Duke University Medical Center Archives

2017

Scholar Grant

Dr. William Eward

Raleigh/Durham, NC

Osteosarcoma (OS) is the third most common childhood cancer and the most devastating primary bone cancer. Therapy for advanced disease is limited and OS carries a poor prognosis that has not improved in several decades. Therefore, there is an urgent need to identify novel therapeutic targets to increase the treatment options for OS patients with advanced disease. The poor predictability of human tumor responses relative to therapeutic screening in many rodent models means that the drug development pathway is costly, with many drug failures, and many rodent models are not serving their purpose. Naturally occurring cancers in dogs can serve as unique models of human disease because they represent biologically complex conditions in a way that is not possible with rodent models.

The goal of this proposal is to develop a novel, cross-species patient-specific modeling platform that can rapidly and accurately screen and validate drugs for translation into the clinic. For this proposal, we have focused our efforts on OS because it is a disease where better models and effective new treatments are desperately needed. An opportunity exists to study pet dogs with OS as unique models of human disease. OS is much more common in dogs than in humans, which enables us to accrue canine patients for clinical trials much more quickly than human patients. Moreover, a dog’s battle with cancer plays out in months rather than years – meaning that discoveries can be made in an accelerated fashion. We have a background of expertise in creating patient derived xenografts (PDX) for developing a precision medicine strategy. We have established a protocol to utilize resected OS from pet dogs as part of this process. Resected tissue from naturally occurring canine tumors is used to establish cell lines and generate PDX for screening and validating new treatments targeted to the patient.

We hypothesize that preclinical models based in canine patients can be used to screen and validate new treatments for OS efficiently and accurately for rapid translation to human treatment. To test this hypothesis, we plan to do the following:
1) Compare and characterize cell line, PDX, and patient tumor mutational landscapes from canine osteosarcomas.
2) Perform a targeted screen of candidate drugs for the treatment of individual osteosarcomas in pet dogs.

By completing this work, we will develop a new precision medicine modeling platform that could lay the foundation for applying this translational platform to human sarcoma patients.

2014

Scholar Grant

Dr. Dan Wechsler

Raleigh/Durham, NC

Improving the outcome of aggressive childhood leukemias depends on developing new targeted treatments. Our laboratory studies a mutant gene called CALM-AF10 that causes high-risk leukemias in children. We determined that the oncogenic properties of CALM-AF10 depend on its interaction with a partner protein called CRM1. We will first examine the molecular mechanisms by which CRM1 enables CALM-AF10 to cause leukemias. These studies will provide insight into the biology of CRM1 and help understand the role played by CRM1 in these leukemias. We will then test the ability of drugs that selectively inhibit CRM1 (Selective Inhibitors of Nuclear Export or SINEs) to stop leukemia growth, first using leukemia cells in tissue culture and then using mouse leukemia models that we have established. These studies will lay the groundwork for new treatment approaches for CALM-AF10 leukemia patients.