State: Tennesseedfdhd

Funded by the Dick Vitale Gala

The overall purpose of our research project is to identify if there are patterns of genetic changes (i.e. mutations) that explain why some children with acute myeloid leukemia (AML) fail to effectively respond to chemotherapy and ultimately relapse. Relapsed disease is strongly associated with poor outcome and early death in children with AML. Frequently, when AMLs relapse they do so through the outgrowth of a cell population (subclone) that was present at a low level at the time of diagnosis. These subclones frequently have mutations that allow them grow better after therapy. Unfortunately, we have a poor understanding of these subclones in pediatric AML and methods to detect them and study them are lacking. The proposed studies in this grant will identify these mutations in a large group of relapsed pediatric AML and then address if sensitive approaches to detect mutations in patients after therapy will increase our ability to predict relapse. Currently our methods to predict relapse are not applicable to all cases and likely do not effectively capture all leukemic subclones for analysis. In the second part of this grant we propose a model system to introduce mutations that will allow us to more effectively study the subclonal complexity of AML to understand why some subclones are more resistant to chemotherapy. Collectively these studies will dramatically increase our understanding of pediatric AML with the long-term goal of pushing the outcomes of pediatric AML closer to pediatric ALL.

Funded by The Hearst Foundation

Important advances have been made in therapeutically targeting molecularly defined subsets of lung cancer that depend on specific molecular alterations for tumor growth. Prime examples include tumors which harbor EGFR mutations or ALK translocations. Many other potential “driver mutations” have also been identified in lung cancer, yet therapeutically actionable alterations are still only found in approximately 50% of lung adenocarcinomas. The principal objective of this proposal is to define a novel molecular cohort of lung cancer characterized by the presence of a previously unreported EGFR exon 18-25 kinase domain duplication (EGFRKDD). This novel EGFR alteration was initially detected in the lung tumor specimen from a young male never smoker with metastatic lung adenocarcinoma. In our preliminary data, we have also detected EGFR-KDD in the tumors from other patients with lung cancer as well as from patients with brain cancer. The proposed research uses in vitro and in vivo models as well as patient-derived tumor samples and clinical data to study EGFR-KDD. Findings from these studies could potentially be immediately relevant and provide a new avenue for precision medicine in these notoriously difficult-to-treat malignancies because there are already several approved EGFR inhibitors in clinical use

Funded by Vs. Cancer

Brain cancer is the leading cause of cancer-related death in children. Current therapies for medulloblastoma, the most common type of aggressive childhood brain cancer, cure 60-80% of patients from their disease, however, these treatments are non-specific, highly toxic, and impose devastating consequences on the developing child. Novel, rationally designed therapies informed by studying medulloblastoma in the laboratory and identifying the causes of this childhood cancer are desperately needed to improve patient outcome and quality of life for survivors and their families.

Studies outlined in this application aim to gain a better understanding of the genes responsible for a large subset of medulloblastoma patients whom are typically associated with an exceedingly poor clinical outcome. There are currently no effective therapies designed to specifically treat these high-risk patients and as such they are treated with standard protocols that carry with them considerable side-effects, effectively stealing any possibility of a normal ‘life after cancer’ for kids fortunate enough to survive.

Discoveries made using state-of-the-art technologies during my recent Post-Doctoral Fellowship revealed important new insight into the genes involved in these high-risk medulloblastoma patients.  The most compelling evidence from my analyses implicated a new gene – KBTBD4 – a gene not previously implicated in childhood brain cancer, nor in any other cancer type. The experiments outlined in this application will directly evaluate the role of this novel, frequently altered gene (most commonly affected gene in high-risk patients) in medulloblastoma and establish its potential as a future target of therapeutic intervention in high-risk patients.