Development of new therapies for children with cancer presents unique challenges. Firstly, the incidence of cancer in children is relatively low; in the United States about 12,400 new cases are diagnosed annually in patients under 20 years old. Each year in Texas, almost 1,200 children and adolescents younger than 20 years of age are diagnosed with cancer, representing 10% of all cancers diagnosed in the U.S. Approximately 200 children and adolescents die of cancer each year, making cancer the most common cause of disease-related mortality for Texans 0-19 years of age.
Nationally, the overall cure rate for all childhood cancers is approaching seventy percent, and in many patients that ultimately fail curative therapy, initial responses to current multimodality treatments (surgery, radiation therapy and chemotherapy) are good, with overall 5-year Event-Free Survival approaching 80%. However, current approaches to curative therapy result in significant morbidity and long- term sequelae, including cardiac dysfunction and cognitive impairment. Further, dose-intensive chemotherapy with conventional agents has not significantly improved outcomes for patients that present with advanced or metastatic disease. Consequently, a new approach to developing effective, less toxic, curative therapy is required and will be the focus of the Pediatric Drug Discovery Initiative (PDDI). Our current understanding of childhood cancers indicates that exome mutations are relatively rare, and that many cancers of childhood are ‘driven’ by oncogenic fusion proteins. Initial projects of PDDI are to:
- validate fusion proteins found in pediatric cancers as targets for drug development and identify synthetic lethal interactions where knockdown of a gene is lethal only in the context of oncogenic transcription factor (OTF) expression;
- purify and characterize OTF complexes, identify critical functional components of OTF’s using HTS RNAi approaches, and develop both cellular and cell-free approaches to identify inhibitors of OTF function;
- develop a collaborative program within to develop robust assays and identify small molecule inhibitors of chimeric transcription factors that are validated ‘oncogenic drivers’ in pediatric cancers utilizing Core facilities established in both the Center for Innovation in Drug Discovery (CIDD) and Institute for Drug Development (IDD).
The proposed Pediatric Drug Discovery Initiative (PDDI) within the Greehey Children’s Cancer Research Institute (Greehey CCRI) will build on programs of excellence already established at the University of Texas Health Science Center at San Antonio and the University of Texas San Antonio to create new capabilities unique in Texas focused on the development of novel therapeutic approaches to develop therapeutics for pediatric cancers that are unique in being defined by chromosomal translocations that result in oncogenic chimeric transcription factors (OTF’s). PDDI will bring together experimental scientists in the fields of biochemistry and biophysics, biology, chemistry and computational science, as well as harness the unique established Centers, Institutes and Cores assembled at UTHSCSA to facilitate bench-bedside drug discovery and development. These include the Center for Innovative Drug Discovery, the Institute for Drug Development and the Integrated Cores for Macromolecular Structure and Interactions [including Nuclear Magnetic Resonance Spectroscopy (NMR), X-ray crystallography, Surface Plasmon Resonance (SPR), Isothermal Calorimetry (ITC), and Analytical Ultracentrifugation (AUC)] supported by the CTRC and VP Research.
The PDDI scientists will use high throughput screening (HTS) approaches to identify critical components of complexes involved in the oncogenic function of chimeric transcription factors. These approaches will include HTS for identifying critical components of chimeric transcription factors through siRNA screens, biophysical approaches to characterize complexes including analytical ultracentrifugation, thermal calorimetry, NMR and where applicable X-ray crystallography. Our ultimate objective is to develop small molecule inhibitors that will selectively inhibit OTF function, through fragment-based approaches utilizing NMR to map specific sites of compound interactions on the target protein or protein complexes, and HTS for small molecule, and natural product inhibitors. An essential component of identifying critical targets in OTF complexes, or downstream effectors, is use of RNAi approaches to silence gene expression combined with High Content Screening (HCS) that can identify phenotypic changes in cells. Greehey CCRI will establish a high-throughput genomics facility that will service the campus for RNAi screening, adding a new capability to the small molecule and natural product HTS and HTC currently available through the CIDD. Specific to the PDDI will be identification of critical components of OTF function through viability and high-content screens.
Whole genome sequencing has shown that mutation frequency in pediatric cancers is very low compared to adult carcinomas, and ‘actionable’ mutations – those that would predict a response to targeted therapy, are extremely rare. Published studies from the NCI Pediatric Preclinical Testing Program (PPTP) and other preclinical data indicate that molecularly-targeted drugs developed for treatment of adult cancers have modest activity against pediatric cancers, indicating that for development of breakthrough therapeutics it is essential to focus on developing novel approaches to inhibiting oncogenic drivers unique to certain pediatric malignancies. The PDDI will capitalize on existing strengths of basic science and Core facilities at UTHSCSA to bring together laboratory scientists, and computational biologists to target these rare but devastating cancers of childhood.