- Novel strategies for glioblastoma therapy and biomarker development
- Clinical translation of biotechnology, engineering devices, and imaging platforms
- Clinical outcomes after glioblastoma surgery
Integrated genomic analyses of glioblastoma specimens are beginning to unveil insights into the native tumor physiology of as it exists within the human brain. My laboratory has focused on developing comprehensive to tools synthesize these insights with our mechanistic understanding of the fundamental biologic processes, such as DNA replication, repair, and mitosis, to identify novel therapeutic and diagnostic platforms. By coupling integrate genomic analysis with patient survival data, we have identified the first predictive biomarker for glioblastoma response to chemotherapy Functional analysis of this biomarker, a microRNA, suggest that it serves as a master regulator of multiple DNA repair processes. Using this approach we have identify other master regulating miRNA of glioblastoma resistance.
Paralleling these efforts, we have carried out genome scale RNAi screens to systematically evaluate genes required for glioblastoma proliferation. Hybridizing these results with genomic mutational landscape and statistically rigorous interrogation of glioblastoma trancriptiome profiles have led to the identification of a number of novel therapeutic targets including the G-Protein Coupled Receptor (GPCR) Dopamine Receptor 2 (DRD2), the mitosis regulating kinase, Polo-Like Kinase 1 (PLK1), and the metabolic enzyme, Lactate Dehydrogenase (LDHA) uncovered systems level cross talk between molecular network mediating , metabolism, and chromatin structure.
Taken together, our studies suggest that combining molecular genetic/cell biologic approaches with integrative cancer genome analysis constitutes a powerful platform toward diagnostic and therapeutic development. However, this approach fundamentally neglects the interactions between the tumor and its microenvironment. To overcome this limitation, we performed studies to examine how glioblastoma biology is altered by the presence of micro-glia and bone marrow cell, both present in the glioblastoma micro-environment. The emerging picture is a reciprocal dynamic synergism whereby the glioblastoma cells express specific cell surface molecules to suppress the immunologic function of microglia and the microglia/bone marrow cells secrete select cytokines to stimulate glioblastma growth. Importantly, significant portions of this dynamic interaction are mediated through secreted microvesicles, suggesting these platforms as a viable platform for diagnostic and therapeutic development.
Our clinical translational efforts are focused in four areas. First, the endothelial cells forming the blood vessels in the brain are joined by specialized tight junctions that preclude approximately 98% of the available drugs from penetration. This barrier significantly restricts therapeutic options for glioblastoma patients. We propose that this barrier can be bypassed by direct therapeutic delivery at the time of surgical resection. To further this strategy and expand the spectrum of glioblastoma, we are collaborating with members of the UCSD Bio-engineering Department (Drs. Michael Sailor and Sungho Jin) to develop suitable nano-particles for drug delivery. We are also conducting clinical trials to surgically delivery genetically engineered oncolytic viruses into the regions. Second, the benefits that glioblastoma patient derived from surgical resection is directly proportional to the completeness of the resection. A major challenge in this regard is that glioblastoma infiltrated brain is sometimes difficult to distinguish from normal brain. To address this challenge, we have also collaborated with Dr. Roger Tsien’s laboratory to exploit nano-technologies that would facilitate tumor visualization as well as with Dr. Ander’s Dale’s laboratory to utilize novel imaging modalities to this end. Third, to improve the quality of glioblastoma patient care, we are analyzing national and regional clinical data base (collaboration with Dr. David Chang) to review the outcome of the various surgical interventions. Insights from these studies are then applied to refine the standard of clinical care. Finally, in collaboration with UCSD Radiation Oncology Department, we are developing technologies that would optimize radiation delivery to brain tumor patients.
Nitta M, Kozono D, Kennedy RD, Stommel J, Ng K, Zinn PO, Kushwaha D, Kesari S, Furnari F, Hoadley KA, Chin L, DePinho RA, Cavenee WK, D’Andrea A, Chen CC. Targeting EGFR induced oxidative stress by PARP1 inhibition in glioblastoma therapy. PLoS ONE 2010; 5: 1-9.
Zhang W, Zhang J, Hoadley K, Kushwaha D, Ramakrishnan V, Li S, Kang C, You Y, Jiang C, Song SW, Jiang T, Chen CC. miR-181d: a predictive glioblastoma biomarker that down regulates MGMT expression. Neuro-Oncology 2012: 14(6): 712-9.
Gibbs D, Kitamoto J, Williams DS: Abnormal phagocytosis by retinal pigmented epithelium that lacks myosin VIIa, the Usher syndrome 1B protein. Proceedings National Academy Sciences. 100:6481-6486, 2003. [Medline]
Huang M, Kennedy R, Ali AM, Moreau1 LA, Meetei AR, D’Andrea AD, Chen CC. Human MutS and FANCM Complexes Function as Redundant DNA Damage Sensors in the Fanconi Anemia Pathway. DNA Repair 2011; 10: 1203-1212.
Pan H, Cervino L, Pawlicki T, Jiang, SB, Alksne J, Detorie N, Russell M, Carter BS, Murphy KT, Mundt AJ, Lawson JD*, Chen CC*. Frameless, Real-Time, Surface Imaging Guided Radiosurgery (SIG-RS): Clinical Outcomes for Brain Metastases. Neurosurgery 2012; (in press). *equal contribution as senior authors.
McDonald CR, White NS, Farid N, Lai G, Kuperman JM, Bartsch H, Hagler DJ, Kesari S, Carter BS, Dale AM*, Chen CC*. Recovery of White Matter Tracts in Regions of Peritumoral Edema using Restriction Spectrum Imaging. American Journal of Neuro-Radiology *equal contribution as senior authors 2013 (in press)