State: California

Funded by the Dick Vitale Gala in memory of Lauren Hill

We have recently demonstrated that neuronal activity in the cerebral cortex can drive the growth of deadly brain tumors called high-grade gliomas. High-grade gliomas include tumors that affect children, teens and adults, such as glioblastoma, anaplastic oligodendroglioma and the childhood tumor diffuse intrinsic pontine glioma (DIPG). High-grade gliomas are the most lethal of all brain tumors. An important way that brain activity promotes the growth of these brain tumors is through release of a molecule called “neuroligin-3”. The purpose of this project is to develop a new therapy for these deadly brain cancers designed to sequester neuroligin-3 like a molecular sponge. We have shown that such a strategy is effective in principle, and now seek to test and optimize this strategy in preclinical models of high-grade glioma.

Funded by the 2015 Wine Celebration Fund a Need

Neuroblastoma is the most common extracranial solid tumor of childhood. Amplification of the MYCN proto-oncogene occurs commonly in high-risk neuroblastoma and marks a particularly aggressive and lethal form of the disease. We and others have described an array of highly targeted inhibitors to block kinases both upstream and downstream of MYCN in neuroblastoma. Among these targeted inhibitors, we have recently described a novel conformation disrupting inhibitor of Aurora Kinase A which potently induces MYCN degradation through an allosteric change in Aurora Kinase A. Because these inhibitors target distinct members of the MYCN pathway, we hypothesize that they will have nonoverlapping toxicities and that combinations of MYCN targeted therapies will more potently block MYCN. In Aim 1 of this proposal we will rigorously test combinations of MYCN targeted therapies for pre-clinical efficacy with the goal of rapidly translating combinations into patients with neuroblastoma. In Aim 2 of this proposal we will develop our novel conformation disrupting Aurora Kinase inhibitor to “dial out” toxic Aurora Kinase A activity and finesse more potent MYCN degradation in neuroblastoma to optimize therapeutic efficacy. Successful completion of this proposal will result in direct and rapid translation of therapeutic combinations of MYCN targeted therapies into children with neuroblastoma and provide new clinical grade drug candidates for conformation disrupting Aurora Kinase A inhibitors.

Funded by The V Foundation Wine Celebration
In honor of Joan and Koerner Rombauer

We have recently discovered that tumors cells with integrin αvβ3 on their surface are particularly difficult to treat because αvβ3 triggers reprogramming events that make tumors immune to certain anti-cancer therapies. Because we identified the pathways by which integrin αvβ3 drives these changes, we were able to reverse this behavior in preclinical research models by re-purposing FDA-approved drugs developed for other indications. Now, funding from the V Foundation will allow us to test whether this strategy can be translated to improve the response to therapy for patients with non-small cell lung cancer.

To do this, we will first look for the presence of integrin αvβ3 on circulating tumors cells that may be present in blood samples from patients who have become resistant to a targeted form of cancer therapy called Erlotinib. Once optimized, this assay could be used as a non-invasive blood test to identify the earliest emergence of drug resistance in lung cancer patients.  Next, we will conduct a Phase II clinical trial to test if patients who have developed resistance to Erlotinib can be “re-sensitized” to the drug by adding a second drug, an inhibitor of the NFκB pathway known as VELCADE. According to our preclinical animal studies, we expect the addition of this FDA-approved drug will allow patients to respond to Erlotinib therapy for a much longer time.

Since there is no clearly defined standard of care therapy for Erlotinib-resistant lung cancer, our project will address this unmet need and, if successful, would change the way lung cancer patients are diagnosed and treated.

In honor of Beth Jarvis