Lindy Zhang, MD PhD
Johns Hopkins University School of Medicine
Targeting the intersection of signaling pathways and immunobiology in malignant peripheral nerve sheath tumors
In Dr. Zhang’s own words:
Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue cancers. MPNST are difficult to treat and there are no drugs that have proven effective in clinical trials for patients with MPNST. It is known that MPNST cells have abnormal over-activation of a major growth signaling pathway called RAS and so, studies have focused on drugs that turn this pathway “off”. However, these studies are often 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 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 a role for immunotherapies, a class of drugs that activates a person’s immune system to kill tumor cells. We predict that using targeted agents will alter the immune landscape in MPNST in a way that will makes it vulnerable to immunotherapies. We aim to 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: SHP2, SOS1, RAS(ON), RAF, and CDK4/6 inhibitor. We will give these drugs individually to the mice with tumors, monitor tumor growth, and then extract the tumors. The tumors will be processed and immune cells within the tumors will be isolated and studied. Our results will be used to design future clinical trials of immunotherapy drugs plus targeted drugs for patients with MPNST.