Research projects

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The following are all current UCLA Brain SPORE research projects.

Project 1

The lack of effective treatments for glioblastoma (GBM) patients remains a significant health problem and highlights the need for novel and innovative approaches. The broad overall goals of this research project are to investigate mechanisms of immune evasion following active immunotherapy, and to develop rational combinations of immunotherapeutic strategies to overcome the immunosuppressive milieu of the brain tumor microenvironment. We postulate that clinically relevant anti-tumor immunity to glioblastoma (GBM) must have two cellular components: 1) significant infiltration of tumor-specific tumor-infiltrating lymphocytes (TIL); and 2) blockade of immune-regulatory antigen presenting cell (iAPC) function within the tumor microenvironment. As such, our hypothesis is that the local cellular interactions between iAPC and T lymphocytes within the brain tumor microenvironment is a critical factor influencing the efficacy of immunotherapies in glioblastoma patients. A better understanding of the biology of these cellular interactions will provide insight into more effective ways to induce therapeutic anti-tumor immune responses for this deadly type of brain tumor.

In Aim 1, we will study the mechanisms by which iAPC limit glioma-specific anti-tumor immune responses in vitro and in vivo.

In Aim 2, will we evaluate the efficacy of combining tumor lysate-pulsed DC vaccination (to induce T-cell infiltration into tumors) with immune checkpoint inhibition  and other novel immunoregulatory targets (to block iAPC function) in pre-clinical syngeneic animal models of glioblastoma, and explore the use of a novel PET tracers as non-invasive imaging biomarkers of immune response.

Finally, in Aim 3, we will develop and validate predictive tumor, immunological and imaging biomarkers of response in recurrent glioblastoma patients enrolled in a Phase II clinical trial of DCVax-L +/- PD-1 blockade. These studies span the continuum of translational research in brain tumor immunotherapy, and will likely provided informative new insights for the development of new, rational immune-based strategies for brain tumor patients.

UCLA Brain SPORE Project 1 Tile

Project 2

Epidermal growth factor receptor (EGFR) signaling regulates the metabolism to fuel the biosynthetic and bioenergetic processes necessary for glioblastoma (GBM) growth and survival. In Project 2 of UCLA Brain SPORE, we hypothesize that therapeutically exploiting this relationship with rationally-selected targeted therapies will lead to increased tumor control.

Aim 1 will evaluate whether targeting EGFR-driven glucose metabolism – with EGFR tyrosine kinase inhibitors (TKIs) – creates a vulnerable metabolic state for the tumor, thereby rendering GBM xenografts synergistically susceptible to pharmacological p53 activation (e.g., with idasanutlin).

Aim 2 seeks to explore the mechanism underlying the synergistic lethality of combined targeting of EGFR-driven glucose metabolism and p53 in GBM.

Finally, Aim 3 will evaluate whether this novel combination is safe in GBM patients, while also obtaining preliminary efficacy data.  Included in this clinical study is the evaluation of whether rapid changes in glucose uptake in vivo – as measured with 18F-FDG PET – is predictive of therapeutic outcome in GBM patients.  Collectively, these studies hope to provide a new treatment paradigm, coupled with non-invasive biomarker, for selectively targeting and exploiting GBM metabolism as a means to the improve the outcomes for GBM patients.

Project 3

Radiation therapy (RT) is currently still one of the most effective treatment modalities against glioblastoma (GBM). However, while RT cures patients from many other cancers, all GBM eventually recur and are ultimately fatal. This data is in sharp contrast to the moderate radiosensitivity of GBM cells in vitro and in vivo, and the relatively high total radiation doses given to GBM patients clinically, thus indicating that RT failure in GBM is not easily explained by the intrinsic radioresistance of GBM cells. Recent experimental data support the view that GBM are organized hierarchically with a small number of radiation-resistant GBM-initiating cells (GICs) capable of re-growing a tumor and giving rise to all lineages of differentiated cells found in GBM, while their progeny lack these features.

According to the cancer stem cell hypothesis, all tumor-initiating cells have to be eliminated to achieve cure. A competing model of GBM is based on the "clonal evolution" model and assumes that all cells in a tumor can stochastically acquire a cancer stem cell phenotype. This model is supported by recent studies demonstrating acquisition of stem cell traits by non-tumorigenic GBM cells under hypoxia, at low pH, upon nitric oxide exposure, and our recent report of radiation-induced generation of induced tumor initiating cells. Since each clinical radiation fraction of typically 2 Gy kills only a portion of the total cellular tumor mass, our data suggest that elimination of GICs alone will be insufficient for GBM cure unless non-tumorigenic GBM cells are eliminated in parallel, and phenotype conversion is prevented.

Using an imaging system for cell populations enriched for tumor-initiating cells, we have screened chemical libraries of over 80,000 compounds and identified classes of compounds, including dopamine receptor antagonists, that interfere with radiation-induced phenotype conversion, eliminate non-stem GBM cells, and prolong survival in a mouse model of GBM. Results from the proposed studies could have a wider impact on cancer, as these principles may apply not only to GBM, but to many other solid tumors as well.

Project 4

This project seeks to develop novel treatments for gliomas with mutations of isocitrate dehydrogenase. This mutation results in epigenetic alterations that cause suppression of genes that regulate cell growth at least partially due to the fact that the enzyme takes on new functional roles. Our goal is to further investigate how this suppression occurs and whether we can utilize therapies directed towards alleviating this suppression. We believe that the transcription factor, Olig2 is playing an important role in the growth and gene regulation of IDH mutant tumors.

We theorize that  reducing the function of Olig2 through inhibition of its expression or its downstream effects, in combination with suppression of the mutant enzyme will enhance survival in patients with IDH mutant gliomas. During the first phase of this project, we will investigate our fundamental hypotheses and perform translational experiments to test the validity of our treatment strategies. The second phase of the project will utilize this information for clinical trials, in which we first use a short period of treatment to determine if our  strategies cause the desired biochemical effects. If the desired results are achieved, we will undertake a longer, interventional trial.

Seed Grant programs

Read more about previously funded projects of the Developmental Research Program and the Career Enhancement Program.