CDMRP 2012 Investigator Vignette

Title: Investigating a Novel Tumor Suppressor That Cooperates with NF1 in MPNST Development

Investigator: Karen Cichowski, PhD; Brigham and Women's Hospital

My current grant focuses on trying to identify a new tumor suppressor that cooperates with the NF1 tumor suppressor.

We identified a new pathway that we think is very important towards the development of these nervous system tumors and that has given us some clues as to what kinds of drugs we could use to help treat them.

Neurofibromatosis is a very common familial cancer syndrome that affects one in 3,500 individuals worldwide. Patients develop the disease as a result of inheriting a loss of function mutation in the NF1 gene. NF1 normally regulates RAS; it turns off RAS. And so when you lose NF1 you get a hyperactivation of the RAS pathway. And it's well known that RAS is an important oncogenic pathway in a number of cancers.

The most common feature of the disease is the development of these benign and malignant nerve sheath tumors. While these tumors are benign, they can grow along any peripheral nerve both internally as well as externally, which can obviously be quite painful, debilitating, and disfiguring. This larger tumor on the right is actually still a benign neurofibroma. But it is from this type of benign tumor that the malignancies arise.

Neurofibromatosis Type 1 patients sort of fall into two categories: Patients that are not so severely affected and patients that are severely affected. And we had noticed that many of the patients that are severely affected not only have a mutation in the NF1 gene, but also a deletion of the 13 genes surrounding NF1 and these are referred to as microdeletion patients.

So, microdeletion patients harbor a complete loss of this region within the NF1 gene that affects NF1 and the surrounding genes. And the reason is because there are these repeats flanking this region and this whole region gets recombined out.

Now interestingly, if you look at the NF1 patients as compared to the microdeletion patients, the microdeletion patients have many, many more neurofibromas. They also developed these neurofibromas much earlier. They're more severely impacted by cognitive features. And they have an increased risk of developing the malignancies as compared to these nondeletion patients.

And so we reasoned that there must be a tumor suppressor in that region that also cooperates with NF1. And the interesting thing about that is not only would it be important to identify that tumor suppressor for NF patients, but that region is often lost, both NF1 in this large region and a number of other cancers such as glioblastoma and colon cancer.

And so we performed a screen and identified a gene known as SUZ12 within this region that appeared to function as a tumor suppressor and cooperates with NF1. Our genetic collaborator Eric Legius then found mutations in the SUZ12 gene that occur in tumor types from all NF1 patients, from tumors from all NF1 patients. So we really think this gene is important for many of the features associated with neurofibromatosis type 1.

The NFRP then funded our research to try to understand how this tumor suppressor gene functions, how it interacts with the NF1 tumor suppressor, and we were able to generate a genetically engineered mouse model looking at mutations in the NF1 gene as well as the SUZ12 gene. And in fact they do cooperate.

There are much more severe tumorigenic phenotypes, much more severe developmental phenotypes, and in fact we found that these animals develop other types of cancers as well, suggesting that this gene in conjunction with NF1 may play a role in these other non-NF1 related cancers as well.

The interesting thing about this tumor suppressor that we found is that it's an epigenetic regulator. So it functions by silencing a variety of other genes by modifying histones. And so when you lose it you-you up-regulate the expression of hundreds of genes at one time. And we hypothesize that this activates new oncogenes and new oncogenic pathways and can cooperate with signals such as RAS activation and NF1 loss to promote tumorogenesis.

Our next focus is to develop therapies for NF. There are currently no therapies for NF; the benign tumors are untreatable, the malignant tumors are largely untreatable, and so we've really been focusing on therapies.

Some of those therapies are going to come from basic biological and biochemical studies that we?ve been performing with support of the NFRP for many years. We are looking right now specifically for what genes are impacted by the combined mutations in NF1 and this other gene. We have hints that they affect pathways that are targetable by drugs and so that is probably an area that we will develop further.