From: Subject: Technique could speed new medulloblastoma drugs Date: Tue, 18 Apr 2006 09:07:35 +0200 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01C662C7.885DCB20" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.2869 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01C662C7.885DCB20 Content-Type: text/html; charset="Windows-1252" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.eurekalert.org/pub_releases/2006-04/sjcr-tcs041706.php Technique could speed new medulloblastoma = drugs

Public = release date:=20 17-Apr-2006
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Contact: Bonnie Kourvelas
media@stjude.org
901-495-3306
= St. Jude Children's = Research=20 Hospital

Technique could speed new medulloblastoma drugs

St. Jude develops strategy for locating 'light bulb = genes'=20 linked to cancer gene mutations, helping to identify which children will = likely=20 respond to novel drug treatments

Investigators at St. Jude = Children's=20 Research Hospital have developed a strategy to speed future development = of more=20 effective and less toxic treatments for medulloblastoma, a type of brain = cancer.=20 Medulloblastomas arise in the back of the brain and account for about 20 = percent=20 of childhood brain tumors.

The new technique could also be used to identify specific pathways in = other=20 types of cancer that might be vulnerable to novel therapies, and = therefore speed=20 development of so-called molecular-targeted therapies for a wide variety = of=20 cancers. Molecular-targeted therapies work by blocking individual = molecules that=20 are key triggers of disease.=20

This St. Jude study is important because the aggressive combination = of=20 surgery, radiation and chemotherapy used to treat medulloblastoma fails = to cure=20 many patients, according to researchers. Therefore, there is a great = need to=20 identify alternative therapies, such as novel drugs that block signaling = pathways that are abnormally activated. Such treatments could not only = save=20 lives but also eliminate the severe side effects caused by current = therapies,=20 according to Richard Gilbertson, M.D., Ph.D., an associate member of the = Department of Developmental Neurobiology at St. Jude and director of the = Molecular Clinical Trials Core. Gilbertson, co-director of the St. Jude=20 Neurobiology and Brain Tumor Program, is senior author of a paper on = this work=20 that appears in the April issue of Journal of Clinical Oncology.=20

The technique is designed to rapidly match a specific novel drug = treatment to=20 those children most likely to respond to it. This approach would avoid=20 trial-and-error therapy that fails in patients who are not ideal = candidates for=20 a specific treatment, researchers said. It would also reduce the chance = that=20 otherwise effective drugs would be abandoned because they failed in such = patients during clinical trials.=20

The key to the new St. Jude strategy is the ability to determine in=20 individual children which biochemical signaling pathway triggers and = sustains=20 the cancer by identifying key genes that are linked to that pathway. The = investigators proved that this strategy is valid by demonstrating that = it is=20 possible to assign children with medulloblastoma into specific groups, = depending=20 on which biochemical signaling pathway is abnormally active. Based on = this=20 classification, novel drugs designed to block a key protein in each = specific=20 pathway could be correctly administered to the children most likely to = respond=20 to them.=20

"Our strategy would ensure that a new drug would get a fair trial by = using it=20 to treat only the appropriate children," Gilbertson said. "That will be=20 important as novel drugs are developed to treat medulloblastoma." St. = Jude=20 researchers reported in the September 2004 issue of Cancer Cell that a = novel=20 drug called ShhAntag effectively targets such a pathway in mice with=20 medulloblastoma and dramatically reduces the size of the tumor:=20 http://www.stjude.org/media/0,2561,453_5297_12301,00.html.=20

The St. Jude strategy overcomes two problems that often pose barriers = to=20 molecular targeted therapies. First, not all children have the same gene = mutations that cause a specific cancer, Gilbertson said, so a novel = therapy that=20 targets only a gene known to cause the cancer in one group of children = will not=20 be effective in a child whose same cancer is caused by a different = mutation.=20 Secondly, scientists have identified only a few genes that are potential = targets=20 for novel drugs in medulloblastomas, and even fewer in other brain = tumors. The=20 current solution to that problem--to identify the DNA sequence of all = the genes=20 in each child's tumor to determine which ones are mutated--is an = enormous and=20 expensive undertaking, he said.=20

However, the St. Jude team used an approach for identifying the = signaling=20 pathways that cause medulloblastoma in different groups of children.=20

"Our strategy is somewhat analogous to the link between a home's = electrical=20 wiring system and a light bulb," Gilbertson said. "You know if a certain = part of=20 the wiring network is working if the light bulb connected to it is on. = In the=20 medulloblastoma cell, the wiring is composed of proteins making up the = specific=20 signaling pathway that is abnormally activated by a gene mutation, and = the light=20 bulb is the group of genes that the pathway causes to be = over-expressed." The=20 St. Jude team showed in samples of medulloblastoma from different groups = of=20 children that it is possible to determine which gene mutations are = present in=20 tumors by studying which genes are expressed by those tumors.

"Since each of these gene expression signatures is regulated by a = specific=20 pathway, these genes essentially report to us which pathway might be = causing the=20 cancer," Gilbertson said. "Using this information, researchers can use = drugs to=20 block that pathway."=20

The St. Jude team proved that the principle of identifying genes = linked to=20 abnormal signaling pathways is valid by generating gene expression = profiles from=20 46 medulloblastoma samples. The investigators identified five = medulloblastoma=20 subgroups that differed from each other by their patterns of gene = expression.=20 These subgroups also differed according to their histologic = (microscopic)=20 characteristics and by how they behaved in patients.=20

For example, medulloblastomas in subgroup B occurred in patients who = were=20 older than 3 years and whose cancer was of the standard or classic type = usually=20 recognized under the microscope. In contrast, medulloblastomas in = subgroup D=20 occurred in children younger than 3 years, and these tumors had = different=20 characteristics from those in subgroup B.

The investigators showed that activation of different signal pathways = contributes to the different medulloblastoma gene expression signatures = found in=20 each subtype. For example, the team found that genes in a pathway called = WNT are=20 especially active in tumors from subgroup B, while genes in the SHH = pathway are=20 especially active in subgroup D.

The researchers then looked at the DNA sequences in the tumors to = show that=20 gene mutations that activate the WNT pathway were only found in = subgroup-B=20 tumors, and mutations that activate the SHH pathway were restricted to=20 subgroup-D tumors. Looking for patterns of gene expression can be done = much more=20 rapidly than looking for gene mutations; therefore, in future studies of = novel=20 drugs, such gene expression signatures could be used to quickly identify = which=20 signaling pathways are responsible for medulloblastoma in specific = children.=20 Only those children would receive the drug during clinical trials.

"Our work showed that drugs that target specific pathways are likely = to be=20 effective in distinct populations of patients with medulloblastomas," = said=20 Margaret Thompson, M.D., Ph.D., clinical fellow in the Gilbertson lab. = She is=20 the first author of the paper. "We believe our technique will provide a = rapid=20 and accurate way to select appropriate patients for clinical trials of = each=20 molecular targeted therapy for medulloblastoma."=20

###

Other authors of the study include Christine Fuller, Twala Hogg, = James=20 Dalton, David Finkelstein, Tom Curran and Amar Gajjar (St. Jude); Ching = Lau,=20 Murali Chintagumpala and Adekunle Adesina (Texas Children's Hospital); = David=20 Ashley (Melbourne, Australia); Stewart Kellie (Sydney, Australia); and = Michael=20 Taylor (Hospital for Sick Children, Toronto). This work was supported in = part by=20 the National Cancer Institute, the Sontag Foundation, the V-Foundation = for=20 Cancer Research, a Cancer Center (CORE) Support Grant and ALSAC.=20

St. Jude Children's Research Hospital
St. Jude Children's = Research=20 Hospital is internationally recognized for its pioneering work in = finding cures=20 and saving children with cancer and other catastrophic diseases. Founded = by late=20 entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely = shares its=20 discoveries with scientific and medical communities around the world. No = family=20 ever pays for treatments not covered by insurance, and families without=20 insurance are never asked to pay. St. Jude is financially supported by = ALSAC,=20 its fund-raising organization. For more information, please visit http://www.stjude.org/ .

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