Dr. Michael Hogarty
Basic Science Research Grant
Children’s Hospital of Philadelphia
Dr. Hogarty’s Research
Dr. Hogarty describes the research associated with the Basic Science Research Grant he has been awarded by the Pediatric Cancer Research Foundation:
Our work addresses the critical problem that most lethal childhood tumors are resistant to available treatments. The paradox is that these cancers endure the most stress of any cells of the body: growing independently, growing where fuel and oxygen supplies are low, and spreading to less hospitable body parts all create stress signals that ought to kill the cancer cells. On top of this, the treatments doctors give are very potent at causing more stress. Work from our lab shows that these cancers don’t survive because they don’t create stress signals, they survive because they have developed powerful ways to block the stress signals. This keeps them alive but makes them entirely dependent on continually blocking the stress signals. We study neuroblastoma and have shown that they use one (and typically only one) of a small number of available survival proteins to block stress signals. These survival proteins work by binding with the stress signal so that it cannot activate the cell’s death program. Some neuroblastomas use a protein called Bcl2 while others use a closely related protein called Mcl1. To exploit this, drugs have been developed that bind even better to these survival proteins, and these can displace the stress signal so that it can kill the cell. If a cancer is using Bcl2 to block stress, a Bcl2-inhibitor drug can kill it. If a cancer is using Mcl1 to block stress, an Mcl1-inhibitor can kill it. We have developed laboratory tools that identify the relevant survival protein in a tumor, and accurately predict which inhibitor will be most active. We are working to understand how particular cancers become addicted to either Bcl2 or Mcl1, and developing more user-friendly tests that can be applied at the time of a child’s cancer diagnosis to define which drugs should work best. With this approach we have shown the ability to “cure” mice with neuroblastomas and are working towards applying this approach to children.