Oregon Health & Science University Archives

2019

Young Investigator

Jacob Henderson

Portland, OR

Executive Summary: Brain tumors are now the leading cause of cancer-related death in children. Chief among these culprits is medulloblastoma (MB), the most common malignant brain tumor of childhood. A particular subtype of MB, MYC-amplified group 3 tumors, pose the greatest challenge, with fewer than 20% of children surviving. Our preliminary studies identified genes associated with the TGFb pathway as necessary for MB survival. We have subsequently validated this biochemically and shown that by inhibiting TGFb activity we can kill the cancer cells and prolong survival in tumor-bearing mice. Further, we have preliminary evidence that in addition to the tumor cell intrinsic role of TGFb signaling, the TGFb tone results in immune cell exclusion and dysfunctional checkpoint expression. We hypothesize that abrogation of TGFb signaling will lead to increased immune surveillance and cell-mediated tumor rejection. To complete this research we are proposing the following:
Specific Aim 1: To evaluate the intrinsic and extrinsic impact of TGFb signaling on the tumor immune microenvironment using immune-competent MB mouse models.
a. Analyze tumor cell intrinsic changes to antigen presenting machinery and checkpoint inhibitor ligands.
b. Evaluate the effect of TGFbR inhibition on T-cells and other immune cells in an immunocompetent mouse model.
c. Study the efficacy of TGFbR1 and OX40 monoclonal antibody treatment as monotherapies and in combination.
Specific Aim 2: To perform correlative biology studies in patients receiving galunisertib (clinical trial concept #PNOC0019) to evaluate for changes in the peripheral immune system and tumor-infiltrating T cells after TGFbR1 inhibition.
a. Determine changes in peripheral T cell subset populations and T cell tumor infiltration with galunisertib treatment.
b. Study changes in tumor cell antigen presenting machinery and checkpoint expression with galunisertib treatment.
Successfully completed, our research will have immediate impact in pediatric MB research and patient care. These studies could justify the initiation of a second clinical trial in high risk MB patients. More broadly, we believe our studies will shed light on a novel relationship between MYC, the TGFb pathway and the immune system as it relates to tumor recognition and rejection. As MYC and TGFb signaling are drivers in multiple other pediatric cancers we think this component of the research has especially impactful and far reaching impacts.
Our overall goals are as follows:
•Characterize the effects of TGFb abrogation in cell intrinsic immune communication (antigen presenting machinery, checkpoint inhibitor molecules, etc).
•Our studies will tease apart a new and important relationship between two known cancer pathways, TGFb and MYC, and how they relate to immune exclusion in MB tumors.
•Validate that TGFb inhibition leads to increased immune surveillance and primes tumors to become more susceptible to immunotherapy.