The Houghton Lab is focused on understanding the basic biology of childhood solid tumors, largely sarcoma. Dr. Houghton has identified a chromosomal rearrangement in rhabdomyosarcoma that leads to downstream over-expression of insulin-like growth factor 2 (IGF2) ligand.
His lab is working to interpret the signaling pathway and is developing therapeutic approaches to block IGF signaling in rhabdomyosarcoma, Wilms’ tumors, neuroblastoma, Ewing sarcomas, and a range of other tumors.
Using Rapamycin to Block TOR
In 1992 Dr. Houghton’s Lab identified rapamycin as a drug that potently blocked IGF-driven proliferation of sarcoma cells. This agent blocks a very specific kinase (TOR) that is downstream of the IGF1 receptor. The kinase targeted by rapamycin regulates autophagy, cell cycle progression, survival and transcription. The team is working to understand which of these processes are critical for tumor cell survival under stress, and to define how low oxygen (hypoxia) regulates the activity of mTOR. Use of rapamycin for treatment of childhood cancer is currently in Phase II clinical trials.
Combining Rapamycin with IGF Inhibitors
When rapamycin is used to block the kinase TOR in the absence of insulin-like growth factors, cellular response is death and not quiescence. However, this only occurs when tumor suppressor p53 is attenuated, which is common in most pediatric cancers. Multiple clinical trials are ongoing or planned to examine the effect that combining rapamycin with an IGF inhibitor has on childhood cancer.
Antibodies as Potential IGF Inhibitors
Antibodies are being considered a potential therapy to block IGF signaling. Studies have shown that antibodies cannot equally block both IGF1 and IGF2 ligands since they are overlapping sites on the receptor, but are not identical. Dr. Houghton has found that there are very marked differences between antibodies that block IGF1 versus those that block IGF2. The IGF1 blockers seem to perform better against Ewing sarcoma and osteosarcoma; the IGF2 blockers seem to perform better against rhabdomyosarcoma and other tumors. Dr. Houghton’s Lab is working to tease out these subtitles, which could be critical as to whether or not a child responds to treatment.
Pediatric Preclinical Testing Program
Visit the Pediatric Preclinical Testing Program website
The Pediatric Preclinical Testing Program (PPTP) is a comprehensive program to systematically evaluate new agents against childhood solid tumor and leukemia models. The PPTP is supported through an NCI research contract to The Research Institute at Nationwide Children's Hospital with Dr. Peter Houghton as the Principal Investigator. Testing occurs both at The Research Institute and also at subcontract sites that have expertise in specific childhood cancers.
The program is based on a substantial body of data showing that appropriate childhood cancer preclinical in vivo models can recapitulate the anti-tumor activity of known effective agents and can prospectively identify novel agents subsequently shown to have clinical activity against specific cancers of children and adolescents. By facilitating development of a more reliable pediatric new agent prioritization process, the PPTP will contribute to the goal of identifying more effective treatments for children with cancer.