The focus of my laboratory is to elucidate how deregulated cell signaling drives cancer. To achieve this we have been taking a multi-faceted approach; combining mouse modeling techniques with basic biochemical and cell biological studies. One of the most commonly deregulated signaling pathways in human cancer is the Ras pathway. Mutations can occur in Ras itself, upstream regulators, or downstream effectors. Therefore we have been focusing on how this pathway promotes nervous system, lung, prostate, and breast cancers. We have also been using our mouse models and insight to develop novel therapies, several of which have been developed into clinical trials.
A new family of tumor suppressors:
One rapidly evolving area of research in my laboratory relates to identifying a new family of human tumor suppressors. While mutations in RAS genes are common in many cancers, RAS mutations are conspicuously rare in breast, prostate and brain tumors, suggesting that Ras is activated via alternative mechanisms. We have recently identified several members of the RasGAP gene family, that function as human tumor and metastasis suppressors. These RasGAPs normally function to turn off Ras, therefore their inactivation results in unrestricted Ras signaling. Moreover, we have found that these proteins often serve as signaling scaffolds, integrating Ras with other important signaling pathways, thus explaining their robust tumor and metastasis suppressing activity.
There has been significant progress in developing targeted therapies for cancers driven by mutations in genes that encode enzymes (e.g. kinases). However, developing effective therapies for cancers that are driven by mutations that do not directly affect a targetable protein represents a major challenge in cancer research. Ras-driven cancers represent an important example of this challenge. We have been taking innovative approaches to develop novel combination therapies for Ras driven tumors and have recently made important advances in developing potential therapies for nervous system malignancies and lung cancer.
Epigenetics and the Ras pathway:
The deregulation of epigenetic processes is rapidly becoming appreciated as an important regulator of cancer. We have recently discovered that the Ras pathway can be regulated by and can cooperate with epigenetic enzymes. Thus, in addition to unraveling new mechanisms that contribute to tumorigenesis, these findings reveal additional genes/proteins that represent new potential therapeutic targets.
The NF1 tumor suppressor:
NF1 was the first RasGAP gene shown to function as a human tumor suppressor. It is inactivated in a common familial cancer syndrome, affecting 1 in 3500 individuals. NF1 patients can develop numerous peripheral nervous system tumors and are also predisposed to developing brain tumors, myeloid malignancies, and cognitive deficits. However, we and others have found that the NF1 gene is also mutated in a variety of sporadic cancers, including glioblastoma. We have been focusing on understanding how this enigmatic tumor suppressor functions on a cellular level in tumors that develop in NF1 patients, and sporadic tumors, and have been exploiting this insight to develop new targeted cancer therapies.
Karen Cichowski, PhD
Professor of Medicine