作者：Nick Mulcahy
出處：WebMD醫學新聞
October 23, 2008 — 根據發表於10月16日Nature期刊中的一篇報告，美國一多中心研究團隊的研究者發展出一種用來治療神經母細胞瘤這種幼童神經系統腫瘤的分子原理。
即使罕見，神經母細胞瘤佔兒童各種癌症死亡的15%，每年約有600名美國小孩發生此癌症，通常發生在腹部、胸部或頸部；約有半數病患是在18個月大之前被診斷出來。
此標靶治療的基本原理來自達那-法柏癌症研究治療中心研究者、哈佛醫學院小兒科助理教授Rani E. George博士，以及哈佛小兒科教授A.Thomas Look醫師；研究者報告指出發現了之前未知的間變性淋巴瘤激酶(ALK)基因突變，在他們的研究中，此突變出現在8%的原發神經母細胞瘤樣本中。
這項發現有其重要價值，因為稱為TAE684的小標靶分子抑制劑，引起試管內帶有兩個突變的神經母細胞瘤細胞株死亡；因為神經母細胞瘤似乎依賴突變的ALK 基因來持續生長，設計來抑制ALK的治療或許可以提供一個有效的治療方式。
本研究團隊所發現的小兒科方面的結果，與ALK受體抑制劑的一個成人臨床試驗結果一致。
Look醫師向記者表示，我們的時機是良好的，因為成人臨床試驗顯示新的ALK受體抑制劑有好的結果，這很快可以運用於小孩的臨床試驗；我們相當希望此藥物能對有這些突變腫瘤的小孩有幫助。需要更多研究，但我們對此藥物的可能性倍感期待，對小孩的神經母細胞瘤治療邁出重要的一步。
【仔細探究ALK】
指出ALK基因在基因分析上的高度重要性之後，科學家試圖確認此影響的程度，分析了94個一般神經母細胞瘤腫瘤的ALK基因，與30個神經母細胞瘤細胞株。
研究者發現，神經母細胞瘤細胞出現ALK 異常者，明顯影響了細胞死亡的過程；再者，他們發現，部分ALK突變對TAE684這個小的有機分子具感受性。
此外，研究者使用基因轉移技術來初始化老鼠細胞中的ALK相關癌症，這些轉變的神經母細胞瘤對TAE684這個ALK抑制劑也有感受性。
【研究努力帶來希望】
神經母細胞瘤之治療通常包括手術、化療、放射線，在一些案例中也包括了幹細胞移植。研究者指出，高風險神經母細胞瘤即使有密集的骨髓摧毀性化療也會迅速惡化，常見復發且幾乎都會致命。
共同作者、佛羅里達大學癌症中心成員、佛羅里達大學醫學院生物統計與健康政策研究員、流行病學研究副教授Wendy B. London博士表示，我們需要為這些小孩擊出一記全壘打；治療有ALK突變的標靶治療將是個突破。
最後，研究者致力於研發可以破壞癌症細胞訊號過程的製劑，且設計檢測這些小分子抵抗致癌突變基因的臨床試驗。
London博士表示，這是轉譯研究的縮影，我們將運用有關ALK突變對於ALK抑制劑的敏感性的瞭解，將這些知識轉為發展治療神經母細胞瘤病患的治療方式。
本研究接受等國家健康研究中心、Friends for Life Neuroblastoma Fund、Children's Oncology Group、Alex's Lemonade Stand基金會、國家癌症研究中心、American Lebanese Syrian Associated Charities與 St. Jude兒童研究醫院等的資金贊助。研究者宣稱沒有相關資金上的往來。
Research on Rare Cancer in Children Takes Step Toward Treatment
By Nick Mulcahy
Medscape Medical News
October 23, 2008 — An American multicenter team of researchers has developed a molecular rationale for a targeted therapy for neuroblastoma, a tumor of the nervous system that occurs in young children, according to a report published in the October 16 issue of Nature.
Despite being rare, neuroblastomas account for approximately 15% of all cancer deaths in children. About 600 American children annually develop the cancer, which often appears in the abdomen, chest, or neck; roughly half the patients are diagnosed before the age of 18 months.
The rationale for the targeted therapy arose out of a study led by Dana-Farber Cancer Institute researchers Rani E. George, MD, PhD, assistant professor of pediatrics at Harvard Medical School, in Boston, Massachusetts, and A. Thomas Look, MD, professor of pediatrics at Harvard. The researchers report the discovery of previously unknown mutations in the anaplastic lymphoma kinase (ALK) gene, which was present in 8% of primary neuroblastoma samples analyzed in their study.
The discovery seems potentially important because a small "targeted" molecule inhibitor, known as TAE684, caused neuroblastoma cell lines carrying 2 of the mutations to die in vitro. Because neuroblastoma tumors seemingly depend on mutated ALK genes for their continued growth, therapies designed to inhibit ALK may offer an effective approach to the disease.
The pediatric discovery by this team is coincident with a new clinical trial in adults of an inhibitor of the ALK receptor.
"Our timing is good because there is a new inhibitor of the ALK receptor that is currently showing promise in clinical trials in adults, and which should be available soon for clinical trials in children," Dr. Look told reporters. "We are very hopeful that this drug will have activity in children whose tumors have these mutations. More studies are needed, but we are excited by the possibility that this drug and others like it will represent a major step forward for some children with neuroblastoma."
Taking a Closer Look at ALK
After noting "high-level amplification" of the ALK gene in a genetic analysis, the scientists set out to determine the frequency of the amplification, and analyzed the ALK gene in 94 tumors representative of general neuroblastomas and 30 neuroblastoma cell lines.
The researchers discovered that ALK abnormalities in a subset of neuroblastoma cells apparently interfere with the cell-death processes. Furthermore, they found some of the ALK mutations were sensitive to TAE684, which is a small organic molecule.
In addition, researchers used gene-transfer techniques to initiate ALK-related cancer in rodent cells. These transduced neuroblastomas also appear vulnerable to TAE684, an ALK inhibitor.
Research Efforts Prompt Hope
Treatment for neuroblastomas usually involves surgery, chemotherapy, radiation, and, in some cases, stem-cell transplantation. High-risk neuroblastomas are rapidly progressive, and even with intensive myeloablative chemotherapy, relapse is common and almost uniformly fatal, note the study authors.
"We need to hit a home run for these kids," said coauthor Wendy B. London, PhD, a research associate professor of epidemiology, biostatistics and health policy research at the University of Florida College of Medicine, and a member of the University of Florida Shands Cancer Center, in Gainesville. "A targeted therapy to treat patients with ALK mutations would be a real breakthrough."
Ultimately, researchers are in search of an agent to disrupt the cancer-cell-signaling process and are designing a clinical trial that would test small molecules against the cancer-causing mutations in the gene.
"This is the epitome of translational research," said Dr. London. "We will use what we have learned about the sensitivity of ALK mutations to an ALK inhibitor and attempt to translate this knowledge into the development of targeted therapy for treatment of neuroblastoma patients in the clinic."
The research was supported by grants from the National Institutes of Health, Friends for Life Neuroblastoma Fund, Children's Oncology Group, Alex's Lemonade Stand Foundation, National Cancer Institute, American Lebanese Syrian Associated Charities, and St. Jude Children's Research Hospital. The researchers have disclosed no relevant financial relationships.
Nature. 2008;455:975-978. Abstract
[ 本帖最後由 goodcat1111 於 2008-11-4 13:09 編輯 ] |
|
