Navigation Links
In a childhood cancer, basic biology offers clues to better treatments
Date:11/9/2011

By studying tumor biology at the molecular level, researchers are gaining a deeper understanding of drug resistance -- and how to avoid it by designing pediatric cancer treatments tailored to specific mutations in a child's DNA. In a fruitful collaboration, pediatric oncologists and biochemists are targeting neuroblastoma, an often-deadly childhood cancer of the peripheral nervous system.

"This scientific study allows us to move ahead in improving drug treatments for children with a particular form of neuroblastoma," said study co-leader Yal P. Moss, M.D., a pediatric oncologist at The Children's Hospital of Philadelphia. Moss teamed up in this research with the study co-leader, Mark A. Lemmon, Ph.D., professor and chair of Biochemistry and Biophysics at the Perelman School of Medicine of the University of Pennsylvania.

"This has been a terrific collaboration," said Lemmon. "We have been working for a long time to understand how growth factor receptors work as signaling 'machines.' With the Moss group, we focused on how control of these receptors is compromised in cancer, and can use the laboratory results to guide directly where to go next in the clinic."

The study appears today in the Nov. 9 issue of Science Translational Medicine.

In neuroblastoma, the most common solid cancer of early childhood, roughly 10 percent of patients have mutations in ALK, the gene carrying the code for the signaling receptor anaplastic lymphoma kinase. Moss, who led a team that discovered this gene's role in 2008, was able to expedite a pediatric clinical trial based on this finding within a year, because an existing ALK inhibitor called crizotinib was already in adult clinical trials for a subset of non-small cell lung cancer patients.

Crizotinib was therefore available for use in a pediatric clinical trial against neuroblastoma, but early results in adult cancers showed that tumors sometimes develop resistance to the drug. The current study combined basic biochemistry and structural biology with studies in tumor-derived cell lines and animal models to investigate how different ALK mutations in neuroblastoma affect how ALK activity and tumor growth respond to crizotinib.

The researchers focused on the two most common ALK mutations found in neuroblastoma patients. They found that crizotinib effectively halted the proliferation of neuroblastoma cells harboring the most common mutation, but that the second most common ALK mutation was more resistant to the drug.

The reason for the different results, say the authors, is that the drug-resistant mutation causes ALK to bind more tightly to a key cellular compound called ATP that drives its signaling. Since crizotinib must displace this compound to inhibit ALK, the increased ATP binding caused by the resistant mutation reduces crizotinib's effectiveness.

The authors say these results justify increasing the dosage of crizotinib in patients with the more drug-resistant mutation, although human studies must first be performed to determine if a higher dose will be safe and effective in children. Fortunately, said Moss, unlike conventional chemotherapy, which attacks both cancerous and normal cells, this type of drug strikes much more specific targets, and tends to have lower risk of overall toxicity.

"This study shows how important it is to integrate basic science into the design of clinical trials, and how useful it can be," Moss added. "If we can better individualize treatment to a child's genetic profile by understanding the effects of mutations on protein structure and function, we may achieve better results for patients," added Lemmon.


'/>"/>
Contact: John Ascenzi
ascenzi@email.chop.edu
267-426-6055
Children's Hospital of Philadelphia
Source:Eurekalert

Related medicine news :

1. NIH scientists discover link among spectrum of childhood diseases
2. Childhood diet lower in fat and higher in fiber may lower risk for chronic disease in adulthood
3. Wayne State University to study effects of risky family environments on childhood asthma
4. Childhood asthma non-profit invests millions in health centers to help children better manage asthma
5. Vaccine for Childhood Diarrhea Helps Kids, Saves Dollars
6. Key regulatory genes often amplified in aggressive childhood tumor of the brainstem
7. White Houses Childhood Obesity Task Force must focus on providing treatment for minority children
8. Largest global childhood pneumonia etiology study launched
9. Unemployment Higher Among Childhood Cancer Survivors in Poor Health
10. Childhood maltreatment linked to long-term depression risk and poor response to treatment
11. Childhood Depression, Anxiety Tied to Pain in Adulthood
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:2/13/2016)... ... February 13, 2016 , ... ... Nursing with an in-kind gift of a VeinViewer® Vision vein finder ... learn how to start an IV and draw blood, combining technology with traditional ...
(Date:2/12/2016)... ... February 12, 2016 , ... Mystic Buddha Publishing House ... Blue SKies Buddha, the biography of Rama - Dr. Frederick Lenz. , ... the love of a Buddhist teacher for teaching and helping others. Valentine’s Day ...
(Date:2/12/2016)... Church, VA (PRWEB) , ... February 12, 2016 ... ... Store?, Feb. 29, 2016 — 1:30 p.m. – 3:00 p.m. EST, http://www.fdanews.com/fixeddosecombination ... issue in the life cycle of pharmaceutical products, garnering increased attention from all ...
(Date:2/12/2016)... Wis. (PRWEB) , ... February 12, 2016 , ... ... second Lean Leadership Series at Zuckerberg San Francisco General Hospital on April 5-7. ... practice new behaviors and create new habits. The workshops cover a broad range ...
(Date:2/12/2016)... ... 2016 , ... The Jones Agency, a family owned insurance company with offices ... cooperative charity drive with the Tarrant Area Food Bank in the hopes of alleviating ... in need, the Tarrant County Food Bank offers hope and security to the one ...
Breaking Medicine News(10 mins):
(Date:2/11/2016)... The primary goal of this research is ... the usage of liquid biopsy. Key information the survey ... Timeframe of liquid biopsy adoption amidst future users - ... type - Sample inflow to conduct liquid biopsy tests ... and so on. - Correlation analysis of sample type ...
(Date:2/11/2016)... Laboratory glassware and plasticware include ... may range from microscope slides to large storage boxes ... borosilicate glass because of its low weight and resistance ... started gaining popularity over the past decade when it ... with plastic in several applications due to its resistance ...
(Date:2/11/2016)... 2016  Governor Andrew M. Cuomo today announced a ... throughout Western New York . This ... Polytechnic Institute, includes a major expansion of Athenex,s North ... Buffalo , as well as the creation of ... Dunkirk . The combined projects are expected ...
Breaking Medicine Technology: