See also our related blogs for the Keller Laboratory and the Pediatric Preclinical Testing Initiative.

Wednesday, March 30, 2011

OHSU Doernbecher Scientists Discover New Approach to Overcoming Drug Resistance in a Childhood Cancer With Low Survival Rates

Discoveries in the lab inform national clinical trial under way at OHSU Doernbecher Children’s Hospital
PORTLAND, Ore. — Researchers at Oregon Health & Science University Doernbecher Children’s Hospital have identified a promising new approach to overcoming drug resistance in children with an extremely aggressive childhood muscle cancer known as alveolar rhabdomyosarcoma. Their findings are published online this week in the journal Molecular Cancer Therapeutics and will be featured on the cover of the journal’s print edition next month.
Rhabdomyosarcoma accounts for more than 50 percent of all soft-tissue cancers in children. Even after extensive therapy, the survival rate among alveolar rhabdomyosarcoma patients with advanced disease is less than 20 percent. Dismal outcomes such as these are what keep researchers in the Pediatric Cancer Biology Program at OHSU Doernbecher working around the clock toward a breakthrough.
“Despite our best efforts, outcomes for metastatic alveolar rhabdomyosarcoma have not improved for decades. That’s why our findings are significant. Our clinical partners now have a new method of mitigating resistance to the current treatment for childhood muscle cancer,” said Jinu Abraham, Ph.D., lead author and senior research associate in the Pediatric Cancer Biology Program at OHSU Doernbecher, and a member of the OHSU Knight Cancer Institute.
Previous studies led by Charles Keller, M.D., leader of the Pediatric Cancer Biology Program at OHSU Doernbecher, have shown an important relationship between increased growth factor signaling through the insulin-like growth factor receptor (Igf1r) and decreased survival in children with alveolar rhabdomyosarcoma, a rare form of muscle cancer that typically occurs in the limbs, chest or abdomen of children and adolescents. Growth factor signaling is required for normal development but impairment of this pathway causes abnormal cell growth.
In the current study, Abraham and colleagues tested whether the non-chemotherapy drug NVP-AEW541 could stop Igf1r signaling in a novel mouse model genetically engineered so that alveolar rhabdomyosarcoma tumors begin and expand in the same places they are found in children. Their results showed the non-chemotherapy drug blocked tumor progression in 33 percent of mice with tumors, but most of the mice developed resistance to the drug. 
To uncover the reason for resistance, the researchers conducted additional experiments that showed Igf1r partners with another tumor surface enzyme known as Her2, which fueled the tumor growth despite the growth factor-inhibiting drug.
“Fortunately, when we treated resistant rhabdomyosarcoma cells with a combination of the Igf1r inhibitor and the Her2 inhibitor Lapatinib, there was a significant increase in tumor cell killing compared with either drug alone,” explained Abraham. “Our study has shown that targeting both Igf1r and Her2 may be a very promising approach in preventing resistance to Igf1r-inhibiting drugs in rhabdomyosarcoma.”
“Understanding why some rhabdomyosarcoma tumors are resistant to Igf1r inhibitors is vital to studying these drugs in the clinical setting. This discovery in the lab gives us an option for trying to overcome this resistance and will guide how we combine these new targeted therapies to treat patients with cancer,” said Suman Malempati, M.D., co-author of the current study and principal investigator for the first national clinical trial using an Igf1 receptor inhibitor in combination with chemotherapy for metastatic rhabdomyosarcoma.
The Children’s Oncology Group (COG) trial, now taking place at OHSU Doernbecher Children’s Hospital and several other COG sites, is the first in North America to incorporate a molecularly targeted drug into a clinical trial for childhood muscle cancer.
The National Cancer Institute, Scott Carter Foundation, Alex's Lemonade Stand Foundation and the Hyundai Hope on Wheels Program funded the current study, “Evasion Mechanisms to Igf1r Inhibition in Rhabdomyosarcoma.”
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Jinu Abraham, Ph.D., is a senior research associate and scientific manager of the Pediatric Preclinical Testing Initiative at the Pediatric Cancer Biology Program, Papé Family Pediatric Research Institute, at OHSU Doernbecher Children’s Hospital; and a member of the OHSU Knight Cancer Institute
Charles Keller, M.D., is the leader of Pediatric Cancer Biology Program in the Papé Family Pediatric Research Institute, and an associate professor of pediatrics (hematology/oncology) at OHSU Doernbecher Children’s Hospital; and a member of the OHSU Knight Cancer Institute and the Oregon Stem Cell Center at OHSU.
Suman Malempati, M.D., is an assistant professor of pediatrics (hematology/oncology) and director of the Oncology Developmental Therapeutics Program at OHSU Doernbecher Children’s Hospital; and a member of the OHSU Knight Cancer Institute
About OHSU Doernbecher Children’s Hospital
OHSU Doernbecher Children's Hospital is a world-class facility that each year cares for tens of thousands of children from Oregon, southwest Washington and around the nation, including national and international referrals for specialty care. Children have access to a full range of pediatric care, not just treatments for serious illness or injury, resulting in more than 165,000 outpatient visits, discharges, surgeries and pediatric transports annually. Nationally recognized physicians ensure that children receive exceptional care, including outstanding cancer treatment, specialized neurology care and highly sophisticated heart surgery in the most patient- and family-centered environment. Pediatric experts from OHSU Doernbecher travel throughout Oregon and southwest Washington to provide specialty care to some 3,000 children at more than 154 outreach clinics in 13 locations.

Contact:         Tamara Hargens-Bradley, 503 494-8231;

[ art credits: Suresh I. Prajapati ]

Monday, March 21, 2011

DIPG research study funded

Congratulations to pediatric neuro-oncologist, Dr. Kellie Nazemi, whose study "Functional Discovery of Therapeutic Targets in Diffuse Intrinstic Pontine Glioma (DIPG)" has received pilot funding from the Friends of Doernbecher grant program.  
This study is an important one in defining therapeutic options for children with this devastating disease.  
[  6/17/2011:  for an interesting talk on this topic, click here to listen to Dr. Mark Kieran's talk regarding a pending clinical trial, tentatively to be available at DCH. ]

Friday, March 11, 2011

Inaugural CureSearch Walk, Portland

Please save the date, Saturday August 6, for the inaugural Portland CureSearch Walk.  The walk will be at the Sellwood Riverfront Park.  To register your walk team, see the website or email Denise Bayles-Muniz at denise.bayles (at)  

CureSearch is the funding support agency of the Children's Oncology Group, which organizes some of the largest clinical trials for pediatric cancers in the US.  

Monday, March 7, 2011

Knight seminar speaker, Dr. Amy Wagers

We are excited to welcome Dr. Amy Wagers to OHSU for her seminar on, "Tissue Stem Cells in Aging and Malignancy" to be presented 4 pm Tuesday March 7 in the OHSU main hospital 8th floor auditorium.  Amy is an accomplished stem cell biologist  at the Joslin Diabetes Center, Harvard, who bridges both hematopoetic and myogenic progenitor fields, and her work on stem cell niches has important implications for cancer biology.