Awarding Grants to Research Projects Focused on Brain Tumor Treatment

"It is my long-term goal to become an independent clinical investigator and leader in the study of neurological cancer. Receiving funding from the American Brain Tumor Association and The Southeastern Brain Tumor Association allowed me to take concrete formative steps toward this goal and further inspired me to continue pursuing this work in my career. During my time as an ABTA-funded medical student investigator, I was able to work with and learn from leaders in the field of neurological cancer research on a cutting-edge project at a top institution. I learned skills needed to develop an impactful project proposal, submit application for funding, execute a project in an efficient manner, and collaborate across institutions. The laboratory techniques honed and collaborative mentoring relationships established during this work has bolstered my confidence and passion and prepared me for the crucial next steps in my career progression. As a direct result of this experience, I am prepared to complete future applications for funding, develop and lead independent research projects, work collaboratively across institutions, design and execute translational research, and mentor others. Thanks to the funded opportunity from ABTA, I feel not only inspired but empowered to continue to advocate for patients and work to discover new treatments for patients with neurological cancers."

His 2016 SBTF awarded grant, "Investigating the role of N-cadherin in the therapeutic resistance of Glioblastoma," provided results which resulted in submission to the Department of Defense and subsequent award of a two-year $664,000 DOD grant issued in February of 2018.

This grant resulted in subsequent federal funding from the Department of Defense for 2 years in the amount of $400,000 (+ Institutional indirect costs of about $200K). The research results were published in 2021 in the prestigious Journal of Clinical Investigation.

Osuka S, Zhu D, Zhang Z., Li C, Stackhouse CT, Sampetrean O, Olson JJ, Gillespie GY, Saya H, Willey CD, and Van Meir EG (2021). N-cadherin upregulation mediates adaptive radioresistance in glioblastoma. J Clin Invest 131, e136098 (in press)

https://www.uab.edu/news/research/item/11897-uab-researchers-identify-potential-therapeutic-target-against-malignant-brain-tumors

"The grant from SBTF supported a project focusing on exploiting glioblastoma cells’ metabolic vulnerability for more effective treatments for this lethal brain tumor. Findings from this project subsequently led to a NIH R01 grant that has allowed us to continue to work on the therapeutic strategy. Specifically, we have devised an approach to target glioblastoma cell’s deficiency in producing purine, metabolites that are essential building blocks for tumor cell propagation. We have been working on gaining new insight into how this therapeutic strategy can work and exploring ways to optimize it.

The support from SBTF has been extremely essential and helpful to our research. None of these accomplishments would have been possible without the generous support from the SBTF."

Dr. Yiping He

Dr. Thompson's project resulted in exciting findings: research reflects a commonly used steroid, dexamethasone, plus a drug efflux inhibitor tariquidar can enhance the efficacy of the targeted chemotherapeutic agent, dastinib to treat DIPG.

Published in the Journal of Neurosurgery June 2019 issue: "ABC transporter Inhibition Plus Dexamethasone enhances the efficacy of convection enhanced delivery in H3.3K27M Mutant DIPG"

The purpose of the research project funded by the SBTF was to enhance the efficacy of chemotherapy delivered directly into diffuse intrinsic pontine gliomas (DIPG). DIPGs are some of the deadliest pediatric brain tumors and are uncurable with surgery. We found that adding steroids and an agent that decreased the ability of DIPG cells to pump out chemotherapy significantly increased the survival of mice with DIPG. These results were published in Neurosurgery in 2020 and add to our understanding of how to improve survival in children with DIPG.

"Your contributions, belief, and support of our work have most definitely allowed us to generate a foundation for gliomagenesis and how the mutations we study contribute to the tumors.  We hope to share with you even more exciting ideas in this next application, which we believe, will be fundamental to future therapies.  The proposal will be dealing with an immunotherapeutic approach to targeting the most common mutation identified in gliomas."

Therapeutic Targeting of Id1 in Glioblastomas

Aim 1.1: Presented at 2015 AACR mtg, expect to submit manuscript in 1-2 months. In planning stages for preparing an RO1 grant proposal to NIH.

Aim 1.2: Unable to demonstrate a significant capacity, will not pursue this avenue of research.

Aim 2: Will continue to test the efficacy, predict the drug will cross blood brain barrier. Experiments ongoing, expect the work will be combined with work from Aim 1.1

This research proved to be an important stepping stone toward clinical trials using polio virus.

Interim report- Phase 1 of clinical trial in patients with recurrent GBM is progressing as planned, remarkable durable, complete clinical and radio-graphic responses in the first patients (as reported in application) are holding up. Currently observing similar responses in further patients.

This research was granted "Breakthrough Status" in 2016 which indicated the FDA wanted to speed up the research and saw great potential in the science.

This research was featured in a 60 Minutes story in March 2015. A follow up interview was held in May of 2016.

As of December 2019, this research was in Phase III Trials at several institutions and is receiving favorable results.

Support from SBTF enabled very important studies towards brain tumor therapy with recombinant poliovirus, PVSRIPO (all SBTF grants were related to this).

We reported clinical results of monotherapy (PVSRIPO alone) in recurrent GBM, showing unprecedented long-term survival and duration of response (New England Journal of Medicine, 2018). PVSRIPO is now (2021) in Phase-2 clinical trials [in combination with anti-PD1 (pembrolizumab)] against recurrent GBM at many leading cancer centers in the US (including at Duke in the Southeast).

We are in discussions with leading brain tumor experts in the country about the best strategy towards the first approved immunotherapy for GBM (PVSRIPO has Breakthrough Therapy Designation from FDA). In addition, PVSRIPO has shown great promise in recurrent, nonresectable melanoma (a Phase-1 clinical trial was just published; Journal of Immunotherapy of Cancer). It is now in Phase-2 clinical trials (in combination with anti-PD1) in recurrent, nonresectable melanoma at many leading cancer hospitals in the US. This trial allows patients with melanoma that has metastasized to the brain.

"Glioblastoma is the most common and aggressive primary brain tumor in adults, with a median survival of 14 months after diagnosis. Tumor recurrence is nearly universal, due to a combination of treatment resistance, tumor invasiveness, and communication with other cells in the brain. It has been found, in particular, that glioblastoma are more aggressive when they grow in neurogenic regions of the brain that normally give rise to healthy stem cells. Preliminary evidence from Dr. Hugo Guerrero-Cazares’ lab indicated that communication between brain tumor cells and stem cells via extracellular vesicles induces a pro-cancer phenotype in neural stem cells. My project explored the role of these vesicles by intercepting their mechanism using a drug called chloramidine, which blocks their release. If the use of chloramidine successfully blocks extracellular communication by glioblastoma cells and results in a decreased cancer malignancy, this would be a novel therapeutic pathway for treating patients with malignant brain cancer. During my time working on this project, we were able to determine concentrations of this drug that were non-toxic to cells, a foundational step for further experiments exploring downstream effects of the drug. Additionally, we began to elucidate a trend in the drug’s ability to stop the release of extracellular vesicles. Experiments in the project are ongoing and seek to determine working concentrations and effects of this drug on cancer progression."

"We made significant headway; now have critical mass of data supporting the role of the antiviral immune response in oncolytic viral anti-tumor activity; applying for federal funding using this data. The SBTF funds allowed researcher to establish an animal model that permits examination of the immune mediated anti-tumor response independent of other viral anti-tumor effects."

"We did indeed publish a manuscript on the project that was supported by our SBTF grant in the journal Cancer Research, and the SBTF support is acknowledged in the publication. Regarding our work on the drug verteporfin, we recently wrapped up our early phase 0/1 trial of verteporfin in human GBM patients and are now trying to publish that research."

"R01 funding on the role of PPM1D in medulloblastoma, funded 2012-2018. This funding was possible in part due to seed funding from SBTF."

Continued studies and submissions which resulted in 5 year RO1 grant from NIH of approx $1.6M

"Research initially funded (in part) by SBTF in 2009 led to additional studies. An immunotoxin from the initial study, conducted by Vidya Chandramohan, Ph.D., Preston Robert Tisch Brain Tumor Center, is now being evaluated in a Phase I/II clinical trial for recurrent Glioblastoma patients. https://www.clinicaltrials.gov/ct2/show/NCT02303678."

"The Brain Tumor Nanotechnology Laboratory has translated the use of the magnetic nano particles proposed in the SBTF grant over four years ago to a canine clinical trial at the University of Georgia.  Canines with spontaneous brain tumors are being treated with the nano particles our laboratory synthesizes for safety and efficacy testing. We had promising results and hope to take this to humans soon. Manuscript has resulted from research."

"Another victory for cancer researchers. This project which reduces tumor thrombosis by regulating the tissue factor pathway yielded findings which showed when tumor suppressor p14ARF is lost during tumor progression, this leads to the cocomitant loss of a factor that normally prevents coagulation". The advances mean anti-thrombotic agents might have anti-tumor effects Next step is to test the hypothesis in an animal model to see if this approach has promise for development of a novel therapeutic approach for patients with malignant brain tumors."

"Brain tumors are the number one cause of cancer related death in children, with medulloblastoma (MB) being the most common subgroup. Genomic-based classification has enabled the stratification of MB into distinct subgroups: WNT, SHH, Group 3 and Group 4, each with its own histology, molecular drivers and outcomes. The standard of care for MB patients includes surgery, followed by radiation of the brain and spinal cord, and subsequent chemotherapy. Although significant survival benefit occurs for many patients, some of these tumors are metastatic and resistant to conventional therapies, and thus classified as high-risk disease. Moreover, many children that survive this standard of care treatment will develop severe cognitive and quality of life issues as they get older. These statistics highlight the urgent need to develop the next generation of cancer therapeutics for MB patients, especially for those harboring high-risk disease.

A natural compound used in Chinese medicine for centuries, triptolide, has been shown to have potent antitumor activity. Despite its well-known efficacy, the mechanism of action of triptolide in cancer remains unclear. We performed computer-based database analysis of genetic biomarkers derived from such patients. Our analyses identified group 3 medulloblastoma patients as likely to benefit from triptolide treatment. Consistent with this prediction, we showed that triptolide attenuates group 3 medulloblastoma growth and increases survival of mice harboring such tumors. Mechanistically, we show that triptolide works by reducing the levels of an enzyme (OGT) capable of modifying the activity of a key driver of gene expression (Myc) and that without this modification MYC was degraded. Like triptolide, Minnelide (a triptolide derivative in clinical trials), reduced the tumor burden of patient derived group 3 medulloblastoma models. Thus, triptolide/Minnelide represents a novel therapeutic strategy to evaluate in MYC expressing group 3 medulloblastoma patients, which represents a cohort of pediatric cancer patients with a dismal outcome."

Dr. Keqiang Ye received a grant funding for a project entitled "PIKE-A/Cdk4 Complex is a Novel Drug Target for Treating Glioblastoma"

Amplification of chromosome 12q13-q15 (Cyclin-dependent kinase 4 (CDK4) amplicon) is frequently observed in numerous human cancers including GBM (Glioblastoma). Phosphoinositide 3-kinase enhancer (PIKE) is located in CDK4 amplicon. However, the pathological significance of CDK4 amplicon in GBM formation remains incompletely understood. We show that co-expression of PIKE-A and CDK4 in TP53/PTEN double knockout GBM mouse model additively shortens the latency of glioma onset and survival compared to overexpression of these genes alone. Consequently, p-mTOR, p-Akt and p-ERK pathways are highly upregulated in the brain tumors, in alignment with their oncogenic activities by CDK4 and PIKE-A stably transfected in GBM cell lines. Hence, our findings support that PIKE amplification or overexpression coordinately acts with CDK4 to drive GBM tumorigenesis. This finding was reported in Oncogene 2017. 

(Co-amplification of phosphoinositide 3-kinase enhancer A and cyclin-dependent kinase 4 triggers glioblastoma progression. Qi Q, Kang SS, Zhang S, Pham C, Fu H, Brat DJ, Ye K. Oncogene. 2017 Aug 10;36(32):4562-4572.) 

Dr. Michael Graner, PhD received funding for a research grant entitled "Heat Shock Protein Vaccines as Immunotherapy against Malignant Glioma."

Dr. Ihrie and Dr. Irish received funding though the Ann Faulkenberry Memorial Award in 2017 for their project entitled “Dissecting the contribution of the niche and immune cells to patient outcome using single-cell protein measurements.”

"Funding from the SBTF to the Ihrie and Irish groups allowed us to leap forward in our studies of primary brain tumor tissue using single cell approaches. With the support of this award, we developed a suite of bench and computational tools, used these to reveal previously unrecognized cells within brain tumor tissue, and identified novel targets in these cells. Our approach focused on measuring many proteins at the same time in millions of tumor cells. This approach revealed types of cells that have not been observed in healthy brains. Out of all the new cell types seen, there were two that stood out – one that was seen only in very aggressive tumors, and another that was a hallmark of tumors with much better than average outcomes. We believe these findings, which were reported in eLife in 2020, represent a fundamental advance in our understanding of glioblastoma. No prior work had resolved glioblastoma cell types that were so closely linked to patient outcomes. We named the two new cell types based on the clinical outcomes of tumors that contain them. Perhaps the most important cell type found is the Glioblastoma Negative Prognostic (GNP) cell subset, which is found in the most aggressive glioblastomas. These GNP cells are the ‘worst of the worst’ within this terrible disease."

One of the main articles supported by this award can be freely accessed here.
Popular coverage of the work and descriptions of their broader collaboration can be found in this article, and on healio.com and was highlighted in an article from Vanderbilt Medicine.

Radiation therapy (RT) for brain cancers often leads to uncontrolled activation of brain’s immune cell microglia and a series of unfortunate events called complement activation. These complement proteins in the brain are important for maintaining the synaptic landscape that forms memory. We used a complement receptor inhibitor (PMX205) to prevent uncontrolled activation of microglia and complement cascade that prevented brain injury surrounding the brain tumor. In a nutshell, we found a way to prevent brain injury and cognitive dysfunction without interfering with the therapeutic efficacy of RT for brain cancers.

PMX205 can be taken orally and it’s currently under clinical trial for ALS in Australia that will facilitate clinical translation in the future.

ABTA Discovery Grant Targeting Glioma Complement Signaling
Distributed via an American Brain Tumor Association (ABTA) Discovery Grant

Dr. Hao's clinical interests are mainly in the molecular diagnosis and classification of brain tumors.

"The combination treatment of GBM with TRAIL and Hsp90 inhibitors” did not show synergistic effects on GBM after we tested the drugs in combination on a panel of glioblastoma cell lines and stem cell-enriched neurospheres."

Yusuf Mehkri’s lab has developed a novel hydrogel vaccine, which can better stimulate immune cells to attack GBM cells in the brain. Yusuf will examine using this novel vaccine in combination with radiation and temozolomide to gauge the efficacy of the vaccine to increase GBM cell death. He also aims to determine the optimal timing of administering the vaccine relative to standard of care. The results of this project could lead to an effective off-the-shelf vaccine for GBM patients.

"Our group has shown that a dendritic cell (DC – a type of immune cell) vaccine can induce a robust anti-tumor response and can extend overall survival in patients with glioblastoma (GBM). The vaccine effectively targets cytomegalovirus (CMV) antigens that are uniquely present in GBM. Studies have shown that CMV can affect the malignancy of GBM cancer cells helping them to survive and evade immune cells in the brain. Although effective, one significant issue with this current DC vaccine model is production. Production takes weeks, is costly, and requires expertise and invasive procedures for patients. To address this issue, we have developed a novel vaccine that can be loaded with a chemokine (chemical signal) to attract DCs and a tumor antigen to initiate an anti-tumor immune response. Thus far, we have shown that this novel vaccine can induce a strong immune response resulting in tumor regression in mouse cancer models.  

We now need to test how this vaccine interacts with standard therapy. Given the immunomodulatory properties of temozolomide (TMZ) and radiotherapy (RT), we hypothesize that timing of RT and TMZ delivery can be used to enhance the immune response generated by our hydrogel-based vaccine. This project will evaluate and compare these effects in mouse cancer models in the hopes of maximizing the vaccine’s therapeutic efficacy. Findings from this project will bring us one step closer to an off-the-shelf vaccine that can be added to the standard of care regimen for patients with GBM. It will also help drive further research into similar vaccine platforms that are easy to produce and effective."

Intratumoral Extracellular Metabolomic Biomarkers of IDH-mutant Glioma

IDH-mutant gliomas generally present at lower grade and are treated, but then recur years later. Therefore, clinical trials can take decades. Dr. Burns will capture biomarker information from patients undergoing treatment and compare it to biomarkers from mouse models. He hypothesizes that the information will yield rapid, individualized information about a patient’s response to a treatment, reducing the time spent on ineffective therapies and ultimately shortening clinical trials.

"IDH-mutant gliomas are the most common gliomas of young adults. Despite initial sensitivity to chemotherapy and radiation, they invariably progress into treatment-resistant and ultimately fatal tumors. Translation of novel therapies for glioma is complicated by the lack of biomarkers that indicate treatment effectiveness. Survival remains the gold standard outcome measure. Clinical trials for patients with IDH-mutant gliomas may require a decade to yield survival results, hampering timely progress in a complex field. When trials fail, as is typically the case, few insights into why the treatment failed are available to guide therapeutic improvements. The cycle is then repeated with new novel candidates leading to a growing list of failed drugs without clear directions for improvement. New tools are urgently needed to accelerate discovery of novel therapies.  Here we propose to evaluate biomarkers from live human IDH-mutant gliomas during surgery, and will compare these to findings from mice carrying human IDH-mutant gliomas. We will also determine if biomarker levels from the live tumor respond to currently available therapies in real time in mice. If so, this work can provide a path forward to more rapidly determine which therapies or combinations are most effective within individual patients.  We are optimistic that this strategy can open a new frontier of rapid individualized feedback which is so urgently needed to cure gliomas."