Ian Davis, MD
Major Research Contributions:
Dr. Davis’s current research projects take genomic and proteomic approaches to explore the relationship between dysregulated transcription factors, chromatin organization and epigenetics in pediatric and adult solid tumors, in particular Ewing sarcoma and renal cell carcinoma.
His lab has identified alterations in chromatin organization that underpin oncogenic transcriptional targeting.
- Transcriptional regulation
- Cancer biology
Transcriptional deregulation plays a critical role in the development of many cancers. Mechanisms that result in oncogenic transcriptional deregulation include alterations in the expression or structure of proteins that modulate transcription directly or through epigenetic modifications.
Hematopoetic cancers and solid tumors (in particular sarcomas) frequently harbor recurrent and specific cytogenetic abnormalities such as chromosomal translocations and amplifications. In many of these cancers, the pathognomonic translocations involve genes that encode transcription factors. Translocations combine features of both native genes to generate unique fused (or chimeric) genes characterized by alterations in expression and structure.
Although the importance of these gene fusions to cancer development has been clearly demonstrated, a fundamental understanding of how these changes mediate oncogenesis remains elusive. Notable examples of translocation-associated transcription factor dysregulation include the MYC or MiT basic helix-loop-helix leucine zipper families which can be amplified or translocated in a wide range of cancers including lymphoma, neuroblastoma, melanoma, pediatric renal carcinoma and clear cell sarcoma.
Similarly, ETS winged helix-turn-helix transcription factors and PAX3 or PAX7 paired box/homeodomain transcription factors are translocated in Ewing's sarcoma and alveolar rhabdomyosarcoma, respectively. In each case, the abnormal transcription factor plays central role in the oncogenic process.
While it is presumed that these deregulated transcription factors mediate oncogenesis by altering target gene expression, we lack a mechanistic understanding of how dysregulation modifies the activity of these transcription factors and their participation in transcriptional networks. Furthermore, in contrast to the success of chimeric kinase inhibition, the molecular attributes of transcription factors make them challenging candidates for therapeutic modulation by small molecules.
Focusing on those classes of transcription factors strongly implicated in oncogenesis, Dr. Davis' lab employs genomic and proteomic approaches to study transcription factor targeting and gene regulation in cancer and in normal development. Through the identification of oncogenic transcriptional mechanisms and relevant transcriptional targets, they hope to develop novel biologically based therapies for these cancers.
Paul Monahan, MD
Self-Complementary AAV2 Factor IX for Hemophilia B
NIH NHLBI RC3 HL103396-01
PI: Scott McPhee, Asklepios Biopharmaceutical
Role: Co-Investigator, Clinical Principal Investigator
Double-Stranded AAV Vectors to Improve Efficacy and Evaluate Safety of Factor IX Gene Therapy
This work was instrumental in building a better understanding of the potential to safely achieve increased factor IX expression using AAV vectors. The current advances in novel technologies for hemophilia and late-phase human gene therapy trials is already underway for patients with factor IX deficiency were made possible through the hard work of Dr. Monahan and others to firmly establish the use of recombinant AAV in animal models.
Barbara Savoldo, MD, PhD
Dr. Savoldo’s research is on T-cell therapy in the fight against cancer. This process re-engineers a type of white blood cell called a T-cell, so that it recognizes and kills cancerous cells. This re-engineering inserts a gene into the T-cell using the ability of certain viruses to insert their genes into host cells.
Her research is primarily on Hodgkin lymphoma and non-Hodgkin lymphoma, two types of cancer marked by uncontrolled growth of certain white blood cells. She plans to open trials for patients with leukemia. She would like to expand this study to include patients with solid tumors, like neuroblastoma and brain tumors.