Blood Cancer &
 Leukemia

August 3, 2004
St. Jude researchers pinpoint leukemia key

Researchers at St. Jude Children's Research Hospital have joined Dutch scientists in suggesting that a small number of genes hold the key to treatment of acute lymphoblastic leukemia. The researchers identified four groups of genes, each of which had a characteristic pattern of expression in leukemia cells that was found to be related to treatment outcome.

The study identified 123 previously unrecognized genes associated with resistance to cancer chemotherapy. Only three of them had been linked previously to drug resistance. These new genes represent potential targets for new agents that could be developed to overcome resistance to drugs currently used to treat the leukemia, according to researchers.

Their study, by investigators from St. Jude and Rotterdam-based Erasmus University Medical Center/Sophia Children's Hospital, appears in the Aug. 4 issue of the New England Journal of Medicine. St. Jude is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases.

Founded by Danny Thomas and based in Memphis, St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization.

Despite St. Jude's role in increasing the cure rate of childhood acute lymphoblastic leukemia from 4% to more than 80% during the past 40 years, the cause of failure in the remaining 20% of children remains unknown, according to St. Jude scientific director William E. Evans. The current findings could help further reduce the number of failures, says Evans, who is a senior author of the Journal report.

"The findings of this study are helping us understand why patients respond differently to treatment and point to new approaches to overcome these causes of disease relapse," according to Evans.

A milestone worth noting in Fallon's leukemia cluster

Steve F. Lyon
August 2, 2004

A somber anniversary worth noting passed in July. It's been two years since the last local case of childhood leukemia surfaced. That's a great thing for the community.

Can we now watch the cluster recede in the rearview mirror? Hopefully. But as far as clusters go, the experts say a few more years will have to go by without new cases to consider this devastating medical mystery officially over.

Those were intense days in the news business back in 2000. The cluster peaked with nine new cases that year on its way to a total of 16. I've been here since 1997, not long enough to be extended an invitation to the good ol' boys club, but I endured the entire media frenzy.

They came from all corners for a juicy story, a thick-cut prime rib of a scoop. They showed up in rented cars with laptop computers. They wanted background on the cluster, contacts and a fresh angle to chew on. For them, it was a huge public health story happening in somebody else's town. For us, we were in the midst of a vortex.

You couldn't win with the vociferous critics on both sides. Some said the near daily news coverage was damaging to business and accused the media of sensationalism. Others said the media was happy to be spoon fed the "official" investigation and played lackey to an alleged coverup.

Everyone had a theory about what caused the childhood cancer, from electromagnetic pulses to chemical trails in the sky spewed by military jets as part of some diabolical plot. The caller could not fathom why nobody pursued this grand conspiracy. As a reporter at the time, I heard my share of news "tips."

If you're thinking about getting into this business, the unabiding news sense you ought to develop is the public has a right to know, both the good and the bad. Let that be your compass as gale force winds blow from every direction.

In the two years since the last case the cancer cluster has grabbed the headlines less frequently. State health officials monitor the situation these days rather than actively investigate. Explosive growth is on the horizon everywhere you look and there's nary a mention of leukemia or arsenic around town.

Two years without a new leukemia case is not much consolation for the parents of Adam Jernee, Stephanie Sands and Timothy Wayne Schweble. They face painful personal anniversaries only those who have lost children can begin to imagine. Jernee died at age 10 in June of 2001, Sands was 21 when she died in September of 2001, and Schweble succumbed to cancer at the age of 22 in August 2002.

Steve Lyon is editor of the Lahontan Valley News

Presidential Symposium: Genetic Predisposition to Leukemia CME

Beverly Lange, MD

Introduction
The short list of constitutional disorders characterized by germline mutations that predispose children to leukemia includes Down syndrome, neurofibromatosis type 1, Noonan syndrome, Fanconi anemia, Nijmegen breakage syndrome, Seckel syndrome, Shwachman-Diamond syndrome, familial platelet disorder, Kostmann syndrome, and Bloom syndrome. With the exception of Down syndrome and neurofibromatosis type 1, which occur in about 1/700 and 1/3000 live births, respectively, these disorders are all quite rare. However, the risk of leukemia in these individuals is exceedingly high, ranging from 1 in 3 for Shwachman-Diamond syndrome to roughly 1/200 in neurofibromatosis type 1, compared with 1/2200 for constitutionally normal children.[1]

The study of these rare disorders is important both for the management of affected children and for our understanding of the pathogenesis of leukemia. For example, the response to cytotoxic therapy by children with constitutional disorders often differs from that of constitutionally sound patients. Indeed, the blasts in megakaryoblastic leukemia in patients with Down syndrome have exquisite sensitivity to cytosine arabinoside, and the disease has a cure rate about twice as high as acute myeloid leukemia (AML) in other children. By contrast, methotrexate L-asparaginase and other standard medications used to treat acute lymphoblastic leukemia (ALL) lead to excessive, sometime life-threatening toxicity. Similarly, patients with Fanconi anemia with AML cannot tolerate standard AML therapy due to the sensitivity of their hematopoietic and gastrointestinal cells to alkylating agents.

It appears that germline mutations in patients with these disorders are frequently the same mutations acquired somatically in the leukemic cells of normal hosts. Investigation of the pathogenesis in these disorders has provided clues to the pathogenesis of not only de novo leukemia but also of other forms of cancer. A symposium highlighting the ongoing research in these fields was held at the 17th Annual Meeting of the American Society of Pediatric Hematology/Oncology (ASPH/O). The findings are discussed below.

Inherited and Acquired Disorders of RAS Pathway Activation in Myeloid Malignancies
Kevin Shannon, MD,[2] from the University of California, San Francisco, presented ongoing findings from his work on genetic mutations. Neurofibromatosis type 1 is a dominantly inherited cancer predisposition disorder caused by mutation of the NF1 gene on chromosomal band 17q. Half of the patients with neurofibromatosis inherit the disease from one of their parents, and the other half developed a mutation in the NF1 gene. Children, but not adults, with neurofibromatosis type 1 are prone to develop myeloid malignancies, including AML, myelodysplastic syndrome (MDS), or juvenile myelomonocytic leukemia (JMML). Dr. Shannon's laboratory has shown that in children with inherited neurofibromatosis type 1 and AML, MDS, or JMML, the NF1 allele in the leukemia is invariably the abnormal allele from the parent with neurofibromatosis type 1; the normal NF1 from the other parent allele has been inactivated by somatic mutation. These studies support the hypothesis that NF1 acts as a tumor suppressor gene.

Subsequent studies from Dr. Shannon's laboratory have demonstrated that in leukemic cells, the mutated NF1 allele codes for a nonfunctional truncated form of the neurofibromin, the gene product of NF1 that regulates activity of the RAS oncogene on chromosome 11. RAS is the gene most frequently mutated in all human cancer; most tyrosine kinase receptor growth factor signaling is transduced through RAS. When a growth factor binds a receptor on the cell's membrane, the signal is transmitted inside the cell to Sarc homology phosphatase 2 (SHP-2) or related proteins. SHP-2 is a tyrosine phosphatase that transduces signals downstream of growth factor receptors through RAS to stimulate proliferation, differentiation, and migration. SHP-2 transduces the RAS-GTPase-activating protein (GAP) that binds to the tyrosine phosphoprotein residue. Thus, GAP regulates RAS, while RAS protein functions as a switch. When GAP is in the active GTP phosphorylated configuration, it turns on RAS, which permits signal transduction to proceed downstream to allow cell proliferation. Neurofibromin switches RAS to the off position by restoring the GAP protein to the inactive GDP form. Mutated forms of neurofibromin cannot downregulate RAS -- and thus allow cell proliferation to proceed unchecked.

Somatically acquired RAS mutations occur in 20% to 40% of myeloid malignancies, including MDS and myeloproliferative syndromes (MPS). JMML is characterized by leukocytosis with a monocytosis and hepatosplenomegaly, and it comprises 1% to 2% of cases of childhood leukemia. The hallmark of JMML is that, in vitro, the leukocytes manifest an exaggerated proliferative response to granulocyte-macrophage colony-stimulating factor (GM-CSF). According to Dr. Shannon, about 25% of patients with apparent de novo JMML have acquired RAS mutations in their leukocytes. However, infants with neurofibromatosis type 1 and JMML never have RAS mutations, probably because the NF1 mutation and RAS mutation are redundant: either mutation allows the cell to proliferate unchecked.

Children with Noonan syndrome also develop JMML. Noonan syndrome is caused by dominant inheritance of a mutation of PTPN11. PTPN11 encodes SHP-2. It has been found that in about 30% of cases of JMML patients who do not have either NF1 or Noonan syndrome, PTPN11 is somatically mutated.[3] Thus, dysregulation of RAS can be accomplished by NF1 mutation, PTNP11 mutation, or RAS mutation. Dysregulation of RAS is central to the pathogenesis of JMML.

Dr. Shannon's laboratory uses several murine models to examine how hyperactive RAS favors the development of MPS. When a mouse with one mutant NF1 allele is treated with cyclophosphamide, it develops MPS. The homozygous NF1 mutation is lethal; however, when cells from the fetal liver of a homozygote are implanted into a lethally irradiated host, the mouse develops MPS. The Mx1-Cre strain mouse is an NF1-conditional mutant in which NF1 can be activated and inactivated. When it is inactivated, the mice develop MPS. Related experiments with introduction of an activated mutated K-RAS allele into the Mx1-Cre strain mouse leads to an aggressive MPS with cells hypersensitive to GM-CSF. These studies reinforce those done in patients showing that hyperactivity of RAS underlies the hypersensitivity to GM-CSF, as well as the subsequent unrestrained proliferation characteristic of JMML and other MPS.

Myeloid Leukemia in Down Syndrome
John Crispino, PhD, of the University of Chicago in Illinois,[4] reviewed some of his findings on mutations predisposing to leukemia among children with Down syndrome. Children with Down syndrome are at risk of developing 3 distinct leukemia disorders: ALL, transient myeloproliferative disorder (TMD), and AML. Down syndrome patients comprise 1% to 2% of children with ALL and over 10% of those with AML. AML in patients with Down syndrome is typically acute megakaryoblastic leukemia (AMKL) or erythro-megakaryoblastic leukemia. The risk of developing AMKL is more than 400 times greater in children with Down syndrome than in those without the disorder. TMD occurs in about 10% of neonates and young infants with Down syndrome and is also a megakaryoblastic proliferation. In the majority of infants, TMD spontaneously regresses within weeks or months. However, about 10% of Down syndrome infants with TMD go on to develop AMKL. It is not clear which genes on chromosome 21 predispose Down syndrome children to leukemia.

GATA1 is an X-linked zinc finger transcription factor that is involved in the regulation of erythroid and megakaryoblastic differentiation and proliferation. GATA1-deficient megakaryocytes are characterized by hyperproliferation, whereas germline mutation of GATA1 causes dyserythropoietic anemia and thrombocytopenia. These observations led Dr. Crispino to ask whether GATA1 regulation could be involved in the pathogenesis of AMKL in patients with Down syndrome. His laboratory found that in 6 of 6 Down syndrome patients with AMKL, the leukemic cells had somatically acquired GATA1 mutations. However, blast cells from Down syndrome patients with ALL, the rare Down syndrome patients with other forms of AML, and non-Down syndrome patients with AMKL did not have acquired GATA1 mutations. These findings have been reproduced and expanded in several other laboratories.

The next set of experiments in Dr. Crispino's laboratory showed that the leukemic cells also had the GATA1 mutations in 7 of 7 Down syndrome patients with TMD. When TMD regressed, the GATA1 mutation was not detectable. However, in the 10% of patients with TMD who later developed AMKL, the identical GATA1 mutation was present in the leukemic blasts. At this time, the demonstration of mutated GATA1 may be helpful in determination of Down syndrome mosaicism in a phenotypically normal child with TMD or AMKL. The molecular assay can be completed in a day, whereas karyotypes of fibroblasts or buccal cells may require weeks. However, the assay for mutant GATA1 is only carried out in research laboratories such as that of Dr. Crispino.

The gene product of mutated GATA1 in Down syndrome blasts is a truncated protein known as GATA1s. GATA1 and GATA1s bind DNA similarly, but GATA1s has decreased activity. In vitro, forced expression of GATA1 in a Down syndrome AMKL cell line leads to erythroid differentiation; GATA1s is incapable of stimulating differentiation in megakaryocyte progenitors.

GATA1 mutation has been found to occur in utero. In 4 Down syndrome children who did not have TMD but who developed AMKL, the Guthrie cards at birth showed GATA1 mutations. In a retrospective study, GATA1 mutations were found in 14% (11/79) of Down syndrome fetuses and in 2/9 fetal liver samples as early as week 25 of gestation. These findings suggest that GATA1 precedes the development of leukemia and may be an initiating event.

At this point, we do not know why this type of GATA1 mutation occurs only in Down syndrome patients, nor what events subsequent to GATA1 mutation are necessary to make AMKL a form of leukemia that requires therapy. Current experiments to explore the pathogenesis of AMKL are underway.

Fanconi Anemia
Alan D'Andrea, MD,[5] of Harvard University School of Medicine, Boston, Massachusetts, discussed mutations in Fanconi anemia, a group of related autosomal recessive disorders characterized by small stature, multiple congenital abnormalities, and mental retardation. Patients with Fanconi anemia develop progressive bone marrow failure early in childhood, and about 10% develop MDS or AML with monosomy 7 in adolescence. Other cancers, most often squamous cell carcinomas, appear in young adults. About a third of patients may be phenotypically normal, a few of whom are diagnosed retrospectively after developing extraordinary toxicity following treatment with alkylating agents or radiation therapy.

The standard diagnostic test for Fanconi anemia has been demonstration of chromosome fragility in the presence of cross-linking agents diepoxybutane (DEB) or mitomycin C (MMC). The fragility in fibroblasts or mitogen-stimulated lymphocytes is manifest as excessive numbers of chromatid and chromosome breakages, gaps, translocations, exchanges, and tri- and quadriradial forms. This chromosome fragility is the result of defective DNA repair, which forms the basis for the somatic abnormalities and cancer predisposition. The chromosome fragility assay in combination with cell fusion techniques led to the recognition of 11 complementation groups (FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, and FANCL), and, more recently, to the molecular cloning of 8 Fanconi anemia genes.

A breakthrough in our understanding of the pathogenesis of Fanconi anemia came when a technician in Dr. D'Andrea's laboratory diagnosed Fanconi anemia based on characteristic chromosome fragility in the MMC assay in a sample from a woman with breast cancer and BRCA2 mutation. This serendipitous finding showed that bi-allelic BRCA2 mutation leads to chromosome fragility identical to that of Fanconi anemia in this assay. With this discovery, Dr. D'Andrea's laboratory then demonstrated that cells from Fanconi anemia patients with FANCB and FANCD1 complementation groups actually have bi-allelic mutations in BRCA2 and express truncated BRCA2 proteins. Accordingly, complementation of FANCD1 fibroblasts with wild-type BRCA2 cDNA restores normal chromosome stability in the MMC assay.

These results implicate the cloned Fanconi anemia proteins and BRCA1 and BRCA2 proteins in a common DNA repair pathway, which also involves other genes known to be mutated in patients predisposed to develop leukemia. Ionizing radiation activates the NBSI gene, which is mutated in Nijmegen breakage syndrome, and ATM, which is mutated in ataxia telangectasia, to phosphorylate FANCD2 protein. The Fanconi complex puts a ubiquitin on the FANCD2 protein that goes to the nucleus to repair damage by homologous recombination. BRCA2 is downstream of FANC2 and plays a direct role in DNA repair through binding of DNA, RAD51, and regulation of homologous recombination.

At this point, the clinical correlates of the 11 Fanconi anemia complementation groups have not been defined. Studies on 4 children from 2 unrelated kindreds suggest that bi-allelic mutations of FANCD1/BRCA2 are associated with development of solid tumors at an early age and poor tolerance to cytotoxic therapy.

In kindred 1, a boy developed medulloblastoma at age 27 months and exhibited severe toxicity with chemotherapy. His brother developed a stage III Wilms tumor at age 15 months. He remained stable without treatment for 3 years, but then developed a medulloblastoma. In kindred 2, a boy developed a Wilms tumor at age 6 months and exhibited severe toxicity. A year later, he developed AML and died of toxicity. His sister developed T-cell ALL just before her fifth birthday, and is being maintained on reduced doses of antimetabolite therapy. None of the patients had evidence of marrow failure before development of their malignancies. Compared with studies in other patients with Fanconi anemia, cytogenetic studies in these children show excessive numbers of spontaneous chromosome breaks, as well as exaggerated breakage and radial formation in DEB or MMC preparations.

These and other studies make it clear that the DEB and MMC assay are not specific for Fanconi anemia. The assays may be positive in patients with BRCA mutations and disorders that are clinically similar to Fanconi anemia, such as Nijmegen breakage syndrome and Seckel syndrome. Indeed, the spectrum of cancer associated with mutation of FANC genes has turned out be considerably broader than appreciated a few years ago. Future studies will concentrate on more precise definition of the phenotype that accompanies each genotype, and on targeting therapy to the specific genetic defect.

References
Genetic Predisposition to Leukemia. Program and abstracts of the American Society of Pediatric Hematology/Oncology 17th Annual Meeting; April 29-May 2, 2004; San Francisco, California. Presidential Symposium.

Shannon KM. Nf-1, Noonan's and inherited and acquired disorders of RAS pathway activation in JMML, MDS, and AML. In: Genetic Predisposition to Leukemia. Program and abstracts of the American Society of Pediatric Hematology/Oncology 17th Annual Meeting; April 29-May 2, 2004; San Francisco, California. Presidential Symposium.

Tartaglia M, Niemeyer CM, Fragale A, et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet. 2003;34:148-150. Abstract

Crispino J. Leukemia in Down syndrome. In: Genetic Predisposition to Leukemia. Program and abstracts of the American Society of Pediatric Hematology/Oncology 17th Annual Meeting; April 29-May 2, 2004; San Francisco, California. Presidential Symposium.

D'Andrea AD. Fanconi anemia. In: Genetic Predisposition to Leukemia. Program and abstracts of the American Society of Pediatric Hematology/Oncology 17th Annual Meeting; April 29-May 2, 2004; San Francisco, California. Presidential Symposium.

Genes May Explain Leukemia Treatment Failures

Findings Could Lead to Better Treatment for Patients

By Jennifer Warner
WebMD Medical News Reviewed By Brunilda Nazario, MD

Aug. 4, 2004 -- A relatively small number of genes may determine whether leukemia treatment succeeds or fails, according to a new study.

Researchers in the U.S. and the Netherlands found the newly identified set of genes were linked to either resistance or sensitivity to the four cancer drugs commonly used to treat acute lymphobastic leukemia (ALL).

The results may help explain why, despite major recent advances in treatment, nearly 20% of children with leukemia still do not respond to treatment.

"We've known for years that certain genetic changes in leukemic cells are associated with a high risk of treatment failure," says researcher William Evans, PharmD, scientific director of St. Jude Children's Research Hospital in Memphis, Tenn., in a news release. "The findings of this study are helping us understand why patients respond differently to treatment and point to new approaches to overcome these causes of disease relapse."

The findings appear in the Aug. 5 issue of the New England Journal of Medicine.

Genes Linked to Drug Resistance

In the study, researchers tested leukemia cells from 173 Dutch children newly diagnosed with leukemia for sensitivity to four common chemotherapy drugs used in leukemia treatment.

Researchers found a particular group of genes that when present in leukemia cells determined their sensitivity or resistance to the four chemotherapy drugs. Of the 124 genes identified, 121 had not been previously associated with resistance to the four chemotherapy drugs tested.

The study also showed that these genes predicted treatment success or relapse in both the 173 Dutch children as well as another group of 98 children with leukemia who were treated with the same drugs at St. Jude.

"The gene expression patterns linked to drug resistance were particularly important since they occurred in both the Rotterdam and the St. Jude patient populations, even though these two groups of children were treated with these drugs in different countries and on different protocols," says Rob Pieters, MD, chair of pediatric oncology/hematology at Erasmus University in Rotterdam, the Netherlands, in the release. "This is strong evidence of the link between these resistance genes and treatment outcome."

Findings Will Lead to Better Treatment

In an editorial that accompanies the study, Naomi J. Winick, MD, of the University of Texas Southwestern Medical Center in Dallas, and colleagues say that these findings will lead to new, more targeted treatments for leukemia.

"The gene-expression patterns these authors describe can be used to begin to define the mechanisms of resistance and will stimulate the development of alternative treatment strategies, targeted to those with resistant disease identified at diagnosis," write the editorialists.

They say the identification of a gene profile that predicts the outcome of treatment would also allow treatment to be personalized early on and avoid use of unnecessary and ineffective drugs.

SOURCES: Holleman, A. New England Journal of Medicine, Aug. 5, 2004; vol 351: pp 533-42. News release, St. Jude Children's Research Hospital and Erasmus University Medical Center/Sophia Children's Hospital.

A crystal ball for cancer treatment?

Test aims to help determine best drug option
By Terri Somers
UNION-TRIBUNE STAFF WRITER
August 4, 2004

Jonathan Diver, the company's associate director of assay development, worked on blood samples that are seen through a microscope. He is developing tests the company hopes to market.

A tiny San Diego startup biotechnology company says it has a test that can identify whether expensive chemotherapy drugs would work on a patient with leukemia, which could improve treatment options and lower costs.

Genoptix recently received the state and federal licenses that allow it to begin selling one of its chemotherapeutic response tests. The company will first use it for people diagnosed with chronic lymphocytic leukemia and plans to later expand its services to other types of cancer.

Genoptix chief executive Tina Nova calls the test a pioneering step in the concept of personalized medicine treating a patient based on their unique genetic makeup as opposed to using a general treatment for a disease.

The test can show whether expensive and promising chemotherapy drugs, such as Rituxan or Gleevec, will work on a specific patient, or whether a doctor should instead prescribe another, less expensive course of treatment. The good news for Genoptix could portend bad news for biotechnology companies that make chemotherapy drugs and could see a reduction in their potential market.

"I think the general public thinks that all drugs work on all people," Nova said. "The truth is that most drugs only work on about half the people."

When a patient receives a chemotherapy that doesn't work, it can cause a reaction that makes the already ailing person even more sick, not to mention the psychological effects.

Studies have shown that if the primary round of chemotherapy is toxic to a patient without providing any benefit, that person becomes less receptive to drugs that otherwise might have worked. One study shows that leukemia patients who first receive a drug to which they are resistant had a survival rate of less than one and a half years less than people who received no treatment at all.

Meanwhile, patients who were receptive to the drug and received it as their first treatment had a survival curve stretching beyond six years.

While developing the test, Genoptix researchers talked to dozens of hematologists and oncologists about how they decide which drugs to use in treating leukemia patients, Nova said. Typically the doctors make their decision based on statistical data surrounding the type of leukemia, the success of different drugs in treating it and the patient's age and condition, she said.

'Roll of the dice'
"It's basically a roll of the dice," Nova said.
The company's sales staff, and most of its top executives, now are trying to convince physicians to use the Genoptix test to help determine the best course of treatment.

So far it's been a tough sell because doctors generally haven't been impressed with other companies' attempts to create a test to determine sensitivity to cancer drugs.

The need for such a test is essential, said Dr. Fred Millard, director of UCSD Cancer Center's clinical trials office. He is not familiar with the Genoptix test.

"There are currently a lot of drugs in use that work only in a minority of patients, so you end up treating the majority of people with drugs that aren't going to help," Millard said. "And you have no way of knowing ahead of time which is which."

But the predictive accuracy of previous tests hasn't been good enough, Millard said.

Part of the problem, Millard said, is that these tests are performed in a petri dish outside the body. All of the biological forces that may come to play in the body may not come to play outside the body, he said.

Another problem is that previous tests involve growing more of a patient's cancer cells in a petri dish for testing. The cells do not represent exactly what is inside the patient.

Nova said the Genoptix test doesn't involve growing a larger cell culture. It can be used on the smallest sample of cells, such as those retrieved through a fine-needle biopsy, she said.

The company tests the samples in its state and federally approved lab in San Diego.

Nova said clinical data supports the test's efficacy. She points to a 1999 study by Dr. Andrew G. Bosanquet, published in the British Journal of Hematology, which includes data showing their type of test is an effective predictor. A larger study is now under way, also in the U.K., Nova said.

Another consideration for doctors is cost and whether insurers will pay for a test. Nova said insurers are covering the test for up to seven drugs on a sample, though the company has the ability to test for 21 drugs.

Founded three years ago, Genoptix studied cells from several types of cancer, including leukemia, breast cancer and lung cancer. It found each cancer type had a unique cellular signature.

Then they tested known cancer drugs on the diseased cells and recorded what happened. The result was that their test could determine the effect of the drugs earlier than many other tests, Nova said.

With a staff of 34, Genoptix executives knew they would have to concentrate on one segment of the cancer market. While there are tests available for other cancers such as breast and lung, the company thought the leukemia market was underserved.

So far many of the company's customers are oncologists who have tried different courses of treatment on patients with no success and hope Genoptix might give them a clue, Nova said.

The company's goal, however, is for doctors to use the test before determining a treatment plan. It also is hoping drug companies will use its tests in clinical trials to identify groups of patients that should be receptive to a drug candidate, Dr. Michael Nerenberg, Genoptix's medical director, said.

Patient education
Educating patients about the tests may be one way to generate doctor interest.
"It just makes sense," said Ted Wilcox, a member of the Leukemia and Lymphoma Society of San Diego.

Wilcox, 50, has acute myeloid leukemia. He received a bone marrow transplant last fall after two rounds of somewhat successful chemotherapy. Before the transplant, his doctors were weighing whether to give him another round of chemotherapy drugs or radiation in preparation for the procedure.

"To be able to have a test so that doctors can say, 'yeah this will work on him so he doesn't need radiation,' would have offered me some peace of mind," he said.

He's known other people with leukemia who received the "standard course of treatment" for their disease only to discover they weren't receptive to the drugs.

"There's not many of them around anymore," he said.

Millard, of UCSD, and other oncologists think the timing may be right for such an effective predictive test, especially with the new drugs such as Rituxan, made by Biogen-Idec, that can be lifesavers for some patients but only a percentage of those who take it.

"If anything, Rituxan is an example of a drug that has probably been overutilized because it's reimbursed (paid for by insurers) and it is a money generator for private treatment facilities. So what's the incentive to show whether it would not be effective on someone?" Millard said.

Drug makers have done little to identify which groups of patients would have success with their therapies, Dr. Bruce A. Chabner, head of Massachusetts General Hospital Cancer Center's Division of Hematology and Oncology, wrote in the most recent issue of the New England Journal of Medicine. He specifically referred to Iressa, a treatment for patients with advanced non-small-cell lung cancer that worked in 10 percent to 15 percent of patients.

Tests like the one from Genoptix would help avoid the medical and financial cost of ineffective therapies, Chabner wrote. "Wasting time with ineffective therapies may entail the loss of a window of opportunity for patients with cancer to receive an effective treatment."

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Terri Somers: (619) 293-2028; [email protected]

Iraqi doctor learns from Hiroshima's past

Shinya Ajima and Shinsuke Takahashi

HIROSHIMA An Iraqi doctor left his war-battered country in April. His destination was Hiroshima, and the purpose of his trip was to obtain knowledge and data on radiation effects in the city once devastated by the first atomic bombing in the world.

Hussam Mahmood Salih, 34, a pediatrician from Basra, said the number of child cancer cases jumped eightfold in the southern Iraqi city between 1988 and 2002, suspecting it was caused by the 1991 Gulf War, in which U.S. forces used depleted uranium shells.

There are also reports in Iraq about newborn babies lacking limbs or craniums. Depleted uranium has been long blamed for such birth defects in babies believed exposed to radiation while in the womb.

"We don't have any decent facilities in Iraq to check the amount of radiation in human bodies. But we can see the incidences of cancer increased greatly during the first four to five years of the 1990s," said Salih, now studying at Hiroshima University Hospital at the invitation of a Japanese civic group.

Under economic sanctions on Iraq that followed the war, Iraqi hospitals were prohibited from obtaining essential drugs as well as new medical equipment like tools for radio therapy because the international community feared they might be used for military purposes, he said.

"So, death and disease, and death and disease...this is the life of people in Iraq. I want to save Iraqi children," said Salih.

The U.S. military uses depleted uranium-tipped shells, known for their armor-piercing capability, against tanks and other hard military targets.

Although Iraqi doctors allege DU weapons cause leukemia and cancer, U.S. authorities deny direct links between DU and the cancer on the rise in Iraq since the 1991 war.

The medical community in Japan, a U.S. staunch ally, is also reluctant to admit a connection.

"Even so, it is sensible for him to visit Hiroshima, which has skills and knowledge on treating leukemia patients," said Atsuko Oe, a representative of Save the Iraq Children Hiroshima, the group that arranged Salih's visit.

In August last year, when some Iraqi doctors visited Japan to deliver lectures, they asked Oe and other civic group members to look for Japanese medical institutions that can train young doctors from Iraq.

Universities in Hiroshima and Nagoya then agreed to accept some doctors from hospitals in Basra through the civic groups.

Salih said he had never hesitated to come to Japan when chosen as a trainee due to his background as an expert on pediatric leukemia.

His visit apparently exposed a new face of Japan as the sole A-bomb victim in the world.

"Hiroshima had suffered a lot from war, deaths and radiation effects, and the Japanese doctors understand about these diseases...and all strategies about detection, treatment and follow-up. I think we cold learn very much from Japan's experiences," said Salih.

He added there are more Iraqi doctors hoping to learn in Japan and bring back advanced techniques, knowledge and equipment that have been unavailable to Iraqis.

"This is a great chance, a very nice chance. They could do better to save patients," he said.

Another civic group invited two other Iraqi doctors for training at Nagoya University Hospital, as well as a young patient whom Salih has treated.

The United States attacked Hiroshima with an atomic bomb on Aug 6, 1945, and dropped another on Nagasaki three days later. Japan surrendered to Allied forces Aug 15.

The bomb dropped on Hiroshima contained high quantities of highly enriched uranium. There are reports that a number of microcephalic babies were born in the western Japan city after the bombing, Oe said.

Salih is learning from Japanese professors at the university hospital, mainly about chemotherapy and bone-marrow transplants.

He has been given access to data stored in many facilities and organizations in this city, and has opportunities to talk with radiation victims as well as their families.

He is also going to attend the ceremony for the 59th anniversary of the bombing of Hiroshima next month.

"We wish Mr Salih could learn something by referring to the stored data and comparing them with those kept in Iraq," Oe said.

Salih will stay in Japan until the fall and return to Iraq, where his wife and two children live.

Governments in Hiroshima and Nagasaki are concerned about the aging of A-bomb victims. Their average age was 72.2 as of March, and thousands of the registered radiation victims die every year.

Both cities are forced to take measures to leave the victims' messages and experiences of the atrocities to succeeding generations.

Salih's stay in Hiroshima shows how Japan should be the first and hopefully last country of A-bomb victims in the world by taking on new roles no other country can undertake, Oe said.

"Each of us has our own role," she said, adding, "If we did not act, there would be a third following Hiroshima and Nagasaki. It is important for us to think how individuals can be involved in peace or antinuclear activities." (Kyodo News)

August 4, 2004

Court notice on cancer drugs marketing rights:

[India News] New Delhi, Aug 6 (IANS) :

The Supreme Court Friday issued notices to the central government and others on a petition alleging that price of a drug for treatment of cancer would spiral if its exclusive marketing rights were awarded to a particular company.

A bench comprising judges Y.K. Sabharwal and D.M. Dharmadhikari issued notices to the centre, the Drug Controller of India, Controller General of Patents and National Pharmaceutical Pricing Authority on the petition against granting exclusive marketing rights to the Swiss pharmaceuticals major Novartis AG.

The court also issued notice to Novartis AG and its Indian firm Novartis India Limited on the petition filed by the Cancer Patients Aid Association (CPAA).

CPAA challenged the grant of marketing rights to Novartis of the drug Gleevec, containing crystalline form of a compound Imatinib Meyslate, used in treating patients suffering from Chronic Myeloid Leukemia -- a life-threatening form of cancer.

As a result of this, Gleevec prices would go up from the present Rs.4,000 to Rs.120,000, the petitioner alleged.

It said an overwhelming majority of 24,000 patients who suffered from Chronic Myeloid Leukemia every year in India would die, as the drug would become unaffordable for most people.

The petitioner said since it was an essential life-saving drug, the centre should exercise its powers in public interest and fix its price so that patients can afford it.

Scientists find gene expression pattern may predict behavior of leukemia

11 Aug 2004

The expression pattern of certain genes may someday help doctors to diagnose and predict whether or not an individual has an aggressive form of B-cell chronic lymphocytic leukemia (CLL), Jefferson cancer researchers have found.

Scientists, led by Carlo Croce, M.D., director of Jefferson's Kimmel Cancer Center and professor and chair of microbiology and immunology at Jefferson Medical College of Thomas Jefferson University in Philadelphia, looked at the expression of genes that encoded microRNAs (miRNAs), tiny pieces of genetic material that are thought to be important in the regulation of gene expression and in the development of cancer. MiRNAs can serve as stop signs for gene expression and protein synthesis, and are thought to play important roles in regulating gene expression in development.

Reporting in both the online and the August 10 print version of the Proceedings of the National Academy of Sciences, the researchers taking advantage of a microarray chip Dr. Croce and his colleagues designed that carries all the known human miRNA genes compared the expression of miRNA genes in human CLL samples with that of normal white blood cells, or lymphocytes, called CD5+ B cells. CLL, the most common adult leukemia in the Western world, is characterized by an abnormal increase in the number of B cells.

"We found two specific genetic signatures," Dr. Croce says. One expression pattern of miRNA genes in CLL correlated with a deletion of a chromosomal region called 13q14. This region contained two small miRNA genes that are turned off in about 60 percent of CLL cases. The deletions at 13q14 represent an indicator of a good prognosis for the disease, he notes.

The other miRNA signature was associated with mutations in the Ig or immunoglobulin gene, which also indicates a good prognosis, says Dr. Croce. The researchers also found that the expression of one of the miRNA genes, miR-16, was reduced in both signatures.

"This suggests that CLL involves changes in miRNA, and that you can predict the behavior of CLL depending on the miRNA genetic signature," says Dr. Croce. "We think we might be able to predict CLL behavior based on the miR-16 signature because that is the only common denominator between the two signatures with good prognosis." But before using miRNA expression as any kind of clinical biomarker, says Dr. Croce, the results need to be verified in a clinical trial screening thousands of patients.

Dr. Croce and his colleagues had previously shown that deletions in miRNA genes were involved in B-cell CLL. They also had reported that human miRNA genes are frequently located at sites of the genome that are altered in human cancers.

The work might enable scientists to gain a better understanding of the roles of miRNAs in cancer and provide targets for future drug development.

Contact: Steve Benowitz
[email protected]
215-955-5291

Phyllis Fisher
215-955-6300
215-955-6060 (After Hours)

Thomas Jefferson University

August 11, 2004
Leukemia stem cells identified by Stanford researchers

A handful of leukemia cells constantly replenish the supply of cancerous cells, according to new work by Stanford University School of Medicine researchers. These self-renewing cells, called cancer stem cells, are the ones chemotherapy must wipe out in order to eliminate the disease. Treatments that destroy these cells could more effectively eliminate cancer, Stanford says.

Current treatments destroy cancer cells indiscriminately, draining the reservoir of cancer cells without specifically eliminating the cancer's source. "We were missing the boat because we were targeting the wrong cell," says Catriona Jamieson, instructor in hematology and first author of the paper.

Other researchers have found cancer stem cells in acute myelogenous leukemia, breast cancer and two types of brain cancer. The current work, published in the Aug. 12 New England Journal of Medicine, is the first to describe these cells in chronic myelogenous leukemia. This is also the first time researchers have identified which cell becomes cancerous, transforming from a normal healthy cell to a cancer stem cell.

Cancer Stem Cells Hint at Cure

By Kristen Philipkoski
Aug. 11, 2004 PT

Researchers have discovered cells that continually replenish leukemia tumors. Killing these infinitely renewing cells could be key to halting the disease.

A genetic mutation causes the leukemia cells to divide out of control and allows tumors to grow, according to research published in the Aug. 12 issue of the New England Journal of Medicine. Previously, no one knew the exact identity of these cells.

Isolating these so-called cancer stem cells paves the way for creation of drugs to target them. Specifically destroying leukemia's stem cells -- the source of the cancer -- could eliminate the disease better than treatments that randomly kill cancer cells.

The work provides opportunities for pharmaceutical companies to investigate drugs that could inhibit the development of cancer stem cells, said Irving Weissman, a stem-cell researcher at Stanford who contributed to the study.

The study focused on the stem cells that lead to chronic myelogenous leukemia. In recent years, researchers have discovered several similar stem cells, including those behind acute myeloma leukemia, two brain cancers and breast cancer. Finding cancers' stem cells is a rapidly growing area of research, Weissman said, and it will be a main focus of the Institute of Cancer and Stem Cell Biology, which he heads at Stanford. The institute was established in December 2002 through an anonymous $12 million donation.

Cancer stem cells make up only a tiny number of the total cancer cells in a leukemia patient, which makes the cells next to impossible to find. In order to grow a larger number of them, the researchers took samples from healthy patients and from patients with chronic myelogenous leukemia. They separated the various types of leukemia cancer cells into separate dishes to find which ones could replenish themselves -- an indication that they are likely cancer stem cells. Further tests confirmed they had found the cells they were looking for.

The promise of this line of research can only be realized, Weissman said, by studying adult stem cells as well as embryonic stem cells, which are controversial because an early embryo is destroyed when researchers remove stem cells from it. While in this study volunteers could provide samples, that won't be the case for all types of disease. An alternative is to take the stem cells from embryos that carry a genetic defect for specific diseases.

"There are whole areas of tissues you can't get at, but which human embryonic stem cells almost certainly will develop daily," Weissman said.

Scientists at the Reproductive Genetics Institute, a private clinic in Chicago, are also studying stem cells to discover the origins of disease. They have isolated 12 new stem-cell lines from genetically flawed human embryos, providing stem cells that will specifically develop seven diseases, including two forms of muscular dystrophy, thalassemia, Fanconi anemia, fragile X syndrome, Marfan syndrome and a type of neurofibromatosis. Couples undergoing in vitro fertilization donated the embryos after the clinic performed prenatal genetic screening.

The Chicago clinic funded the research privately. President Bush declared on Aug. 9, 2001, that only research on existing stem-cell lines would qualify for federal funding. He said at the time that 64 stem-cell lines were available. Today, the National Institutes of Health lists 21 lines that are available for federal funding.

Increased Diesel Exhaust Exposure Increases Risk Of Ovarian Cancer

NEW YORK AUG 13, 2004 (Reuters Health) - The risk of ovarian cancer, but not esophageal or testicular cancers, increases with increased exposure to diesel exhaust, according to a new study in the August 20th issue of the International Journal of Cancer.

"Occupational exposure to diesel exhaust has been classified as probably carcinogenic and that to gasoline engine exhaust as possibly carcinogenic to humans," Dr. Johannes Guo, of the Finnish Institute of Occupational Health, Helsinki, Finland, and colleagues write. "Earlier results concerning cancers other than lung cancer are scarce and inconsistent, and exposure-response relations have seldom been reported."

The researchers assessed the risk of leukemia and cancers of the esophagus, ovary, testes, kidney, and bladder associated with engine exhaust. They followed a cohort of active Finns born between 1906 and 1945 for 30 million person-years during 1971 to 1995. A record linkage with the Finnish Cancer Registry was used to identify incident cases of esophageal cancer (n = 2198), ovarian cancer (n = 5082), testicular cancer (n = 387), kidney cancer (n = 7366), bladder cancer (n = 8110), and leukemia (n = 4562).

A job-exposure matrix was used to convert occupations from the population census in 1970 to exposure to diesel and gasoline engine exhausts. The team calculated cumulative exposure (CE) as product of prevalence, level and estimated duration of exposure.

There was an increased risk ratio (RR) for ovarian cancer with increasing CE to diesel exhaust (p = 0.006). The RR was 3.69 in the highest CE category. The RR was significantly increased only in the middle CE category for gasoline engine exhaust (RR = 1.70).

"A significant increase of the RR (1.17) was found for kidney cancer among men with the lowest CE levels to diesel exhaust, but there was no increase at higher exposure levels," Dr. Guo and colleagues write. "An excess of bladder cancer was observed only at the lowest level of exposure to gasoline engine exhaust."

"In conclusion, our study suggests a positive exposure-response relation between occupational exposure to diesel exhaust (or a factor related to diesel exhaust) and ovarian cancer," the authors conclude. "Our results do not support previous findings suggesting an association between engine exhausts and risk of esophageal, testicular, kidney, or bladder cancers, or that of leukemia."

SOURCE:

International Journal of Cancer 2004;111:286-292.

Health Watch Chronic Leukemia

August 16, 2004 --

Ben Swann-KFOX Morning News Anchor/Reporter

It's been 5-years since the cancer drug Gleevec was introduced in clinical trials to treat a Chronic Leukemia. Gleevec was so successful, that it received one of the fastest approvals ever for a cancer therapy. Now researchers are studying it's application in other cancers.

You'd never know looking at him now that 4-years ago, Ken Geihsler was fighting for his life. He was diagnosed with chronic myelogenous leukemia, or CML. After six months on interferon, his disease was progressing and he was suffering side effects. All that changed when he entered a clinical trial at M. D. Anderson Cancer Center studying Gleevec.

Ken Geihsler-Patient: "I've been on the study four years. The results have been fantastic, as far as I'm concerned. I don't even feel like I'm sick. In fact, people keep saying that there's no way that you can absolutely have cancer or have leukemia the way you look, the way you act, the energy you have and all the activities you are involved in."

Gleevec is what is known as a targeted therapy; in this case, a drug specifically designed to inhibit certain proteins involved in the development of CML.

Dr. Hagop Kantarjian-M. D. Anderson Cancer Center: "It's like a magic bullet that removes the protein that causes the cancer cells to become cancer and to progress, and so by removing the feeding system or the protein, those cancer cells die, and the normal cells come back. So, in the past, we talked about an average survival in CML of 3 to 5 years. Now, we estimate that the average survival is going to be 15 years and that perhaps half of the patients will have complete elimination of the disease."

The success of Gleevec in treating CML, demonstrated to researchers how effective targeted therapies can be in cancer treatment. The concept of targeted therapy is being studied in a wide range of cancers. Meanwhile, Ken whose 66-years-old, continues on Gleevec, with minimal side effects.

Ken Geihsler-Patient: "I certainly will not object to taking the Gleevec for the rest of my life."

If you would like more medical news, visit our health partners websites:

M.D. Anderson Cancer Center:http://www.mdanderson.org/

The Mayo Clinic:http://www.medicaledge.org

Baylor College of Medicine:http://public.bcm.tmc.edu/

New study suggests link between maternal diet and childhood leukemia risk

By Sarah Yang, Media Relations | 19 August 2004

BERKELEY A new study led by researchers at the University of California, Berkeley, suggests that women who eat more vegetables, fruit and foods containing protein before pregnancy may have a lower risk of having a child who develops leukemia, the most common childhood cancer in the United States.

The study, published in the August 2004 issue of Cancer Causes and Control, is the first time researchers have conducted a systematic survey of a woman's diet and linked it to childhood leukemia risk.

The researchers compared 138 women who each had a child diagnosed with acute lymphoblastic leukemia (ALL) with a control group of 138 women whose children did not have cancer. The children of all the women in the study, which is part of the Northern California Childhood Leukemia Study, were matched by sex, age, race, and county of residence at birth.

After comparing the women's diets in the 12 months prior to pregnancy, the researchers found that the higher the intake of vegetables, fruit and foods in the protein group, the lower the risk of having a child with leukemia.

"Fetal exposure to nutritional factors has a lot to do with what mom eats," said Christopher Jensen, a nutritional epidemiologist at UC Berkeley and lead author of the paper. "These findings show how vital it is that women hoping to get pregnant, as well as expectant moms, understand that critical nutrients in vegetables, fruit and foods containing protein, such as meat, fish, beans and nuts, may protect the health of their unborn children."

The few studies that have been conducted on maternal diet and childhood cancer risk looked only at specific foods or supplements, and results have been mixed. This study is the first attempt to capture a woman's overall dietary pattern - using a 76-food-item questionnaire - and its relationship to the development of leukemia in a child.

Although the researchers only surveyed the foods eaten in the year before conception, they point to studies showing that dietary patterns remain stable throughout the pregnancy.

"The general habits of what you like and don't like to eat are not likely to change during pregnancy," said study principal investigator and co-author Gladys Block, UC Berkeley professor of epidemiology and public health nutrition. "If you hated liver before you got pregnant, you'll probably hate liver while you're pregnant."

Within the fruit and vegetable food groups, certain foods - including carrots, string beans and cantaloupe - stood out as having stronger links to lower childhood leukemia risk. The researchers point to the benefits of nutrients, such as carotenoids, in those foods as potential protective factors.

"This finding is consistent with research about the benefits of a diet high in fruits and vegetables in preventing adult cancers," said Block. "The positive message here is that mothers may be able to transfer some of those benefits to their children."

The researchers also studied the use of vitamin supplements, but did not find a statistically significant link to childhood leukemia risk.

One of the more surprising results of the study is the emergence of protein sources, such as beef and beans, as a beneficial food group in lowering childhood leukemia risk.

"The health benefits of fruits and vegetables have been known for a long time," said Block. "What we found in this study is that the protein foods group is also very important."

The researchers looked further and found that glutathione was the nutrient in the protein group with a strong link to lower cancer risk. Glutathione is an antioxidant found in both meat and legumes, and it plays a role in the synthesis and repair of DNA, as well as the detoxification of certain harmful compounds.

National guidelines recommend that people eat at least five servings of fruits and vegetables every day, and two to three servings of foods from the protein group.

A growing number of scientists believe that genetic changes linked to cancer later in life begin in the womb. Prior studies on children diagnosed with leukemia have found that blood samples taken at birth tested positive for the same genetic markers that were later found in the cancer.

"It goes back to the old saying to expectant mothers, 'You're eating for two,' " said Patricia Buffler, study co-author, UC Berkeley professor of epidemiology and head of the federally funded Northern California Childhood Leukemia Study. "We're starting to see the importance of the prenatal environment, since the events that may lead to leukemia are possibly initiated in utero. Leukemia is a very complex disease with multiple risk factors. What these findings show is that the nutritional environment in utero could be one of those factors."

Other co-authors of the paper are Xiaomei Ma at the Yale University School of Medicine, Steve Selvin at UC Berkeley's School of Public Health and Stacy Month of Kaiser Permanente in Oakland, Calif.

Funding from the National Institute of Environmental Health Sciences helped support this study.

Auto Repair Shops Linked To Childhood Leukemia

French Study: Exposure To Benzene Emissions May Cause Illness

August 23, 2004
A new study shows a possible cause for some cases of leukemia -- living close to a gas station or auto repair shop.

French researchers believe benzene emissions are the reason for the link to leukemia. Workplace exposure to benzene has already been linked to adult leukemia.

The study by the French National Institute of Health and Medical Research showed that children living within 200 yards of a gas station or repair shop were four times more likely to develop leukemia. The study showed the risk increased the longer the child is exposed to the emissions.

Dr Charles Sawyers and colleagues at the University of California hope their treatment will help such people. The drug's safety still needs to be tested, they reported in Science. Glivec, or Gleevec in the US, works by homing in on the faulty enzyme that allows leukaemia cells to multiply out of control.

Dodging death

Cancer cells become resistant to Glivec by mutating to change the structure of this enzyme so the drug can no longer fit its target. Tests on mice showed an experimental drug BMS-354825 sidestepped this problem. It does not hold the target to such tight structural constraints as Glivec. This "sloppiness" means it can kill the cancer cells when Glivec cannot.

Dr Sawyers said: "We realised if we want to develop drugs that inhibit the mutants they need to be a little sloppier, less demanding in their binding rules." Laboratory tests on human bone marrow cells showed the drug stopped cancer cells growing that were resistant to Glivec. Some cells were resistant to both Glivec and BMS-354825, however. It's a significant development. Glivec resistance is something that has been worrying doctors

Leukaemia Research Fund spokesman

Fellow researcher Dr Neil Shah said: "In the future we may be combining therapies that can, amongst them, override all the resistance mechanisms that allow cancer to evade individual therapies. "Cancer may be treated similarly to HIV, with a cocktail of drugs," he said.

The researchers are conducting further tests to make sure the drug is safe in humans. A spokesman for Leukaemia Research Fund said: "This is obviously welcome news. It's a significant development. Glivec resistance is something that has been worrying doctors because it's the drug of choice. It is very effective." But he said the authors of the report had indicated that safety of the new drug had not yet been demonstrated, although current trials are addressing this issue.

Safety

"When they were first developing Glivec people were concerned that it might kill all the healthy cells as well as the cancer cells. Thankfully, this did not happen because Glivec is very targeted towards the cancer cells. "The new drug is less selective. It is sloppier and binds more readily to target molecules within the cell than Glivec.

"If you use a drug that is less exactly targeted there's a theoretical risk that it will cause damage to other cells. You have to demonstrate that you can use this drug safely," he said. He said studies have shown when some people who are resistant to Glivec stop the treatment for a few months the resistant cells become sensitive to Glivec again.

"If that's the case, it may be that when Glivec resistance develops you only need to switch to something else for a couple of months and then switch back to Glivec later when they are sensitive to it again," he said. Professor Junia Melo, professor of molecular haematology at Imperial College's Hammersmith Hospital London, has been doing similar research.

She said: "It's a very good piece of work. It's good news for people with chronic myeloid leukaemia. "We have been experimenting with a number of compounds similar to the BMS drug. "The beauty of this one [BMS-354825] is, like Glivec, it's a very soluble compound so you can think about an oral formulation," she said.

Paul Travers, deputy head of research at the Anthony Nolan Trust, said: "It's very interesting and attractive research which promised to help a lot of patients in the future. "However, it's some way to go for that promise to be realised and even if it does fulfil that promise, there will still be some patients that it will not treat. "In some cases, for example in very young children, the preference may be to have a bone marrow transplant," he said.

Eating broccoli with tomatoes protects from cancer much more than eating them separately

16 Jul 2004
Cancer researchers say we should eat foods together rather than on their own if we want better protection from cancer. Rather than eating your broccoli and tomatoes separately, you should eat them together.Mixed up compounds offer better protection, according to studies carried out on rats. Supplements will not work on their own to prevent cancer. The study was carried out at the University of Illinois, Urbana, USA.

Study leader, John Erdman, said "We decided to look at these foods in combination because we believed it was a way to learn more about real diets eaten by real people. Of course, it's important to analyze how specific food components influence our health, but such findings provide only the tools for further study. They should open the debate, not close it down,"

Tomatoes are thought to protect against prostate cancer because they contain lycopene. However, the scientists found that lycopene on its own offered much less protection (in rats). In this study the rats were given powdered tomato and/or dried broccoli. Some of the rats got a combination while others just got one or the other. Some of the rats also got finasteride. They were all injected with human prostate tumors.

The rats that were given both the tomato and broccoli combined had the smallest tumours. The ones to fare the worst were the ones that just got the finasteride. Erdman said "Separately, these two foods appear to have enormous cancer-fighting potential. Together, they bring out the best in each other and maximize the cancer-fighting effect.

New Drug Helps Kids Fighting Leukemia

Drug Protects Heart From Chemotherapy-Related Damage

July 7, 2004 -- For kids fighting leukemia, a new drug prevents heart damage often caused by chemotherapy. The drug, called dexrazoxane, targets harmful free radicals -- reducing or even preventing the often fatal heart damage that occurs from cancer therapy, new research shows.

The full report appears in this week's New England Journal of Medicine. It is being heralded as an "important step" in treating these children. Chemotherapy for childhood leukemia is a double-edged sword. The very treatment that is most effective against leukemia carries the threat of creating serious heart problems. Risk of death from heart damage is eight times higher for these kids -- and the risk continues even 25 years after leukemia treatment ends.

Not all kids who receive chemotherapy have this heart damage, but for many there are long-term problems that "are pervasive, persistent, and often progressive," writes researcher Steven E. Lipshultz, MD, a pediatrician with the University of Miami School of Medicine. Dexrazoxane is a free-radical scavenger drug that has shown promise in preventing injury to the heart, he writes. However, there has been some concern that the dexrazoxane may protect tumor cells from chemotherapy decreasing the tumor response to chemotherapy, he adds.

In his three-year study, Lipshultz tracked the progress of 206 children being treated at the Dana-Farber Cancer Institute in Boston. Half of the children were treated with the chemotherapy drug Adriamycin alone; the other children got both Adriamycin and dexrazoxane. Adriamycin is one of the most common cancer-fighting drugs used in children, and heart-damaging side effects are among the most frequent and serious side effects of these types of medications.

Researchers tested the children's blood before, during, and after treatment with adriamycin for troponin -- an elevated level is a marker for heart injury. Of those receiving the heart-protective drug dexrazoxane, only 21% had signs of heart damage, compared with 50% of children who didn't get dexrazoxane -- a significant difference.

Also, dexrazoxane did not dilute the effectiveness of the chemotherapy, at least in the short term, he adds. The study found no difference in survival; both groups of children had similar rates of remission. Longer follow-up will show how dexrazoxane finally plays out. Lipshultz's findings regarding dexrazoxane "is an important step" toward protecting these young hearts, writes Leontine C.M. Kremer, MD, PhD, in an accompanying editorial. Kremer is a pediatric oncologist with the University of Amsterdam.

Other strategies used to lessen heart damage -- such as using other chemotherapy drugs and lowering drug dosage -- are not always optimal nor are they fully tested. While more study is needed of the long-term effects on the cancer, dexrazoxane looks promising for heart protection, Kremer says.

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SOURCES: Lipshultz, S. New England Journal of Medicine, July 8, 2004; vol 351: pp 145-153. Kremer, L. New England Journal of Medicine, July 8, 2004; vol 351: pp 120-121.

Study May Reveal Cause of Fallon Cancer Cluster

July 6th, 2004
An Arkansas doctor hopes a genetic study reveals the cause of the cancer cluster in Fallon. 19 children have been diagnosed with leukemia in the area and 3 have died from the disease. Numerous, extensive studies have not been able to find the cause of the cluster, including one by the Centers for Disease Control.

The Arkansas Children's Hospital hopes to build on the CDC's study and focus on any genetic causes of the cluster. The CDC study found higher than normal concentrations of arsenic, antimony, tungsten, cobalt and uranium in the northern Nevada town, but found no single cause for the leukemia.

Childhood Leukemia Survivors Risk Genetic Damage from Therapy

Children who undergo chemotherapy and survive acute lymphocytic leukemia (ALL) experience a 200-fold increase in the frequency of genetic damage, researchers report.

July 1st, 2004
BURLINGTON, Vt. - Newswise Children who undergo chemotherapy and survive acute lymphocytic leukemia (ALL) experience a 200-fold increase in the frequency of genetic damage, researchers from the University of Vermont (UVM) College of Medicine reported in the July 1 issue of the journal Cancer Research.

According to Barry A. Finette, M.D., Ph.D., a professor of pediatrics at the UVM College of Medicine and Vermont Cancer Center member, the genetic changes that occur within the children's chromosomes following chemotherapy may elevate their risk for developing new cancers and other diseases later in life.

"The treatments that are used to help children defeat this disease are keeping a very large percentage of them alive," Finette said. "Pediatricians are continually monitoring these children as they live beyond five, 10, and more recently, 15 years after their ALL is in remission. We now need to be proactive about studying any long-term genetic ramifications that these children may face due to the treatment therapy they endured during their bout with cancer."

Finette noted that children who are cured of ALL after chemotherapy have five to 20 times' greater risk of developing new cancers, as well as other complications. Subsequent illnesses may be associated with increased changes in the patient's genes resulting from their treatments during ALL therapy.

Finette and his team of scientists examined the frequencies of alterations found within a marker gene in the blood cells of ALL patients at four intervals, between the times they were diagnosed until after they had completed their treatments. The treatment for ALL consists of a three-phase treatment that lasts about three years. The researchers estimated how frequently chemotherapy altered the DNA sequence by examining the number of T cells - a type of immune cell - in the patients' blood that contained mutations in the HPRT reporter gene. The HPRT reporter gene is a non-essential gene involved with DNA metabolism that is located on the X chromosome. It is often analyzed in the study of mutational events in humans.

The research showed that at the time of diagnosis, the blood of patients contained an average of 1.4 cells with HPRT mutations out of every million T cells, Finette said. By the time the patients completed the second phase of treatment, an average of 52 T cells per million cells contained HPRT mutations. By the final stage of treatment, an average of 93 of every million T cells had mutations in HPRT. After treatment was stopped, an average of 271 of every million T cells contained HPRT mutations, more than a 200-fold increase.

The study included 45 children with ALL who averaged 5.5 years of age at time of diagnosis. The number of HPRT mutations found in the patients at the time of diagnosis did not differ from healthy children of the same age, the researchers reported. The frequency of genetic mutations seen in children treated for ALL patients increased over the course of their treatments.

"These therapies have the potential to cause genetic damage to many different cell populations in their rapidly growing bodies," Finette said. "Because they have larger numbers of replicating cell populations during their growth and development stages than adults have, they are more susceptible than adults to genetically toxic effects of the chemotherapies."

ALL is the most common childhood cancer, but most ALL patients respond well to chemotherapeutic interventions. Since the 1960s, the five-year survival rate for children with ALL has increased to almost 80 percent. Patient remission and long-term survival is credited to the development of national standardized chemotherapeutic treatment protocols. More than 70 percent of ALL children less than 20 years of age and 85 percent of children less than 15 years old participate in the standardized ALL chemotherapy treatment regimes.

"Because of the effectiveness of the treatment employed today, we are able to give many more children a chance for a long life without cancer," Finette said. "Our studies are aimed at enabling us to better understand further challenges that we may face in keeping these patients healthy as they get 10, 15 or more years out from overcoming ALL."

In addition to Finette, the senior investigator of the study at UVM, other investigators included Sederick Rice, Ph.D., a 2004 UVM doctoral degree recipient who led the study; Pamela Vacek, Ph.D., biostatistician in medical biostatistics and research assistant professor of pathology; Alan Homans, M.D., associate professor of pediatrics; Terri Messier, senior researcher in the Vermont Cancer Center; Jami Rivers, formerly of the Vermont Cancer Center; and Heather Kendall, a graduate student in the department of microbiology and molecular genetics.

Family members - grandparents, uncles, aunts and cousins - have been tested with no luck. Now the only birthday present Vince Panetta, 40, wants to give his beloved wife of 18 years is the gift of life. He has scraped together every cent the family has to offer the reward and has begged every Victorian adult to be tested.

"I would give a million dollars if I had it," Mr Panetta said, his voice breaking with emotion. "Desperate times require desperate measures and I'm desperate. "I'm not giving up. I refuse to give up. I will do whatever it takes to save my wife. "I would give my arm, or my leg, or my sight to save her. "I'd do it without even thinking twice about it." Victorian state law prohibits payment for human tissue, including bone marrow, but allows for the payment of reasonable expenses incurred in taking the tissue.

Mr Panetta said he expected the money, if accepted, to cover the cost of lost wages, medical and other expenses for the donor of up to $10,000. Ms Panetta received the terrible news of her leukemia after visiting her family doctor on December 3 last year because of a sore back. Within hours, she was on a drip in the Peter MacCallum Cancer Centre preparing for chemotherapy.

"I couldn't believe it. I thought 'they've got the wrong person'," Ms Panetta said. "I've never been sick a day in my life. This all has to be a dream." Chemotherapy initially put the cancer into remission but the Panettas received a devastating blow last week when tests showed it was back. This time, doctors hold little hope that chemotherapy will work.

"I tend not to think about it. I've got a lot to lose. I don't want to not have Vince and the kids," Ms Panetta said, her voice quavering. "I want to see my kids grow up. I want to dance at their weddings and see them have kids. I'm only 37.

"You're not meant to die at 37. But I won't let it get me down, I won't. When you're dealt lemons, you've got to make lemonade." Mr Panetta said he couldn't imagine life without his soul-mate and the mother of his children. "I go every Sunday to St Pat's. I light candles. I pray very hard. I've got to be strong for the kids and for Josie but my heart is breaking. I only wish it was me," he said.

He said he found it heartbreaking to try to discuss the predicament with their children Dani, 15, Stephanie, 11, and Joseph, 7. "I don't want to have to say 'mummy's in heaven with Jesus'. How do we tell them? We can't tell them. We've got to beat this. It's the only option," Mr Panetta said through his tears. "Josie is the most beautiful person. She's the most generous person, the kindest person. She puts Christmas presents under the tree at K mart for poorer kids.

"She'd be the first in line if someone else was in her place. She's a lady. And she's a wonderful mum." He begged all Victorian adults to contact their local doctor or the bone marrow registry today and be tested. "I know there is someone out there that has to be a genetic match for Josie. I've just got to find them," he said. "It could be anyone. It can be the person next door or the next suburb, or an Eskimo. It could be you. Please help us." PEOPLE interested in becoming bone marrow donors should contact the Australian Red Cross blood service on 9694 0101.

Leukemia Drug Side Effects Worse When Vitamins Low

Mon Jul 5, 2004
NEW YORK (Reuters Health) - Findings from a new study suggest that kids with leukemia do not take enough antioxidant vitamins, which raises their risk of side effects during chemotherapy.

Chemotherapy produces changes that stress the body's antioxidant defense system, Dr. Kara M. Kelly, of Columbia University, New York, and colleagues write in the American Journal of Clinical Nutrition. Therefore, it's important that the diets of cancer patients contain adequate amounts of antioxidants.

In a 6-month study, the researchers examined antioxidant intake and chemotherapy side effects in 103 children with acute lymphoblastic leukemia (ALL), the most common cancer in kids.

During the study period, "subjects ingested vitamin E, total carotenoid, beta-carotene, and vitamin A in amounts that were 66, 30, 59, and 29 percent, respectively, of the US recommended dietary allowance or of the amounts specified in the third National Health and Nutrition Examination Survey," the investigators note.

The authors also found that greater intake of vitamin C was associated with fewer therapy delays, less side effects, and fewer days spent in the hospital. Similarly, the risk of infection and side effects decreased as vitamin E and beta-carotene intake increased.

"Our results suggest that it would be prudent for children with ALL to receive nutritional counseling to ensure that they are meeting their needs for antioxidant nutrients," the authors conclude.

SOURCE: American Journal of Clinical Nutrition, June 2004.

1: Semin Hematol. 2004 Apr;41(2 Suppl 4):6-12.

Myelodysplastic syndromes: From pathogenesis and prognosis to treatment.

Fenaux P.

Service d'Hematoilogie, Clinicique/ Paris XIII University, Avicenne Hospital, France. [email protected]

Myelodysplastic syndromes (MDS) are clonal hematologic disorders characterized by ineffective hematopoiesis resulting in peripheral cytopenia and by increased progression to acute myelocytic leukemia (AML). With the exception of allogeneic stem cell transplantation, there is generally no curative treatment for these disorders. As the contribution of diverse pathologic processes to ineffective hematopoiesis in MDS continues to be clarified, promising new avenues for treatment are being identified. Agents that interact with newly defined biologic targets and that are under investigation include arsenic trioxide, DNA methylation inhibitors, farnesyl transferase inhibitors, thalidomide, immunomodulating agents, and histone deacetylase inhibitors.

PMID: 15190510 [PubMed - in process]

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