or refractory multiple myeloma patients. This study enrolled 351 patients from 50 clinical sites internationally with data available from 176 patients randomized to REVLIMID plus dexamethasone and 175 patients randomized to placebo plus dexamethasone. The median patient age was 63 years in the REVLIMID plus dexamethasone arm, compared to 64 years in the placebo plus dexamethasone arm of the trial. An Independent Data Monitoring Committee reviewed the planned interim analysis and determined that this International Phase III trial overwhelmingly exceeded the pre-specified efficacy stopping rule of p< 0.0015 for the primary endpoint, time-to-disease progression. Consistent with the findings of the interim analysis, the available clinical data as of March 31, showed best response rates of 58.0% in patients treated with REVLIMID plus dexamethasone, compared to 21.7% of patients treated with placebo plus dexamethasone.

In both trials, patients treated with REVLIMID and dexamethasone had an increase in side effects as compared to those patients only treated with placebo plus dexamethasone. Grade 3 / 4 toxicities included neutropenia, thrombocytopenia and anemia. Deep vein thrombosis occurred in 13.5 and 4.5% of patients treated with REVLIMID plus dexamethasone, compared to 3.5 and 3.4% of patients treated with placebo plus dexamethasone in the North American and International trials, respectively. Pulmonary embolism occurred in 2.9 and 4.0% of patients treated with REVLIMID plus dexamethasone, compared to 0.6 and 1.1% of patients treated with placebo plus dexamethasone in the North American and International trials, respectively.

BJC - Evolving treatment strategies for myeloma

British Journal of Cancer
http://www.nature.com/bjc/journal/v92/n2/full/6602341a.html

Myeloma is a malignant disorder, which is characterised by an excess of abnormal bone marrow plasma cells producing a clonal paraprotein detectable in the serum and urine in the majority of patients. Common clinical sequelae include lytic bone lesions, fractures, myelosuppression and renal failure. It is a relatively common disease with approximately 2500-3000 new cases each year in the UK. The incidence increases with age, and the majority of cases occur over the age of 60 years. With effective treatment, the median survival is approximately 4 years. After years of few therapeutic advances, we find ourselves standing at the site of a marked expansion in treatment choices and the challenge now is how to test these new treatments against the best previously available.

Until recently, the basis of myeloma chemotherapy was aimed at the achievement of a disease phase called 'plateau' where there is an absence of overt clinical symptoms and paraprotein levels are stable. Despite this aim, it was generally accepted that the quality of life of patients in plateau phase was poor although a small percentage of patients lived for a prolonged period with a relatively good quality of life. With the advent of new agents that are able to achieve better responses and outcomes, it has become increasingly important to define the appropriate clinical settings and the therapeutic strategies with which to use them. The clinical settings are relatively easily recognised, including therapy for induction, maintenance, relapse and refractory disease. In this article, we will argue that the strategic aim with which to use novel treatments should be to maximise clinical responses. This is based on what has been learnt over the last 20 years and the clinical characteristics of a complete response (CR), a disease phase where there is a good quality of life and few ongoing symptoms. Responses obtained should be maintained for the maximum time period, which will require the development and implementation of novel antimyeloma therapies suitable for the maintenance setting. At present, the maximum number of CRs is achieved after high-dose therapy (HDT) (Attal et al, 1996; Davies et al, 2001a; Child et al, 2003), and the impact of new agents has to be compared to this current gold standard. In this setting, it is important to distinguish between agents that give good but transient responses and those for which overall responses may be less but which may be maintained for longer. Normally in myeloma treatment trials, it is conventional to consider the impact of a single line of treatment on overall survival (OS) as the major end point. However, it is becoming increasingly apparent that during the average disease course of a patient with myeloma, the patient will receive multiple courses of treatment, the sequencing of which may or may not be important. A good example of this is the observation of the beneficial therapeutic effect of HDT whether it is used at presentation or at relapse (Attal et al, 1996; Fermand et al, 1998; Child et al, 2003). Consequently, it is important to distinguish the end points of OS and progression free survival (PFS), both of which can give useful information, and also recognise that OS may be affected by subsequent treatment regimens.

THE DEVELOPMENT OF CURRENT TREATMENT STRATEGIES
Initial myeloma trials showed that early death was, and still is, a significant problem, and addressing the causes of this is important including early diagnosis, the treatment of infection, hydration and the choice of the most appropriate chemotherapy. Melphalan, an alkylating agent, has been shown to be an effective treatment and no evidence of a superior treatment regimen emerged in early clinical trials, although it was shown in an early MRC trial that single agent cyclophosphamide was equivalent to melphalan (MRC, 1980). In the 1980s, several groups investigated the value of using combination chemotherapy compared to single agent melphalan. In the UK, the MRC Myeloma V trial compared melphalan alone to ABCM (adriamycin, 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU), cyclophosphamide and melphalan) and showed a significant benefit for the combination, including significant differences in achievement of plateau (61 vs 49%) and in median OS (32 vs 24 months) (MacLennan et al, 1992). However, systematic reviews of published and of individual patient data from a number of clinical trials did not show a significant advantage for other combinations (VMCP (vincristine, melphalan, cyclophosphamide and prednisone), VBAP (vincristine, BCNU, adriamycin and prednisone) and VCAP (vincristine, cyclophosphamide, adriamycin and prednisone)) (MTCG, 1998), although relatively few of these combinations included the use of an anthracycline as in the ABCM regime.

At the same time, alternative combinations, dose schedules and modes of administration of active chemotherapeutic agents were being explored. High response rates were reported with dexamethasone alone and in combination with VAD in which vincristine and adriamycin were given by a 4-day intravenous infusion together with high-dose dexamethasone (Samson et al, 1989). Dexamethasone was recognised as a key component in this regime, and good response rates were noted using this agent alone but such responses were not maintained long term. A major feature of this regimen is its lack of toxicity to the haematopoietic stem cell compartment, making it an ideal regimen for use for stem cell harvest before autologous transplantation. Concurrently, investigators at the Royal Marsden Hospital looked at the role of melphalan dose escalation. Doses of 140 mg m^-2 were found to achieve high response rates, with CRs being reported in about 30% of patients, and for the first time bone healing was noted (McElwain and Powles, 1983). The development of autologous stem cell rescue allowed safe escalation of the dose of melphalan to 200 mg m^-2 and resulted in even higher remission rates, with CR being reported in approximately 50% of patients compared to the very few CRs that were traditionally seen with standard dose treatments such as oral melphalan. As a result of these clinical investigations, a high-dose treatment strategy emerged, consisting of VAD initially, to induce disease response, at which stage haemopoietic stem cells are collected. These cells are then used to support high-dose melphalan, which consolidates the responses obtained. Analysis of the effect of response after HDT suggested that patients achieving a CR had a better PFS and OS than those who did not (Barlogie et al, 1999; Lahuerta et al, 2000; Davies et al, 2001a).

It became important, at this stage, to understand how the intensive treatments aimed at achieving maximum response rates compared to standard dose chemotherapies. The first of a series of randomised trials was carried out by the Intergroupe Francophone du Myelome (IFM) (Attal et al, 1996). In an intention to treat analysis, they demonstrated a significant advantage for patients in the intensive arm in terms of response rate, response duration and survival, with a median OS of 56 months compared with 44 months in the standard arm. The MRC Myeloma VII trial addressed the same question, comparing ABCM with C-VAMP (cyclophosphamide, vincristine, adriamycin, methylprednisolone) followed by high-dose melphalan (Child et al, 2003). A total of 400 patients aged less than 65 years were randomised. There was a significant improvement in OS of patients treated with intensive therapy compared with those treated conventionally, with a median survival of 54 months compared with 42 months. Response rates and response durations were also improved in the HDT arm. A published data meta-analysis of similar trials confirmed the beneficial therapeutic effect of the intensive treatment approach, establishing it as the standard treatment for suitable presenting patients.

Over the years, a number of maintenance strategies have been investigated in order to prolong responses post-HDT and improve quality of life. Interferon has been used in this setting but has not been taken up widely on account of a number of features. It significantly impaired quality of life, was expensive, and in meta-analyses, although it was shown to be statistically significantly better than no maintenance therapy, the benefit was not clinically significant (MTCG, 2001). Dexamethasone has also been used, and in a small study looked effective but again the side-effect profile particularly in the elderly has not led to its general uptake (Berenson et al, 2002). The therapeutic profile of a drug useful in the maintenance setting is likely to be different from one used in the induction phase of treatment, and while efficacy is important, tolerability is crucial.

NOVEL TREATMENTS
To date, the majority of new agents have been tested in the relapse and refractory setting in order to determine clinical efficacy and safety profiles. Many of these agents are now being moved into earlier disease stages where combination regimens based on in vitro synergy can be tested. VAD is the classical treatment used to achieve response before HDT. New therapies, working by alternative mechanisms, incorporated into induction regimes prior to transplant may improve the numbers of responses achieved before transplant. They could also be used after transplant as part of a strategy to maximise responses for patients who fail to achieve a CR, if they did not induce severe myelosuppression. An alternative to this approach, if the responses suggested in initial studies are achieved, is that novel combinations could be used in place of HDT. However, as HDT is recognised as an effective regimen, it is still likely to be used at some stage of the disease process. Before novel combinations can be compared with HDT in a randomised setting as part of induction therapy, the response rates and lengths of remission need to be firmly established; however, such a comparison is tempting as intensive therapy involves periods in hospital with a long period of recovery.

THALIDOMIDE AND ITS DERIVATIVES
The recognition that thalidomide was active in myeloma was based on its antiangiogenic activity in in vitro models together with the unexpected description of neo-angiogenesis in the bone marrow of myeloma patients. Initial studies of single agent thalidomide in relapsed refractory disease showed a remarkable 30% response rate (Singhal et al, 1999). In vitro characterisation of its mechanism of action demonstrated a variety of effects including direct toxicity to the myeloma plasma cell, alteration in cytokine secretion, interruption of the myeloma cell stromal cell interaction and increase in T and NK cell activity (Hideshima et al, 2000; Davies et al, 2001b). Thus, thalidomide is not a classical cytotoxic providing a rationale for combining it with other treatments. The addition of thalidomide to standard regimens for older less-fit patients unsuitable for transplant options is of great clinical interest. Complete responses with MP (melphalan and prednisone) are in the order of 10%, but preliminary data using MPT (melphalan, prednisone and thalidomide) suggest that these rates can be increased to 50%, a level comparable to those achieved with HDT (Palumbo et al, 2003). Current questions relate to whether this improved response rate translates to improved survival and if it does, the balance of standard vs intensive treatment may alter and necessitate a specific randomised comparison.

Regimens have also been developed including combinations of thalidomide and dexamethasone with or without cyclophosphamide (Rajkumar et al, 2002; Cavenagh and Oakervee, 2003; Weber et al, 2003). These combinations represent an oral version of VAD and have the potential to improve significantly pretransplant responses, at the same time removing the need for an indwelling catheter. An ongoing phase III study, MRC myeloma IX, is comparing CTD (cyclophosphamide, thalidomide and dexamethasone) with CVAD (cyclophosphamide, vincristine, adriamycin and dexamethasone). However, it seems highly likely that these new regimes will be more effective and be associated with fewer side effects than VAD and will become the new standard induction therapy prior to HDT. Intensification of these regimes further by the addition of other agents has been useful for refractory patients. DT-PACE (dexamethasone, thalidamide, cisplatin, adriamycin, cyclophosphamide, etoposide) has been developed for patients who have not responded to standard treatments and are candidates for HDT. This regimen is effective and able to rescue significant numbers of patients who can then proceed to HDT (Lee CK et al, 2003). Whereas other maintenance strategies have not been widely taken up, thalidomide maintenance for patients who have achieved a response is appealing because of its multiple modes of action, especially its immunomodulatory effect. It is currently being explored in this setting, in particular looking at its side-effect profile. A UKMF phase II study of 84 patients receiving thalidomide maintenance post-HDT suggests that long-term treatment is possible at low doses (Feyler et al, 2003). In spite of this down side, at a recent meeting in Torino, preliminary results from the IFM suggest an improvement in PFS when it is used following HDT. It is not unreasonable to suggest that similar effects would be seen after treatment with oral standard dose chemotherapy.

For this reason, thalidomide derivatives offer an interesting alternative because of their favourable side-effect profiles. A number of such derivatives of thalidomide including RevlimidÔ and ActimidÔ have been developed, which potentially offer the opportunity of a decrease in side effects (phocomelia, thrombosis, peripheral neuropathy) with an increase in antimyeloma activity. The immunomodulatory drugs (IMiDs) are 50,000 times more potent at inhibiting TNF secretion, more potent inducers of T-cell proliferation with IFN and IL-2 secretion, and inhibitors of IL-1B and IL-6 secretion, and in in vitro studies demonstrate an increased myeloma cell kill (Hideshima et al, 2000). Initial phase I and II studies of RevlimidÔ and ActimidÔ are extremely encouraging with response rates between 38 and 58% with CRs in the order of 10% and no significant somnolence, constipation or neuropathy (Richardson et al, 2002, 2003a; Streetly et al, 2003). A phase III randomised trial is ongoing.

BORTEZOMIB AND PROTEASOME INHIBITION
Bortezomib (VelcadeÔ) is a boron-containing molecule, which reversibly inhibits the proteasome. The 26S proteasome is a large multi-subunit protein, which is present in all eukaryotic cells and functions to degrade proteins targeted to it by ubiquitination. Ubiquitinated proteins enter at one end of the proteasome and are degraded to their individual peptides, which are shed from the far end of its barrel-like structure. It consequently has a critical role in maintaining intracellular homeostasis allowing complex intracellular signalling events to take place, which are essential for the control of cell cycle progression, transcription and apoptosis, as well as mediating inter-cell signalling events such as those leading to chemotaxis, angiogenesis and adhesion (Adams, 2004). Proteasome inhibition with bortezomib can induce apoptosis even in myeloma cell lines resistant to conventional chemotherapy, suggesting that it works by a distinct mechanism not affected by the drug resistance mechanisms leading to alkylator and steroid resistance. One central mechanism by which Bortezomib functions in myeloma is likely to be via inhibition of the breakdown of IB and consequently stabilisation of the NF-B complex. This prevents NF-B translocation to the nucleus with consequent inactivation of multiple downstream pathways. In addition, other molecules stabilised by proteasome inhibition include p53, p21 and p27, and one possible mechanism of apoptosis is the simultaneous accumulation of cell signalling and cell cycle regulatory molecules. Bortezomib decreases the adhesion of the myeloma plasma cell to stromal cells, which increases sensitivity to apoptosis, as well as interrupts prosurvival paracrine and autocrine cytokine loops in the bone marrow microenvironment mediated by IL-6, IGF1, VEGF and TNF (Hideshima et al, 2001).

A phase II study of 202 patients with relapsed refractory myeloma demonstrated that 35% of these heavily pretreated patients achieved a response to treatment and 10% had a CR or near CR (Richardson et al, 2003b). These are truly remarkable response rates for this late stage of the disease, suggesting that even greater response rates would be seen earlier in the natural history of the disease. The median survival was 16 months with a median duration of response of 12 months. Response to treatment was associated with improvement in a range of clinical parameters and quality of life. A phase III trial has recently been closed early due to the improved efficacy in disease free survival of bortezomib over dexamethasone. Much like with thalidomide, bortezomib combinations are being developed based on in vitro data (Ma et al, 2003). There is evidence for an additive effect with dexamethasone, and this is supported by data from the phase II trial in which patients who failed to respond to bortezomib alone showed evidence of a response when dexamethasone was added. In vitro, at nontherapeutic doses, it has been possible to sensitise cell lines to the cytotoxic effects of melphalan, doxorubicin and mitoxantrone (Mitsiades et al, 2003). Ongoing clinical trials are using bortezomib in combination with other agents, including melphalan, thalidomide and cyclophosphamide (Yang et al, 2003; Zangari et al, 2003). These combinations may be particularly effective for refractory disease and could potentially achieve greater response rates than current high-dose treatment strategies and could be the subject of randomised comparisons. It remains an open question as to the stability of remissions induced by such combinations, and the potential role of thalidomide/revlimidÔ maintenance needs to be considered.

TARGETED TREATMENTS ON THE HORIZON
Targeted treatment is not a new concept and has in fact underpinned strategies for treating cancer since their inception. However, novel targeted approaches rely upon the identification of a specific molecular target and the design of specific small molecules to inhibit them. The activity of proteasome inhibition in myeloma highlights the importance of protein checkpoints and also points towards the importance of the unfolded protein response in plasma cells (Lee AH et al, 2003). Indeed protein synthesis may be the Achilles heel of the myeloma cell as it clearly distinguishes plasma cells from many other cells within the body. In this respect, it is not surprising that preclinical work evaluating inhibitors of molecular chaperones using HSP90 inhibitors has been shown to be effective in myeloma models. The study of multistep models of cancer progression has suggested that in addition to genetic changes such as translocation and loss of heterozygosity, heritable epigenetic effects such as methylation of CpG islands and modulation of chromatin structure via acetylation of histone tails can lead to loss of expression of key genes and disease progression. The key feature of these changes is that they are amenable to therapeutic manipulation, which can result in upregulation of gene expression associated with normalisation of the cellular phenotype. Agents in clinical trial in myeloma include the demethylating agents 5-azacytadine and decytabine and the histone deacetylase inhibitors SAHA and LAQ.

As our understanding of the pathogenesis of myeloma improves, the heterogeneity in outcome is becoming increasingly obvious. Current prognostic factors such as B2M and more recently the International Staging System (ISS) although effective are not biologically based (Greipp et al, 2003). It is widely anticipated that expression microarrays will identify patterns of gene expression, which can be used to define outcome, identify targets and direct treatment decisions. Perhaps the best examples of how to target treatment rely upon defining a specific molecular lesion known to be important. In myeloma, approximately 15% of patients harbour the t(4;14), which deregulates the tyrosine kinase FGFR3 and can be targeted using specific inhibitors. Inhibiting this is effective in cell line models, but proof of concept in humans has not yet been completed (Trudel et al, 2004). If this is achieved, it will argue for the molecular characterisation of myeloma before selecting a treatment, and would suggest that therapeutic approaches should be tested in trials for specific molecular subtypes. In order to bring this approach to fruition, it is important that we invest in the full characterisation of the myeloma genome.

CONCLUSION
In the future, descriptions of myeloma currently characterised by the statement 'myeloma is an incurable disease' will be replaced by statements such as 'myeloma is a highly treatable condition, which is associated with prolonged survival and good quality of life if the correct treatment decisions are made'. While this is an accurate description of the current clinical situation, this message has not yet fully reached the majority of physicians who treat myeloma. Achieving the full advantage of these new therapeutic options will rely upon making these approaches available to all patients diagnosed with myeloma at an early stage in the natural history of their disease. Making this possible will involve education for general practitioners and hospital physicians alike. In addition, once patients are diagnosed, equitable access to novel therapeutics in an environment where the haemato-oncologist using the drugs has adequate experience in their use is also important and provides a strong argument for the establishment of specialist clinics and centres that treat adequate numbers of myeloma and can advise on the delivery of treatment. The expansion of new therapeutics means that we have to develop systems to evaluate and rapidly introduce agents shown to be effective into the clinical arena. This demands a full interaction between the pharmaceutical industry, clinicians and the regulatory authorities.

Velcade and del(13)

According to results recently presented at the 2005 annual meeting of the American Society of Clinical Oncology (ASCO), treatment with Velcade (bortezomib) may overcome the poor prognosis associated with del(13), or deletion of chromosome 13 in multiple myeloma.

By conventional cytogenetics, del(13) is considered a poor prognostic indicator for survival in multiple myeloma. However, it was discovered through the SUMMIT trial in which Velcade was utilized as treatment in multiple myeloma that del(13) was not associated with differences in survival or response rates. Thus, researchers were led to believe that Velcade may play a role in negating the detrimental effects associated with del(13) in multiple myeloma, and further evaluation of this possible correlation was necessary to confirm findings.

STAT-3

Scientists from Isis Pharmaceuticals, Inc. in collaboration with scientists at the Department of Pathology and NYU Cancer Institute, New York University School of Medicine and the Department of Pathology and Center for experimental Research and Medical Studies (CERMS), University of Torino, have reported in Nature Medicine that the STAT-3 gene is required for the generation of B-lymphomas in mice carrying a mutation implicated in some human lymphomas and that reducing the expression of STAT-3 with a second-generation antisense drug targeted to STAT-3 resulted in impaired growth of human and mouse lymphoid tumors in animals. These results suggest that the second-generation antisense inhibitor of STAT-3 might be an effective treatment for human lymphomas, multiple myeloma, and other cancers. The drug, ISIS 345794, is in preclinical development at Isis.

"It has been known for sometime that spontaneously occurring rearrangements on genes in human chromosomes can cause some cancers. For example, in some forms of human lymphomas, a cancer-causing gene is aberrantly relocated in the chromosome and inappropriately activated. We used genetic techniques to show that in a mouse model of human lymphoma and myeloma that the loss of STAT-3 prevents progression of disease and, in some cases, reverses the growth of existing lymphomas," said Dr. Giorgio Inghirami, senior author of the publication. "Although modern genetic methods can lead to important insights into diseases, one of the central challenges is to rapidly convert the information to new drugs that will benefit patients. Antisense technology gives researchers the ability to target a specific protein, such as STAT-3, to clearly determine its pathogenetic role, and to efficiently treat the cause of the disease."

"This study was one of the studies that supported our understanding of the biological function of STAT-3 and reinforced our enthusiasm for this very exciting drug. Through the use of antisense technology, we confirmed with our collaborators that inhibition of STAT-3 prevented the progression of cancer," said Brett P. Monia, Ph.D., Isis' Vice President of Antisense Drug Discovery. "Once we have a functional understanding of a particular molecular target, we can progress the specific antisense inhibitor used to validate the target rapidly into drug development. ISIS 345794 is an excellent example of the value and efficiency of the technology for the treatment of human disease."

ONJ -- Bisphosphonates and Dentists

Novartis and FDA notified dental healthcare professionals of revisions to the prescribing information to describe the occurence of osteonecrosis of the jaw (ONJ) observed in cancer patients receiving treatment with intravenous bisphosphonates, Aredia (pamidronate disodium) and Zometa (zoledronic acid). The prescribing information recommends that cancer patients receive a dental examination prior to initiating therapy with intravenous bisphosphonates (Aredia and Zometa), and avoid invasive dental procedures while receiving bisphosphonate treatment. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition.

Velcade Report

"VELCADE has been successfully combined with standard and emerging multiple myeloma therapies and has achieved some of the highest overall response rates in the front-line setting, ranging from 67 to 95 percent," said David Schenkein, M.D., senior vice president, clinical research, Millennium. "As the only single-agent therapy with a significant survival advantage in relapsed multiple myeloma, new data presented at ASCO also demonstrated a survival advantage in patients with poor prognostic factors, such as chromosome 13 deletion."

VELCADE is approved in the U.S. for the treatment of patients who have received at least one prior therapy. To date, more than 12,000 patients have been treated with VELCADE. Clinical studies in the front-line setting were the subject of several presentations at the recent International Myeloma Workshop in Sydney, Australia. The results of five studies indicated VELCADE based regimens induced high response rates in MM patients and toxicities were manageable. These studies were the basis of three large, multicenter international, randomized phase III trials, and are part of a broad co- development program between Millennium and Johnson & Johnson Pharmaceutical Research & Development.

VELCADE® (bortezomib) for Injection in Newly Diagnosed MM Patients (Abstract 6653) Interim results from the front-line multicenter phase II, IFM cooperative group trial, led by Jean-Luc Harousseau, M.D., of the Hospital Hotel-Dieu in France, assessed the efficacy and safety of VELCADE in combination with standard therapy dexamethasone as an induction treatment prior to autologous stem cell transplant. Patients received four treatment cycles followed by stem cell harvest and autologous stem cell transplant. Results reported for 48 patients include:

Ÿ         Overall response rate was 67 percent, including complete and partial responses with complete response rates of 21 percent and very good partial responses (90 percent reduction in M-protein) in an additional 10 percent of patients;

Ÿ         Stem cell harvest was successful in 100 percent of patients who  proceeded to autologous stem cell collection;

Ÿ         Stem cell harvest was sufficient to support single autologous stem cell transplant in 100 percent of patients who went on to transplant and overall responses were improved post-transplant;

Ÿ         Overall response rate after single transplant was 90 percent with 33 percent complete response and 21 percent very good partial response, comparable to results after tandem transplants; and

Ÿ         Treatment was well tolerated and most frequent toxicities included gastrointestinal events, peripheral neuropathy, fatigue, skin toxicity, infection and hematologic toxicities.

"The results from this study and other studies assessing VELCADE based regimens for induction therapy prior to transplant in the front-line setting have shown patients achieve high complete and very good partial responses and were able to undergo transplant successfully," said Professor Harousseau. "Longer survival has previously been associated with these quality responses and may offer new hope to newly-diagnosed multiple myeloma patients."

VELCADE in Relapsed High-Risk MM Patients

Additional analyses were reported at ASCO from the multicenter phase III APEX study which compared VELCADE to high-dose dexamethasone under the direction of Ken Anderson, M.D., and Paul Richardson, M.D., of the Dana Farber Cancer Institute of Boston, MA. These new subset analyses showed significantly improved outcomes and quality of life in relapsed patients. Results include:

    -- Patients with Chromosomal 13 Deletion Abnormality (Abstract 6501)

Ÿ         The survival benefit was maintained despite the presence of a chromosomal 13 deletion, a poor prognostic factor associated with inferior outcomes.

    -- High-Risk and Elderly (65 years or older) Patients (Abstract 6533)

Ÿ         Median time to progression was significantly improved in the elderly and in those patients who had greater than one prior therapy, B2M >2.5 mg/L (blood protein associated with disease severity) and who were refractory to prior treatment;

Ÿ         Response rates were significantly higher in the elderly and those patients who had greater than one prior therapy, B2M >2.5 mg/L and who were refractory to prior treatment.

    -- Quality of Life Assessment (Abstract 6535)

Ÿ         Significantly better outcomes were demonstrated in global health and physical role, cognitive and emotional functioning and symptoms of total neurotoxicity, nausea, dyspnea, sleep, diarrhea and financial impact.

"The new analysis of patients with a chromosome 13 deletion demonstrated survival outcomes for VELCADE treated patients is independent of the genetic abnormality," said Sundar Jagannath, M.D., St. Vincent's Comprehensive Cancer Center, New York, NY. "This is the first time a therapy has overcome this poor prognostic indicator."

Seattle Genetics Update on SGN-40 Clinical Program

Seattle Genetics, Inc. today reported SGN-40 has shown evidence of biological activity in multiple myeloma, and the company has modified the dose and schedule of SGN-40 administration in the ongoing phase I clinical trials to minimize first dose effects that are potentially attributable to cytokine release.

In our SGN-40 clinical trials, we have seen preliminary indications of activity, including decreasing serum M-protein, urine protein and B-cell levels during treatment of several patients with multiple myeloma."

SGN-40 Phase I Clinical Trials

SGN-40 is a humanized monoclonal antibody that targets the CD40 antigen, which is expressed on most B-cell lineage hematologic malignancies, including multiple myeloma, non-Hodgkin's lymphoma and chronic lymphocytic leukemia. Seattle Genetics is conducting open-label, multi-dose, single-arm phase I studies designed to evaluate the safety, antitumor activity and pharmacokinetic profile of escalating doses of SGN-40 in patients with relapsed or refractory multiple myeloma or non-Hodgkin's lymphoma.

In the multiple myeloma study, 16 patients have been treated with SGN-40 at dose levels of 0.5, 1, 2 or 4 mg/kg. Patients were heavily pretreated with a median of 5.5 prior therapies, median time from initial diagnosis of 6.5 years and median age of 60 years. Repeated infusions of SGN-40 at doses of 0.5, 1 and 2 mg/kg were well tolerated. At 4 mg/kg, two of three patients experienced grade 3 headaches and were diagnosed with aseptic meningitis, from which both patients fully recovered. Seattle Genetics has amended the original protocol, including dose and schedule modifications, to attenuate potential cytokine release following the first infusion. Several patients demonstrated disease stabilization and decreasing M-protein in the blood and urine during treatment with SGN-40. The study is open for accrual and continued dose escalation.

Thalomid Update

Thalidomide increases a patient's chance of achieving multiple myeloma remission when combined with standard drug therapy, according to research released at this week's meeting of the American Society of Clinical Oncology.

The drug, known by the Celgene brand name Thalomid, also reduces the risk of recurrence when added to standard treatment, researchers reported.

"The results are better than anything published to date, and show that myeloma does not have to be a death sentence, said Dr. Bart Barlogie, director of the Myeloma Institute for Research and Therapy at the University of Arkansas and lead author of the study.

In a study of 668 patients with multiple myeloma treated with several rounds of chemotherapy and stem-cell transplantation, 62% of those receiving thalidomide achieved complete remission, compared with 43% of those whose treatments didn't include the drug.

IMF Launches "Bank on a Cure"

The International Myeloma Foundation (IMF) today announces the launch of Bank On A Cure®, the first myeloma-specific, cancer-patient DNA bank in history. Bank On A Cure was created to advance research, to provide better treatments in the short term, and to find a cure for multiple myeloma, a cancer of the plasma cells in the bone marrow.

As part of today's public launch event at the Millenium Hilton in New York City, Geraldine Ferraro will contribute a sample of her DNA to Bank On A Cure through a simple, painless procedure known as "swish and rinse." Ms. Ferraro was diagnosed with myeloma in 1998.

"Bank On A Cure holds tremendous potential to move our understanding of myeloma forward by leaps and bounds," said Ms. Ferraro. "I am delighted to take part in a project that will benefit not only current myeloma patients such as myself, but also cancer patients for years to come."

"The International Myeloma Foundation is privileged to have the Honorable Geraldine Ferraro participate in Bank On A Cure," said Susie Novis, IMF president. "We foresee a time in the near future when each patient's treatment will be tailored to his or her own genetics, allowing better, more effective therapies. This important project will move us closer to that goal and to finding a cure for myeloma."

"This personalized molecular approach to myeloma research and treatment is a key component to the IMF's research efforts to introduce molecular medicine into day-to-day myeloma management," said Dr. Brian Durie, IMF Chairman of the Board.

Created by the IMF, Bank On A Cure is the world's first databank of myeloma patient DNA and information. The project brings together the global myeloma community to create a truly collaborative research environment with the ability to analyze complex genetic information from thousands of myeloma patients around the world. Bank On A Cure has already collected DNA samples from more than 5,000 myeloma patients. Researchers are currently looking at patients' responses to treatment to improve the benefits of existing therapy, reduce side effects, and improve patients' quality of life right now.

Institutions, researchers, patients and family members who would like to participate in Bank On A Cure can do so by contacting the IMF at (800) 452-CURE or www.myeloma.org.

Donating DNA to Bank On A Cure

Because every cell in the human body contains the same DNA, a convenient source is the surface cells inside the mouth. These cells, called buccal cells, can be collected through a simple, painless procedure called "swish and rinse." A patient drinks a small cup of mouthwash -- provided by Bank On A Cure as part of the collection kit -- "swishes" it around in his or her mouth, and then "rinses" the sample into a coded collection cup. The DNA sample is then returned to the Bank On A Cure laboratory at the University of Minnesota Cancer Center, for analysis.

Nano-news

Drug molecules not only have to be effective at treating disease, they also have to be robust enough to get from the place where they enter the body to the place where they are designed to act. Given that bodies devote a lot of effort to hunting down and destroying things that are in the wrong place—whether those things be molecules, viruses, bacteria or even errant body cells—designing drugs that can do this is no mean feat.

That is doubly true when the drug in question actually acts by stimulating one of these “thing-in-the-wrong-place” mechanisms—which is precisely how drugs that provoke a phenomenon called RNA interference work. RNAi, as it is known for short, is an approach to pharmacology that might revolutionize the field if it could be made to work routinely. It uses a natural anti-virus mechanism to block the activity of disease-causing genes, so any illness caused by the activity (as opposed to the inactivity) of a particular gene might, in principle, be treated by it.

Getting RNAi drugs into the cells that need them is, though, proving harder than people expected. So news that Siwen Hu and Timothy Triche, of the Children's Hospital in Los Angeles, and Mark Davis, of the California Institute of Technology, think they have worked out how to do so in the case of one form of cancer could prove to be an important advance.

RNAi works by mugging one of the cell's molecular messengers. The information needed to make proteins—the molecules that do most of the work in a cell—is stored as genes in the double-stranded DNA of a cell's nucleus. When a particular protein is needed, this information is copied into a single-stranded molecule called RNA. The RNA then carries the message to the places where proteins are made, and the message is translated into protein.

Many viruses work by subverting this mechanism—injecting their own RNA into a cell in order to make that cell produce viral proteins instead. But viral RNA is often double-stranded when it enters a cell, so a nifty way for a cell to deal with viral invasions is to recognize and destroy double-stranded RNA. Which is exactly what happens. Double-stranded RNA of any variety is rapidly chopped up by most cells.

RNAi hijacks this process to stop the production of disease-causing proteins. Its drug molecules are also strands of RNA, but they are the chemical complements of the disease-causing messenger strands. That means they pair up with their targets to form double-stranded molecules, and those molecules then get chomped by the anti-virus mechanism. What has defeated researchers is getting the complement strands into diseased cells in large enough numbers. This is where Dr. Hu, Dr. Triche and Dr. Davis come in.

Their solution is to wrap the therapeutic RNA inside a “nanoparticle” made of two polymers called cyclodextrin and polyethylene glycol, and coated with a protein called transferrin. It is the transferrin that provides the magic. Its usual job is to carry iron atoms, which cannot penetrate cell membranes by themselves, into cells. It does this by grabbing hold of those atoms and then latching on to a cell-membrane protein called a transferrin receptor, which escorts it into the cell. The researchers reasoned that transferrin and its receptor might perform the same trick for their nanoparticles, and they knew that tumour cells have more transferrin receptors than healthy ones. So they reckoned this might be a way to get the nanoparticles to concentrate in tumours. Once inside, the acidic environment of the cell would dissolve the particle, releasing the RNA.

To test this idea out, they injected their nanoparticles into mice that had been engineered to suffer from Ewing's sarcoma, a rare childhood cancer. They chose this disease because it is caused by a novel gene not found in healthy individuals, and thus provides a clear and unambiguous target for the therapeutic RNA. The novel gene is created when two chromosomes, numbers 11 and 22, each break in two at particular weak spots, and part of chromosome 11 joins with part of chromosome 22. As bad luck would have it, the DNA at the junction forms a sequence that the cell's gene-reading machinery recognizes as a gene, and this gene spurs uncontrolled cell growth (in other words, cancer) in certain bone and muscle cells.

Mice injected with human Ewing's sarcoma cells develop secondary cancers similar to those seen in human patients. However, when the researchers injected their nanoparticles into the bloodstreams of animals with Ewing's tumours, the growth of those tumours slowed. Even better, if they injected the animals with nanoparticles shortly after injecting the cancer cells, they stopped the formation of secondary cancers in the first place.

Other scientists have shown that they can use RNAi to slow tumour growth in mice, but they have had to inject their RNA directly into the tumour, which is tricky. Dr. Hu, Dr. Triche and Dr. Davis are the first to demonstrate that they can inject it into an animal's bloodstream and then let it find its own way to the target. The three researchers are now working to perfect the system, so that it can be tested in people, and they are also making sure that it works in cancers other than Ewing's sarcoma. If they can do both of these things, they may have come up with the much-sought mechanism for propelling RNAi into the big time.

Ontario cancer patients petition for drug funding

Source: http://toronto.myeloma.org/york_region_interview.htm

The dates are etched in their memories, intertwined with other landmark occasions that map a human life. For Marion State, it was June 1996. Dorothy Plourde recalls July 1999. Everyone remembers when they were diagnosed with cancer.

A retired Thornhill nurse, Ms State was told she had multiple myeloma, a relatively rare and incurable bone marrow cancer leading to immune dysfunction, brittle bones and kidney failure. Some 1,800 Canadian cases are reported annually.

Doctors gave her seven years to live.

Undaunted, she founded the Toronto and District Multiple Myeloma Support Group in 1997. There are 350 members -- myeloma survivors, family members and caregivers -- underpinning each other and sharing information on the condition and treatment options.

Last Jan. 31 was another significant day for the group.

On that winter day, hope was delivered by Health Canada when it approved Velcade, a new drug treatment for multiple myeloma patients who are unresponsive to current front-line therapies.

The Ortho-Biotech drug, which won its research scientists a 2004 Nobel Prize in chemistry, is available through all provincial drug programs except Ontario where, at 730 new cases per year, myeloma is most prevalent. Here, only a handful of clinical trial participants can access the treatment proven to disrupt the growth of myeloma cancer cells.

At a cost of $7,200 for a 21-day course of treatment, Velcade is out of reach for most patients. The Ontario Drug Benefit plan continues to hedge on funding approval for Velcade, saying it is currently eighth in the queue for discussion, and an answer won't be forthcoming for at least eight to 10 months.

Myeloma patients can't wait that long, said Ms Plourde, a North York retiree who is one month into a clinical Velcade trial at Princess Margaret Hospital.

"At diagnosis, I had two stem cell transplants and Thalidomide as maintenance therapy," she said. "It worked for a while then I came out of remission. I was told Velcade would work best for me and I was accepted into the eight-month trial.

"The only way to get it is to travel downtown. It takes five hours out of my day to get a three-second infusion."

Ms State's research suggests myeloma is the second fastest-growing blood cancer in North America.

"With new therapies such as this we have a longer quality of life," she said. "Ontario is dragging its heels. It's the only province without a process in place to provide Velcade. No one has heard of myeloma. The other cancers get the big bucks."

Ms State and her group have pushed the issue, briefing Thornhill MPP Mario Racco on the government's dangerous procrastination.

"I have written the (health) minister," Mr. Racco said. "We have spoken. Unfortunately it takes time. We must follow normal protocol with out slowing (the process) down."

Meanwhile, myeloma patients must wait for yet another hopeful date.

"It's sad for us, we're losing our friends," Ms Plourde said.

"Lives are at risk," Ms State added. "I hope we get approval. Right now the province is doing us a disservice."

For information, visit www.toronto.myeloma.org
Chris Traber, Staff Writer - York Regional Newspapers

Honokiol - Dana-Farber Cancer Institute Announcement

Honokiol (HNK) is an active component purified from Magnolia, a plant used in traditional Chinese and Japanese medicine. Here we show that HNK significantly induces cytotoxicity in human multiple myeloma (MM) cell lines and tumor cells from patients with relapsed refractory MM. Neither co-culture with bone marrow stromal cells nor cytokines (interleukin-6 and insulin-like growth factor-1) protect against HNK-induced cytotoxicity. Although, activation of caspases 3, 7, 8 and 9 is triggered by HNK, the pan-caspase inhibitor z-VAD-fmk does not abrogate HNK-induced apoptosis. Importantly, release of an executioner of caspase-independent apoptosis, apoptosis-inducing factor (AIF) from mitochondria is induced by HNK treatment. HNK induces apoptosis in SU-DHL4 cell line, which has low levels of caspase-3 and -8 associated with resistance to both conventional and novel drugs. These results suggest that HNK induces apoptosis via both caspase-dependent and -independent pathways. Furthermore, HNK enhances MM cell cytotoxicity and apoptosis induced by bortezomib. In addition to its direct cytotoxicity to MM cells, HNK also represses tube formation by endothelial cells, suggesting that HNK inhibits neovascurization in the bone marrow microenvironment. Taken together, our results provide the preclinical rationale for clinical protocols of HNK to improve patient outcome in MM.