Malignant brain cancers rank fourth in cancer deaths in the US and are second only to leukemia in children. Despite significant advances in neurosurgical techniques, radiation oncology, and numerous clinical trials, high-grade brain tumors, in particular Glioblastoma (GBM), remain incurable diseases. Understanding the molecular basis of the therapy refractoriness of GBM is one of the most important areas of glioma research.  

In this proposal, we will define the role of a novel glioma oncoprotein, termed isocitrate dehydrogenase-1 (IDH1), in driving progression and therapy resistance of GBM. IDH1 is a critical enzyme of the citric acid cycle (CAC). The CAC is a master regulator of metabolism that controls cellular energy production, lipid biosynthesis and cytoprotective guard mechanisms counteracting therapy-induced tumor cell death. Building on our preliminary studies documenting robust overexpression of IDH1 in human GBM tumor specimens, and high-level induction of IDH1 by anti-glioma therapies, we will molecularly characterize the precise mechanism, by which IDH1 protects glioma cells from therapy-induced cell death using glioma cell and mouse models. To target IDH1 signaling in GBM, we will leverage these model systems and mechanistical knowledge to develop and preclinically characterize RNA interference RNAi-based nanomaterials. Here, we will generate RNAi-functionalized spherical nucleic acids (SNAs) that neutralize IDH1 expression in established gliomas. RNAi, the biological mechanism by which double-stranded RNA induces gene silencing by targeting complementary mRNA for degradation, was awarded a Nobel Prize in 2006. Early studies indicated that RNAi has the potential to silence expression of various cancer genes implicated in growth and cell death, and consequently has motivated myriad preclinical studies to assess the potential of RNAi as anti-cancer therapeutics. Due to the negative charge of the RNA backbone, however, siRNA oligonucleotides do not penetrate negatively charged membranes effectively, cannot silence gene expression robustly and persistently in tissue in vivo, exhibit rapid renal and hepatic clearance and degradation by nucleases, have significant cytotoxic side effects, trigger auto-immune responses, and cannot cross the blood-brain-barrier (BBB). In contrast, SNAs are able to transverse cellular membranes, do not require the use of toxic auxiliary reagents, and accumulate in cells and intracranial tumors very effectively. They also exhibit extraordinary stability in physiological environments, cross the BBB, are highly resistant to nuclease degradation, and thus, can move through biological fluids and avoid being destroyed as “foreign materials.” We propose to preclinically evaluate these IDH1-tageting nanoconjugates to provide a fundamentally novel treatment option of patients diagnosed with GBM and will aid in successfully implementing RNAi-based therapies into neuro-oncological practice.

Cancers are heterogeneous diseases that, in many cases, are not effectively managed with existing treatments. Oncolytic viruses are promising biotherapeutic tools for cancer, whose clinical and commercial development is progressing rapidly. Currently, a major preclinical initiative in the field is to engineer next generation viruses or virus/drug combinations that break through the barriers to successful treatment. 

Our goal is to harness the innate cytokine response of the immune system — normally a major impediment to oncolytic virus therapy — to attack and kill tumours. Our preliminary experiments demonstrate one strategy to accomplish this: antagonizing the Inhibitor of APoptosis (IAP) gene family. In this case, a drug that antagonized the “Inhibitor of APoptosis” (IAP) gene family rewired tumour cells to initiate a self-destruct sequence upon exposure to cytokines, which were strongly induced in tumours infected with an oncolytic virus.  

To build upon these data, and to broaden the underlying concept, we propose a research plan to (1) elucidate the mechanisms responsible for synergy between oncolytic virus therapy and IAP antagonism, and (2) identify new opportunities to reprogram tumour cells to die in response to the cytokine cloud generated by oncolytic virus therapy.

Our group is exploring the use of gene therapy techniques to engineer viruses to stimulate the immune system to fight pancreatic cancer. In this proposal we will modify a vaccinia virus (similar to the virus used to immunize against smallpox) to produce hormones that attract a certain kind of tumor fighting immune cell called T cells to the sites of tumor.  

We have already administered a similar virus to patients and found that it is able to be delivered through the blood stream safely, travel to sites of tumor and infect the tumor cells. We have also shown that a special way to stimulate the immune system to generate tumor fighting T cells called aDC1 is effective in patients with a very aggressive kind of brain tumor.  

In this study we will combine these two approaches (stimulate T cells with aDC1 and attract them to the tumor with the vaccinia virus) in patient who have pancreatic cancer. There are several clinical trials examining immunotherapy for pancreatic cancer in progress at this time, we believe our approach will be a significant improvement on current trials.