Inova Fairfax Archives - Hyundai Hope On Wheels

2014

Scholar Grant

Dr. Sadhna Shankar

Falls Church, VA

Survival remains low among children with non-metastatic osteosarcoma who show poor response to initial chemotherapy. Modifying therapy after initial treatment in poor responders has not changed these outcomes. Predicting poor responders at the time of initial diagnosis could lead to alternative therapies at the outset, which could improve survival.
Genetic variation may account for the wide variation seen in the response and toxicity related to chemotherapeutic agents. Conflicting results have been observed in previous studies that have used a “candidate gene” approach, to explain a drug’s efficacy or toxicity by identifying one gene and even one variation within that gene. An integrative approach combining whole gene sequencing with multiple data sets and defined clinical data could better capture pathway associations, and identify clinically actionable variants.
The aim of this study is to identify, test, and validate a pharmacogenetic “resistant” genotype to cisplatin, doxorubicin, and methotrexate (MAP), using pre-clinical in vitro and clinical in vivo data sets.
Whole exome genetic sequencing data and drug sensitivity data on the NCI-60 cell lines will be used to identify a genotype resistant to MAP. Clinical outcomes and whole genome genetic datasets from our clinic as well as the NCI’s TARGET database for osteosarcoma will be used to identify a resistant genotype among patients. Probablistic network analysis will be used to identify the resistant genotypes from these datasets. The resistant genotype identified from the cell line and patient datasets will be validated by using a new set of genotype and outcomes data from the TARGET study. Finally, ethnic and racial prevalence of this “resistant” genotype will be defined utilizing a large database at our institution of non- cancer patients for whom whole genome sequencing is available. Germline pharmacogenetic profile could be used to predict sensitivity or resistance to therapy and provide personalized cancer therapy.