Identify the epigenetic vulnerabilities of Group 4 medulloblastoma (MB)
Group 4 MB has few recurrent mutations, and many of these are in enzymes that regulate the epigenome.
We will perform a comprehensive analysis of DNA and histone modifications in Group 4 MB.
We will then test whether drugs targeting these enzymes can inhibit tumor growth in vitro and in vivo.
A CRISPR screen will determine which of 119 proteins overexpressed in Group 4 MB are essential to tumor cell survival and would thus make potential drug targets.
These studies will allow us to identify effective epigenetic therapies for Group 4 MB.
AIM2
Define immunological targets in Group 4 MB
We will characterize the immune landscape of Group 4 MB to identify suppressive signals that prevent immune responses and find strategies for blocking these signals to augment immunotherapy.
In addition, will use DNA and RNA sequencing as well as mass spectrometry of tumor cells to identify antigens that tumors present to the immune system, and that could be used for vaccination.
Finally, we will test these strategies in vitro and in vivo (using humanized PDX models) to determine whether they are effective at inhibiting growth of Group 4 MB.
AIM3
Identify synergies between targeted therapy and immunotherapy for Group 4 MB
Recent studies have suggested that drugs that regulate the epigenome, in addition to inhibiting growth of tumor cells, can also enhance responses to immunotherapy.
We will test candidate therapies identified in Aim 1 to determine their effects on the immunological properties of tumor cellsas well as on the activity of immune cells.
Based on these studies, we will evaluate the efficacy of selected combinations of epigenetic and targeted therapies on group 4 tumors in vitro and in vivo.
