Current Research

TWIST1 transcription factor function in glioblastoma (GBM)

TWIST1 is a master regulator of EMT that we first reported in GBM.  Our subsequent studies demonstrated its functional importance for glioma malignancy and tumorigenicity in part through promoting stem cell and mesenchymal phenotypes.  Loss of function studies support the potential therapeutic relevance of inhibiting TWIST1 or its regulated targets and pathways including Periostin (POSTN) and Akt among others. We also showed that site specific TWIST1 phosphorylation and dimer motifs regulate gene expression and invasive phenotypes.  Transcription factors present challenges to direct pharmacologic inhibition.  Therefore, in addition to basic mechanistic studies including novel protein-protein interactions, our current research is also addressing novel ways to target TWIST1 in part by leveraging these mechanisms of action.

PMIDs: 31540485, 29754406, 20646316

Oncoslice”; Microfluidic Drug Delivery for Pre-Clinical Screening of Patient Derived Tumor Cultures

The in silico predictions provided by genomic analyses do not always reliably predict actual patient treatment responses. In collaboration with the Folch lab and Ray Monnat at the University of Washington, Departments of Bioengineering and Genome Sciences we developed and tested a novel pre-clinical screening platform to bridge this gap. Using a microfluidic platform, multiple drugs are delivered to tumor derived slice cultures. Current research is focused on validation of predictive power in animal models, testing of immunotherapies and alternative tissue formats (3D bioprinting and tumor spheroids).

PMIDs: 32435696, 32270149

Large animal glioma model

In collaboration with Phil Horner (Director, HMRI Center for Neuroregeneration) and supported by a CPRIT grant we are developing a porcine syngeneic glioma model by orthotopic transplantation of transformed of SVZ derived pig neural progenitors into SLA matched pigs.  Unlike the rodent, the pig brain approximates the human in size and structure, thereby permitting more relevant studies of glioma growth patterns, imaging and surgical interventions.  This projects is further supported by collaborations with Larry Schook and Kyle Schachtschneider (Univ of Illinois) as well as HMRI CMP expertise and resources that permit clinical grade large animal surgery and MR imaging.

Intratumoral Molecular Heterogeneity

Intratumor molecular heterogeneity is a presumed result of selection pressure imposed by therapy and the tumor environment in the context of underlying tumor cell genomic instability. This heterogeneity has great implications for treatment resistance and tumor progression and the implementation of precision oncology. In collaboration with the Shendure Lab (University of Washington) we previously demonstrated intratumoral mutational heterogeneity in gliomas. Current studies involve the characterization and examination of the functional importance of epigenetic (collaboration with Dr Karol Bomsztyk at the University of Washington) and matrix protein intra-tumor heterogeneity.

PMID: 25608559

MGMT promoter methylation

Methylation of the MGMT promoter is a validated biomarker associated with longer survival after treatment with standard of care temozolomide and XRT “Stupp protocol”.  However, the impact of different assays and pre-analytic tissue variables on the determination of methylation status have not been rigorously analyzed.  In collaboration with Karol Bomsztyk (UW) and funded by an NIH U01 we are assessing the impact of different assays (methylation specific PCR, pyro-sequencing and MeDIP), fixation techniques, warm/cold ischemia time and intra-tumor heterogeneity on MGMT methylation in GBM.

Aging

Aging is arguably the most robust prognostic factor for outcomes in human gliomas but the mechanisms of aging that contribute to glioma malignancy are not well understood.  To address the lack of an aging appropriate glioma model to inform the study of aging mechanisms we generated a first in kind syngeneic glioma model employing transformed neural progenitor/stem cells from different aged donors implanted into different aged hosts.  We observed age dependent cell intrinsic effects on survival associated with age dependent increased genomic instability, hypoxic tolerance and hypoxia regulated gene expression and resistance to TMZ and XRT which recapitulated key features of human age-dependent glioma phenotypes.  Current research is aimed at further dissecting the roles of Hif1a and epigenetic changes as mechanisms regulating age-dependent genomic instability and glioma malignancy.

PMIDs: 23711239, 22958206, 21948688, 21900249

Brain Metastases

As their incidence increases and system therapies improve, brain metastases (BMs) are becoming a more prominent factor in outcome and quality of life for cancer patients.   In collaboration with Drs. Steven Wong and Hong Zhao (co-PIs) we are studying mechanisms of astrocyte tumor cross-talk in brain metastasis as a potential therapeutic target.  In addition, we are comparing expression and PET imaging of TSPO, a tumor and pro-inflammatory protein, as a potential biomarker of human brain metastasis malignancy and treatment responses.