Cancer Biology and Genetics
Memorial Sloan Kettering Cancer Center
Our research focuses on studying the roles of the non-coding fraction of the human genome and on developing new tools to model cancer in mice.
By doing so we hope to achieve two related objective: the first is to fully understand the genetic and molecular mechanisms through which a normal cell becomes a cancer cell; the second is to create better mouse models of human cancers that can be used to rapidly test and develop novel therapeutic approaches.
Dr. Ventura grew up in the small village of Furci Siculo, on the eastern coast of Sicily. He went to medical school in Rome and obtained am MD in 1997. In 1998 he was accepted into the PhD program of the European Institute of Oncology in Milan, where he worked under the supervision of Pier Giuseppe Pelicci studying the biological functions of Shc proteins. From 2003 to 2008, Dr. Ventura was a postdoctoral fellow at the Massachusetts Institute of Technology, working in the laboratory of Tyler Jacks. During this time, he published the first demonstration that sustained loss of the p53 tumor suppressor that is required for tumor cell survival in vivo. He also became interested in the biology of microRNAs and reported the first example of genetically engineered mice carrying targeted deletion of an entire family of miRNA clusters. At the end of 2008, Dr. Ventura accepted the position of assistant member at Memorial Sloan Kettering Cancer Center and was the recipient of the Geoffrey Been junior faculty chair. Since joining MSKCC, he has continued working on non-coding RNAs in cancer and development, which remains a major interest of his laboratory. More recently, his group pioneered the use of CRISPR-based somatic genome editing to engineer oncogenic chromosomal rearrangements in vivo and he is exploring additional applications of this powerful technology. He received a postdoctoral fellowship from the American Italian Cancer Foundation, a Kimmel Scholar Award for young investigators, and is a William Guy Forbeck Foundation Scholar.”
A Novel Approach to Model and Study Oncogenic Gene Fusions in Mice
The ability to manipulate the mouse genome via gene-targeting in ES cells has enabled scientists to mimic the genetic lesions observed in human cancers. Thanks to these tools we can study how cancer develops and we can test treatments directly in vivo. While the use of genetically engineered mouse models of human cancers has contributed to greatly advance our understanding of this disease, two major technical limitations have slowed progress until recently. The first was our inability to accurately model a common class of cancer-associated mutations known as chromosomal rearrangements. The second was the lack of effective tools to introduce specific mutations directly into somatic cells of adult mice.
“This prize will be crucial for my group in at least two ways. It will allow us to continue and expand our work on somatic genome editing to create preclinical models for a wide array of human cancers. These models will enable us to define the molecular mechanisms through which gene fusions lead to cancer formation and will accelerate the development of new therapeutic approaches. In addition, I am sure that the opportunity to network with the other awardees and with biotech companies in the New York area will lead to useful collaboration and to new ideas for further studies.”
The recent advent of new genome-editing technologies, and in particular the CRISPR-Cas9 system, is revolutionizing biomedical research and promises to overcome these limitations. We have recently shown that the CRISPR-Cas9 system can be adapted to induce specific chromosomal rearrangements in the lungs of adult mice. We have used this approach to generate a novel mouse model of lung cancer.
Building upon these initial successes, this proposal has two major goals:
1) To use this lung cancer model to identify the molecular mechanisms underlying lung cancer initiation and progression and to model and possibly overcome acquired resistance to targeted anti-cancer therapies.
2) To determine whether the approach we have developed can be extended to model other chromosomal rearrangements associated with human lung and brain cancers.
Successful completion of this proposal will advance our understanding of human cancer, will generate useful preclinical models for drug development, and will provide the scientific community with a series of new and powerful genetic tools.
“Innovation to me means having the courage and the resources to tackle old unsolved problems in new ways. It also means being willing and ready to take advantage of unexpected, serendipitous, findings to explore new areas. This is in a way what happened to us recently, we started working on gene editing for completely unrelated reasons, and ended up developing innovative tools to advance cancer research.”