Maria G. Castro, Ph.D.

Research Focus

Pediatric and adult brain cancer biology and therapeutics. Epigenetics, cancer metabolism, and signaling networks that mediate tumor progression. Uncovering the role of secreted cancer ligands in hematopoietic stem cell development and anti-tumor immunity. Nanotechnology to develop novel anti-cancer therapies. DNA damage, DNA damage response, and development of novel combination therapies for both adult and pediatric brain tumors, including novel immunotherapeutic approaches.

Current Research Activity

Mutant IDH1 Glioma Project

Glioma genetic models are needed to uncover mechanisms that mediate tumor progression, the interplay with the tumor microenvironment (TME) and response to therapeutics. We have generated the first genetically engineered mutant IDH1 mouse glioma model and isolated primary neurospheres (NS) from the tumors, which exhibit cancer stem cell-like properties. This has enabled us to develop a transplantable mIDH1 glioma model amenable to testing novel therapies. NS are derived from fully immune-competent (C57BL/6) mice, thus allowing examination of the TME and the impact of tumor mutations on the immune response. Our goals are to assess the effect of mIDH1 on transcription (using mRNA-seq) and on global DNA and histone methylation. The mIDH1 glioma model will also be used to identify promoter/enhancer region-specific changes in histone methylation marks (using chromatin immunoprecipitation followed by deep sequencing, or ChIP-seq). We are collaborating with Dr. Mats Ljungman, who pioneered bromouridine sequencing (Bru-seq), to identify and quantify nascent mRNA and gene transcription rates. Uncovering epigenetic patterning of histone 3 hypermethylation and cytosine modifications using next generation sequencing (NGS) technologies will contribute to the identification of novel pathways and gene regulatory networks which will provide novel insights into disease biology and uncover novel therapeutic targets.

DIPG Project

Diffuse intrinsic pontine glioma (DIPG) is a brainstem tumor that affects mainly children and for which there is no effective treatment. The most frequent DIPG mutations affect the N-terminal tail of histone variant H3.3 (encoded by H3F3A) and histone variant H3.1 (encoded by HIST1H3B) and result in the change of a lysine to methionine at residue 27, precluding methylation or acetylation of this key regulatory post-translational modification. In addition, six recurrent somatic activating mutations in ACVR1, which encodes for a bone morphogenetic protein (BMP) type-I receptor, have also been identified in DIPG tumors. BMP has very context-specific roles in the brain during development but its role in pediatric cancer remains unknown. We are using the Sleeping Beauty Transposase System to generate spontaneous in vivo tumor models that will allow us to analyze the contributions of these genes to DIPG pathogenesis. This work will elucidate how ACVR1 and H3K27M mutations contribute to DIPG progression and evaluate their impact on tumor response to DNA damaging agents. These studies will uncover novel therapeutic targets to improve prognosis for patients who suffer from DIPG.

Immunotherapy Development

The adult and pediatric brain tumor models we have established in our lab are ideal for developing and testing novel immunotherapies as they are implemented in mice with a fully competent immune system. We are using both immune mediated gene therapy strategies and nanoparticle-based vaccination approaches to develop new treatment strategies for these devastating brain cancers.

Clinical Trials

Our innovative work has led to an FDA-approved gene therapy Phase 1 clinical trial for malignant brain cancer which is currently enrolling patients at the University of Michigan.