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:10/13/2017)... ... October 13, 2017 , ... The American Board of Family Medicine's (ABFM) Board ... Chief Executive Officer, succeeding Dr. James C. Puffer upon his retirement. Dr. Newton will ... Dr. Puffer’s retirement at the end of 2018. Upon assuming the role of President ...
(Date:10/13/2017)... ... 2017 , ... PurhealthRX , a leading Health and Nutrition Company, is ... to full spectrum CBD oil will revolutionize the rapidly growing CBD market by reducing ... easily incorporated into liquid products, while reducing costs to end users. , The team ...
(Date:10/13/2017)... , ... October 13, 2017 , ... Lori R. Somekh, ... member of ElderCounsel, a national organization of elder law and special needs planning attorneys. ... and rules. It also provides a forum to network with elder law attorneys nationwide,” ...
(Date:10/13/2017)... ... 13, 2017 , ... Many families have long-term insurance that covers care for ... a waiver for care if the client has a cognitive impairment diagnosis. , ... care, is often waived, so the benefits from their insurance start immediately,” said Mechell ...
(Date:10/13/2017)... ... October 13, 2017 , ... Ellevate Network, the leading ... to advocate for action towards gender equality at their inaugural Summit in New York ... globe, and reached a social audience of over 3 million. To watch the Mobilize ...
Breaking Medicine News(10 mins):
(Date:10/12/2017)... Oct. 12, 2017   Divoti USA will ... to the standard of the latest FDA requirements, which stipulates new ... Anyone in need of Medical ID jewelry such as Medical ... are engraved in terms of the new FDA requirements ... Divoti offers this dark ...
(Date:10/11/2017)... Oct. 11, 2017  Caris Life Sciences ® , ... the promise of precision medicine, today announced that St. ... Precision Oncology Alliance™ (POA) as its 17 th ... St. Jude Crosson Cancer Institute will help develop standards ... of tumor profiling, making cancer treatment more precise and ...
(Date:10/10/2017)... , Oct. 10, 2017  NDS received FDA 510(k) clearance in ... medical-grade battery-powered display stand specifically designed for endoscopy environments. An innovative ... into a clinical solution to support the improvement of patient outcomes, ... Design ... Solution ...
Breaking Medicine Technology: