The immunomodulatory effects of RAS signaling pathway inhibitors in MPNST
Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue cancers and one of the most common types of soft tissue cancers in children and adolescent/young adults. MPNST is most often associated with Neurofibromatosis type 1 (NF1), an inherited syndrome, and it is the leading cause of death in these individuals. MPNST are difficult to treat because they do not have great responses to chemotherapy or radiation. Currently, there are no drugs that have proven effective in clinical trials for patients with MPNST. Patient outcomes are poor and have not improved in decades. It is known that MPNST cells have abnormal over-activation of a major growth signaling pathway called RAS, similar to other cancers. Recent trials are focused on drugs that turn this pathway “off”. In laboratory models of MPNST, our lab has shown effective use of a SHP2 inhibitor, targeting the RAS pathway, in combination with a CDK4/6 inhibitor, targeting how the cells regulate cell division. However, these experiments were done in mouse models that lack an immune system; and so, we do not yet know how the presence of immune cells that support the tumor, which is more like the human condition, may affect the drugs’ efficacy or how the drugs impact these immune cells. Understanding the interactions between the immune system and MPNST cells will identify targets for future therapies that can then activates a person’s immune system to kill tumor cells. This class of drugs, called immunotherapies, has been approved to treat different cancers, but have not shown benefit when given alone in soft tissue cancers. Recently, researchers have identified ways that targeted drugs change the immune cells around tumors. We, therefore, proposal that using targeted agents will alter the immune landscape in MPNST in a way that will makes it susceptible to immunotherapy. To do this, we will use a MPNST mouse model with an intact immune system to test a panel of Ras pathway targeted drugs that currently have good safety profiles in humans. We will give SOS1, RAS(ON), and RAF inhibitor (drugs that target RAS pathway) individually to mice with tumors and measure the tumor growth. After up to 28 days of treatment, the tumors will be extracted and the immune cells within the tumors will be isolated. We can identify and quantify the immune cell populations after each individual treatment. These findings will give us information about how the immune cells and the tumor cells are affected by each drug. We will also take these cells and study them individually, giving us more details on how the drugs alter the activity within the cells. By doing this, we can compare the changes that such treatments have on the immune cell populations. These carefully designed techniques will reveal what is not yet known about how the immune system and MPNST cancer cells interact. Our results will be used to design future clinical trials of immunotherapy drugs plus targeted drugs for patients with MPNST.