LAB PROJECTS
CANCER RESEARCH
Understanding the Importance of LonP1 in Glioma Biology
LonP1 is a mitochondrial master regulator that plays an important role in driving tumor progression, treatment resistance, and other hallmarks of epithelial-mesenchymal transition in various cancers. The current investigation seeks to understand the importance of LonP1 in the context of the IDH1 mutation in astrocytoma and broader glioma biology. We have ongoing collaborations with Dr. Chris Hughes and Dr. John Lowengrub to mathematically model glioma tumor progression using vascularized micro-tumor systems. We also have several technical collaborations, where we share resources and methods with Dr. Chris Hubert at the Cleveland Clinic, Dr. Maria Castro at the University of Michigan, and Dr. Carolyn Suzuki at the University of Rutgers.
Learn More: Douglas C et al., 2022 and Douglas C et al., 2021
Developing and Evaluating the Efficacy of Proteasome Inhibitors with the Standard-of-care
Previously, proteasome inhibitors have failed to improve survival in the clinic. Our lab is investigating LonP1 and proteasome inhibitors in the context of improving the standard-of-care in glioma. This includes the use of methods elucidating the mechanism of cell death, disease progression, and various metrics related to proneural-mesenchymal transition with radiation, chemotherapy, and novel dual LonP1 and proteasome inhibitors. We work in collaboration with Long Island University and Dr. Bhaskar Das, who is a trained pharmaceutical chemist using structure-activity relationship modeling to develop new potential proteasome and LonP1 small molecule inhibitors.
Learn More: Douglas C et al., 2020
Proteasome Inhibitors in Glioma Treatment
The proteasome plays a vital role in the physiology of GBM, and our lab is currently investigating how proteasome inhibition can be used as a strategy for treating malignant gliomas. Marizomib is a second-generation irreversible proteasome inhibitor which has a more lipophilic structure, suggestive of a potential for penetration of the blood brain barrier (BBB). It has a broader and more prolonged inhibition proteasome inhibition profile than bortezomib and carfilzomib, the two proteasome inhibitors approved for treatment in multiple myeloma. Our studies showed that marizomib significantly inhibited survival of GBM cells and markedly decreased cell migration and invasion. Monkey studies revealed robust baseline chymotrypsin-like (CT-L) proteasome activity inhibition in brain tissue when treated with marizomib. Similar effects were seen against the caspase-like (C-L) activity. Additionally, mice treated with marizomib survived significantly longer than the control animals. These preclinical studies demonstrate that marizomib can cross the BBB and inhibit proteasome activity in primate brain, and elicit a significant anti-tumor effect in a rodent intracranial model of malignant gliomas.
Learn More: Di K et al., 2016
Oncogenic Effects of TRIM11 in Gliomas
TRIM11 (tripartite motif-containing protein 11) belongs to the TRIM/RBCC (the RING B-box coiled-coil) family of E3 ubiquitin ligases. Members of this family have been implicated in development, neurodegenerative diseases, and cellular response to viral infection and cancer. TRIM11 is known to be involved in the development of the central nervous system, but its oncogenic effects have yet to be identified in gliomas. Our previous work demonstrated that TRIM11 was over-expressed in high-grade gliomas and the expression pattern of TRIM11 strongly correlated with that of CD133 and nestin, and with the differentiation status of malignant glioma cells. TRIM11 could promote proliferation, invasion, migration in vitro and tumor growth in vivo, suggesting TRIM11 is a target for malignant glioma treatment. Based on homology modeling, we designed and synthesized small library of TRIM11 inhibitors. We are currently working on identifying the anti-tumor effects of these investigational compounds both in vitro using cell lines and in vivo using xenograft animal models.
Learn More: Di K et al., 2013
Uncovering the Role of Magmas in GBM
We are interested in understanding how cancer cells undergo metabolic reprogramming in response to standard of care treatment. In collaboration with Dr. Maria Cristina Kenney, Dr. Bhaskar Das, and Dr. Anita Lakatos, we utilize biochemical, genetic engineering, and proteomic approaches to understand the mechanisms on how cancer cells can alter their metabolism and whether they can be exploited through pharmacological inhibition for potential future therapies.
Learn More: Di K et al., 2019
Treating Pediatric Medulloblastoma and Diffuse Intrinsic Pontine Glioma (DIPG)
Through a collaboration with CHOC Children’s and Dr. Suresh Magge‘s recently established pediatric brain tumor program, we are interested in studying pediatric medulloblastoma and diffuse intrinsic pontine glioma (DIPG). Medulloblastoma is the most common type of cancerous brain tumor in children and typically occurs in the cerebellum. Despite current aggressive multimodal therapy, approximately 30% of patients eventually succumb to this disease and survivors cope with the long-term side effects that have significant impact on their quality of life. To find a better treatment strategy, our collaboration aims to study the role of mitochondria and its biogenesis in medulloblastoma. We are specifically exploring whether or not the inhibition of Magmas (a structural mitochondrial protein) can be used as a potential therapeutic strategy in pediatric medulloblastoma. DIPG is the deadliest pediatric brain tumor, accounting for about 10% of all brain malignancies and the survival rate is typically less than 2 years. Despite many approaches being used, no therapy has successfully improved average survival beyond one year. Using available cell lines and animal models, we are looking at developing new therapeutic interventions for this devastating disease.
Learn More: Hoerig C et al., 2022
CHEMOTHERAPY IMPLICATIONS RESEARCH
Cancer-Related Cognitive Impairment
We study the cellular and molecular mechanisms of cancer-related cognitive impairment (CRCI). This includes investigating mechanisms of chemotherapy-related neurotoxicity on neural precursor cells and hippocampal neurons, rodent models of CRCI, and examining therapeutic strategies for preventing neural damage and cognitive impairment. Our previous studies found that oxidative stress and mitochondrial dysfunction are associated with cisplatin-induced cognitive impairments in rats. Our laboratory employs stem cell-based and pharmacological approaches to examine the neurobiological mechanisms of CRCI and develop translational therapeutic strategies to ameliorate these deficits. In collaboration with Dr. Kalpna Gupta, we are examining mechanisms of CRCI and chemotherapy-induced peripheral neuropathy (CIPN) associated with ovarian cancer. Platinum-based chemotherapy is commonly used for ovarian cancer, which may cause neurotoxicity leading to painful neuropathy, ‘chemobrain’, and alterations in gait with increased propensity to fall/fractures, which may continue even after the discontinuation of treatment. We hypothesize that oxidative stress plays a critical role in cisplatin-induced damage to the nervous system and that inhibition of pathways associated with oxidative stress will attenuate cisplatin-induced neurotoxic side effects in female mice with ovarian cancer. We expect that the results of our study will lead to the development of novel therapeutics to reduce the debilitating sequelae of cisplatin in women with ovarian and other cancers.
Learn More: Lomeli N et al., 2021
Role of BDNF in Cancer-Related Cognitive Impairment (CRCI)
Brain-derived neurotrophic factor (BDNF) plays an essential role in neurogenesis and neuroplasticity. Our work and that of other groups have shown that chemotherapy-induced dendritic damage is associated with reduction in BDNF levels. Reductions of BDNF may contribute to cognitive impairment associated with cancer treatments. In collaboration with Dr. Lilibeth Torno at CHOC Children’s Hospital, we are assessing serum BDNF levels in adolescent and young adult (AYA) cancer patients. Current studies in our lab are examining the therapeutic potential of augmenting BDNF levels to prevent CRCI.
Learn More: Gooch M et al., 2022
CLINICAL RESEARCH
Clinical Research in Malignant Brain Tumors
As a translational research lab in the UC Irvine School of Medicine, our team is also actively involved in a number of clinical trials within the UCI Health System and beyond. We are part of a number of collaborative efforts to identify new targets for malignant glioma immune therapies, including a a multi-institutional, multinational effort to design a new autologous and allogenic tumor vaccine (ERC1671). Our other clinical trials explore the use of dendritic cell vaccines and novel CAR-T multi neo-antigen targeted approaches as innovative strategies for glioma treatment. In addition to immune therapies, our lab is focused on the clinical translation of specific, targetable oncogenic pathways in malignant glioma stem cells, and our translational research has directly led to clinical trials using proteasome inhibitors in an effort to improve survival in newly diagnosed and recurrent glioblastoma patients. To learn more about our clinical trials or to become a research participant, please visit the UC Irvine Chao Family Comprehensive Cancer Center page for more information.