Research Funding & Impact

ABTA-Funded Research Projects

2021 Newly Awarded Grants

Jack & Fay Netchin Medical Student Summer Fellowship

A Medical Student Summer Fellowship is a three month, mentor-guided summer research experience, intended to motivate talented medical students to pursue a career in neuro-oncology research.

Jessica Chen, PhD

Institution: University of California, Los Angeles

Mentor: Stephanie Seidlits, PhD 

A glioblastoma is composed of many different tumor cell types. As a tumor is being removed from a patient and grown in the laboratory, many of the cells that may be responsible for treatment resistance and invasion will die. Without those cells, researchers are not able to test drugs that can be used to prevent or combat cancer recurrence in the future. Therefore, our laboratory is testing a new way to grow cancer cells by creating a structure, or “scaffold,” for those cells to grow in, like a new home. By making the scaffold look very similar to the cancer’s original home in the body, we can increase cell survival after relocation. Saving as many tumor cells as possible will also allow brain tumor scientists everywhere to research cancer progression more effectively. In a matter of a couple of days, we can grow cells on many sets of scaffolds from a single patient’s tumor. This enables us to test many different drugs outside of an individual patient very quickly and all at once, instead of testing one drug at a time in one patient. Additionally, if the variations in tumors across patients can be more accurately characterized, physicians will be better informed when developing personalized treatment plans. For a cancer as aggressive and lethal as glioblastoma, a fast and reliable means of obtaining more information and testing more drugs, has the potential to yield significant improvements in patient outcomes. 

Nicholas Cho, BS

Institution: University of California, Los Angeles

Mentor: Benjamin Ellingson, PhD

Tribute: Supported by BrainUp

Molecular imaging techniques can provide functional information about brain tumor metabolism, biochemistry, and behavior. One important aspect of brain tumor physiology is glucose metabolism, or more specifically glycolysis, in which glucose is broken down and converted to energy quickly producing lactic acid as a side product. Our previous work has shown that different molecular subtypes of brain tumors have distinctly different metabolic behavior. Specifically, IDH-wild type gliomas, or gliomas that exhibit characteristics typical of these cell types, tend to exhibit more traditional metabolic characteristics, including elevated glycolysis and lactic acid production, whereas IDH-mutant gliomas have lower glycolysis and acidity due to their unique biology. We have developed a new imaging technique called “Aerobic Glycolytic Imaging”, or AGI, that we hypothesize can be used as a non-invasive imaging biomarker for glycolysis using MRI systems in the clinic. Thus, the purpose of the current project is to:  

  1. Biologically validate AGI using retrospective image-guided biopsy data from glioma patients  
  2. Explore whether successful IDH inhibition results in a shift in metabolism toward higher levels of  glycolysis due to reduction in 2HG concentration, an oncometabolite generated by IDH-mutant tumor cells.  

We theorize AGI may provide key insights into IDH-mutant brain tumor metabolism and behavior, allowing clinicians to identify and ultimately exploit potential therapeutic vulnerabilities. 

 

Mihai Dumbrava, BMSc

Institution: Mayo Clinic in Rochester, Minnesota 

Mentor: Jann N Sarkaria, MD 

Tribute: Supported by Uncle Kory Foundation 

Glioblastoma (GBM) is one of the most common and deadly adult brain cancers with an average survival rate of 14 months following diagnosis. GBM has a dire prognosis despite aggressive surgical removal, radiation, and chemotherapy, and there is a need to develop novel and curative treatments. Unfortunately, GBM tumors are often resistant to the current FDA-approved treatments including temozolomide and lomustine (CCNU). Several key molecular biomarkers, including O6-methylguanine methyltransferase (MGMT) activity and DNA mismatch repair (MMR) status, are linked to the variable response of GBM tumor patients to therapy. 
 
VAL-083 is a promising small-molecule chemotherapeutic that has a mechanism of action distinct from temozolomide and CCNU which may be able to overcome resistant GBM tumors. The mechanisms of sensitivity and resistance to VAL-083 in GBM are largely unknown. We hypothesize that the pathways involved in the repair of interstrand DNA breaks created by VAL-083 are dysregulated in GBM tumors sensitive to VAL-083. Therefore, in my project, I will attempt to classify tumors into different subgroups based on their genetic aberrations and response to VAL-083. Identifying a molecular signature sensitive to VAL-083 therapy alone and in combination with other agents will help to develop personalized treatment plans for brain tumor patients. 

 

Jovanna Tracz, BS

Institution: Eastern Virginia Medical School 

Mentor: Alberto Musto, MD, PhD 

Tribute: In memory of George Surgent

Glioblastoma Multiforme (GBM) is recognized as the most aggressive known cancer of the central nervous system in both children and adults. While the different classes of GBM are diverse, there is evidence that each major class expresses synaptic genes, permitting glioma cells to form neuron-glioma connections. These connections not only induce neuro-hyper-excitability in adjacent brain areas (causing symptoms such as epileptic seizures), but also allow glioma cells to further integrate into functional neural circuits and proliferate (expand and divide, resulting in more tumor cells). The precise mechanism by which these connections are established remains unknown.  

Our hypothesis states that the molecular cascades promoting synaptic formation result from the abnormal activation of specific proteins that induce signaling in both tumor cells and nearby functional neurons. As a result, the brain tissue surrounding the tumor expresses specific inflammatory molecules, such as CD-40, that further promote tumor growth. We use a mouse model, immunohistochemistry, and electrochemistry to study this mechanism by which diseased glioma cells reach out to healthy neurons to form cell-to-cell connections. These findings will help to identify molecular markers that can be visualized during neurosurgery and targeted with medical treatment. 

 

Michael Meadow, BS

Institution: University of Rochester 

Mentor: Nimish Mohile, MD

Tribute: Supported by Uncle Kory Foundation

Glioblastoma (GBM) is the most common malignant brain tumor in adults and it takes a devastating toll on patients and their families. Despite decades of research, GBMs remain incurable and invariably lead to rapidly progressive illness and death. Current treatment options are invasive, come with grueling side effects, and they fail to prevent tumor recurrence.  

It is the goal of this project to provide a new perspective as to how GBM tumors form and how to go about treating them. We aim to do this by understanding the regulation of an understudied protein in GBM: Sirtuin 6 (SIRT6). In GBMs, it is known that levels of SIRT6 become significantly reduced, but the exact relationship between SIRT6 and the tumor’s biology remains unclear. We will take three approaches to understanding SIRT6 and establishing it as a molecular partner in GBM treatment: 

  1. Study how SIRT6 is regulated in healthy astrocytes (a type of brain cell that can become a glioma, including GBM) compared to cancerous astrocytes, to gain insight into why the levels of SIRT6 are depleted in GBM. 
  2. Re-establish normal SIRT6 levels in GBM tumors to determine whether increasing SIRT6 will lead to the death of the cancer cells.  
  3. Begin development of a therapeutic, ncPROTAC, which may be able to use normal cell functions to stabilize SIRT6 in GBM cells and boost cancer cell death.  

Overall, these findings will yield unique insights into the biology of malignant gliomas and provide a novel therapeutic approach for the potential treatment of GBM. 

Yusuf Mehkri, BS

Institution: University of Florida 

Mentor: Maryam Rahman, MD

Tribute: Supported by Southeastern Brain Tumor Foundation 

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.

 

Rohan Rao, BS

Institution: University of Cincinnati 

Mentor: Soma Sengupta, MD, PhD 

Tribute: Supported by Uncle Kory Foundation 

Glioblastoma (GBM) is the most common malignant brain tumor in adults. Unfortunately, the mean survival time for a patient with a GBM is 12-15 months. The common treatment paradigm or standard-of-care for GBM is surgical removal of the GBM tumor, followed by radiotherapy and chemotherapy. The poor prognosis despite available treatments arises from the significant challenges of treating GBM tumors, including: (1) the physical barriers to drugs to be delivered to the brain and tumor cells and (2) the highly heterogeneous nature of the cells that form GBM tumors, which leads to recurrence of GBM even when treated by standard-of-care.  

Over the past few decades, advances have been made in understanding the biology of these tumors, but the treatment options for GBM still fall woefully short of the therapeutics that the patient population needs and deserves. As such, we are investigating the use of an advanced technology that is capable of transiently and non-invasively opening the blood-brain and blood-tumor barriers combined with the administration of small lipid-based, non-toxic nanoparticles carrying an RNA-based therapeutic payload designed to shut off key molecules that contribute to GBM cancer cell proliferation and growth. We have already conducted studies demonstrating that this combined approach is capable of killing brain tumor cells in an animal model. Our proposed research has the potential to eventually empower clinicians to combat GBM, as well as other brain tumors, more efficiently. 

 

Paul Rowley, BS

Institution: University of California, San Francisco

Mentor: Janine Lupo, PhD 

Glioblastoma is the most common tumor arising from the brain itself. Even with best current treatments, nearly all patients have a recurrence within two years and die within five years of diagnosis. Glioblastoma rarely spreads outside the brain and overall survival is correlated with the extent of surgical removal. These observations together suggest improving local control, or stopping cancer growth at its point of origin, is essential to improved survival. Radiation therapy after surgery does indeed improve local control, more than doubling median survival. However, radiation can cause fatigue and bystander damage to healthy brain tissue. Furthermore, minimizing radiation exposure, particularly to areas of the brain that serve memory and learning, is linked to better cognitive outcomes. Thus, optimizing radiation targeting is crucial in preventing disease spread and sparing healthy brain tissue.  

The current approach for radiation treatment uses structural brain imaging to generate a target based on a uniformly enlarged area surrounding the tumor, without considering common migration patterns of tumor cells in the brain. Our proposed study will use advanced MRI to uncover metabolic and microstructural features that can better determine where tumor cells are hiding in normal-appearing brain tissue for patients receiving modern standard of care radiation therapy. We aim to design a model to more accurately predict the location of tumor recurrence and demonstrate how it can be used to improve radiation treatment planning by creating a more accurate target for radiation therapy. 

 

Kaitlin Stitz

Institution: The Hospital for Sick Children 

Mentor: Vijay Ramaswamy, MD, PhD 

One of the most common brain tumours of childhood is ependymoma, a tumour type that represents one of the biggest challenges in pediatric neuro-oncology. Current treatments are limited to invasive surgeries and radiation. Children as young as one year of age have undergone these treatments. Despite this aggressive therapy, outcomes remain poor, with survival rates of less than 30% for those who can have a partial surgical removal, and only 60-70% in those patients with a complete surgical removal, owing primarily to the tumour cell not responding to radiation. Unfortunately, the reason why some ependymomas cannot be surgically removed is because they invade critical brain structures, which makes complete removal impossible. Some subsets of childhood ependymoma have a dismal outcome irrespective of aggressiveness of the surgery. Those children that survive have lifelong side effects of surgery and radiation to the developing brain. As such, new treatments are urgently needed. Our proposal will seek to identify drugs to make ependymoma cancer cells more sensitive to radiotherapy by using the cancer cells own response against it. We hope that this proposal will narrow down a list of therapeutic targets which are important to overcome resistance to radiotherapy. This will help us identify novel compounds that will expand our understanding of why some ependymomas do not respond to radiation and prioritize these drugs to take forward for further investigation.

2020 Awarded Grants

Research Funding—2020

Guided by our mission, and advised by a multidisciplinary team of experts, the ABTA is dedicated to funding research that has the potential to change the lives of people affected by brain tumors. We also aim to “seed the field” with promising up-and-coming researchers in the brain tumor space.

  • The ABTA awarded $418,000 in grants to 12 new projects
    • $200,000 funded 2 Basic Research Fellowships
    • $200,000 funded 4 Discovery Grants
    • $18,000 funded 6 Medical Student Summer Fellowships
  • The 2020 funded projects span multiple tumor types:
    • Atypical Teratoid/Rhabdoid Tumor
    • Glioblastomas
    • Malignant Gliomas
    • Medulloblastomas
  • Research areas of focus:
    • Drug Therapies/Experimental Therapeutics
    • Epigenetics
    • Immunology/Immunotherapy
    • Gene Expression/Transcription
    • Stem Cells

Basic Research Fellowship

The Basic Research Fellowship is a two-year, $100,000 grant, awarded to post-doctoral fellows who are mentored by established and nationally-recognized experts in the neuro-oncology field.

Emily Darrow, PhD

Institution: St. Jude Children’s Research Hospital

Mentor: Paul A. Northcott, PhD

Medulloblastoma is a common and deadly brain cancer diagnosed in children. Despite advances in therapy, an unacceptable number of affected children will either lose their battle to cancer or suffer severe long-term side effects from current treatment. Medulloblastoma is no longer considered a single disease and can be split into four distinct groups on the basis of biological and clinical differences. These medulloblastoma groups, known as subgroups, are believed to originate from different cell types in the brain of the developing child. During development, our genes respond to a series of environmental cues that ultimately give cells their identity and unique functionality. This process is controlled in part by proteins known as chromatin modifiers that regulate which genes are active and when.

Mutations in chromatin modifiers are especially common in Group 4 medulloblastoma; however, studies investigating the molecular consequences of these mutations and how they contribute to cancer development are largely lacking. The overall aim of this proposal is to determine how specific chromatin modifier mutations convert normal cells of the developing brain into Group 4 medulloblastoma cancer cells.

To achieve our research objective, we will apply state-of-the art molecular techniques to medulloblastoma patient samples and model systems. This research will advance our understanding of Group 4 medulloblastoma biology and provide more effective treatment options for affected children.

Tyler Miller, MD, PhD

Institution: Massachusetts General Hospital

Mentor: Bradley Bernstein, MD, PhD

Tribute: In honor of Joel A. Gingras, Jr.

I believe the best chance of a cure for aggressive brain tumors is to harness the immune system. Cancer immunotherapies require T-cells to migrate into a tumor and maintain their killing ability. T-cells are a type of immune cell that helps to create immunity to a specific foreign particle such as a signal on a cancer cell.

Brain tumors are packed with myeloid cells that should kill tumor cells and recruit T-cells; however, the tumors reprogram these myeloid cells to an immunosuppressive state, preventing T-cell migration and function. My aim is to revert tumor-associated myeloid cells to an anti-tumor state; for effective immunotherapy for brain tumor patients. To do this, I must characterize the functions and origins of immune cells in brain tumors. I have developed methods to simultaneously analyze gene expression, genetic mutations, and protein markers in single cells at massive scale, and am using these technologies to deeply characterize the immune microenvironment of brain tumors at unprecedented resolution. I am using these data to predict new therapeutic strategies that could kill or reprogram immunosuppressive macrophages. In this proposal, I am testing these new interventions using a recently developed brain tumor organoid model that maintains all of the tumor microenvironment, including immune cells.

This revolutionary model system allows me to test therapeutic strategies on patient-specific human myeloid cells, interacting with human T-cells and cancer cells outside the human brain, something previously not possible. It also allows me to test many more therapeutic strategies than is possible in a mouse model. Using this new model system, I hope to accelerate the discovery of transformative therapies that harness the immune system to attack brain tumor and extend survival for patients.

Discovery Grant

A Discovery Grant is a one-year, $50,000 grant to support cutting-edge, innovative approaches that have the potential to change current diagnostic or treatment standards of care for either adult or pediatric brain tumors.

 

Munjal Acharya, PhD

Institution: The University of California, Irvine

Tribute: Supported by Southeastern Brain Tumor Foundation

Radiation therapy (RT) for brain cancers leads to cognitive deficits that badly impact the quality of life. This is a particularly serious problem for childhood cancer survivors who have a normal lifespan but experience reductions in 3 IQ points per year. Unfortunately, few if any effective treatments exist for RT-related cognitive deficits. Our study will provide novel insights into the mechanisms by which RT impacts brain function. Using a mouse model, we will determine how RT disrupts the brain’s inflammatory communication by a series of unfortunate molecular events. We found that RT activates signaling proteins of the complement system, which is part of the immune system that enhances antibody and other immune cells to clear cell waste and pathogens and to promote inflammation. In the brain, it plays important roles in maintaining the memory units called synapses that form memory.

RT leads to uncontrolled activation of complement proteins that eventually leads to inflammation and, may help to spread cancer. Our studies, using an experimental drug (PMX205) to specifically target a component of complement, found that disruption of complement signaling is neuro-protective against radiation injury. This drug is currently under clinical trials in Australia for motor neuron diseases, can be taken orally and showed a minimal toxicity and a very good safety profile. This proposal will determine if combined treatment with radiation and PMX205 will provide an efficient solution to kill cancer as well as preserve normal brain function. Thus, our project will lay the foundation for a novel therapy designed to thwart cancer without damaging the brain function.

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Bikash Debnath, PhD

Institution: University of Michigan

Mentor: Alnawaz Rehemtulla, PhD

Tribute: In memory of Mark McLaughlin and in honor of all of those who have given on GBM Awareness Day

Glioblastoma (GBM) is the most aggressive cancer of the brain with the average time of survival being approximately 12 months. Nearly 13,000 new cases of GBM are expected to be diagnosed in 2021 with the expectancy to live 5 years being only 5.9%. Currently, there is no curative treatment option for GBM. 

DNA damage therapies such as radiation and temozolomide initially cause accumulation of DNA double-strand breaks (DSBs) as a part of their tumor cell killing mechanisms. The DNA repair protein, RAD51 plays a major role in the repair of DSBs and contributes to the resistance in GBM stem cells (GSCs). Our bioinformatics analyses discovered a significant association between RAD51 and poor overall survival of GBM patients. 

We have recently identified compounds that bind RAD51 using super computer-based machine learning models. Our laboratory experiments confirm that the compounds are effective at sensitizing GBM cells to radiation as well as temozolomide. 

Given the fact that RAD51 is associated with radio- and chemo-resistance as well as a poor overall survival and disease progression of GBM patients, we hypothesize that inhibition of RAD51 using small molecule inhibitors will sensitize GSCs to radiation and chemotherapy and improve overall survival of GBM patients. 

These hypotheses will be addressed in the experiments of the two Specific Aims: (1) to optimize using medicinal chemistry approaches to create more effective compounds; and (2) to evaluate the effectiveness of RAD51 inhibitors in a mouse GBM model. 

Lan Hoang-Minh, PhD

Institution: University of Florida

Mentor: Duane A. Mitchell, MD, PhD

Tribute: Supported by Humor to Fight the Tumor

 Despite decades of research, the prognosis for pediatric and adult patients diagnosed with glioblastoma and medulloblastoma remains poor, and novel treatment strategies are urgently needed. Harnessing patients’ own immune system has immense potential for cancer treatment. Among cancer immune therapies, adoptive T cell therapy (ACT), in which patient-derived immune cells are activated against tumor cells, multiplied, and then reintroduced into patients, is particularly promising. In preclinical as well as clinical studies at our institution, ACT has shown increased effectiveness over standard therapies in treating aggressive brain tumors. The success of ACT for brain cancers necessitates innovative approaches that increase T cell trafficking to brain tumor sites, as well as biomedical imaging modalities that enable the non-invasive monitoring of transferred T cell accumulation and persistence in the tumors, thus avoiding the need for serial biopsies.

Our project seeks to optimize ACT in new, clinically relevant preclinical models of recurrent glioma and medulloblastoma, while pioneering the application of novel and non-invasive magnetic particle imaging technology for the tracking of transferred T cells. Our studies will provide a better understanding of ACT dynamics and help optimize immunotherapy strategies against malignant brain tumors. Importantly, the development of magnetic particle imaging could lead to non-invasive treatment monitoring in patients, as several clinical scanners are rapidly being developed.

Gary Kohanbash, PhD

Institution: Children’s Hospital of Pittsburgh of UPMC

Mentor: Ian Pollack, MD

Tribute: Supported by Southeastern Brain Tumor Foundation

Immuno¬therapy is only moderately effective against deadly gliomas. Glioma tumors are full of myeloid cells that help the tumor grow and block immune response to immunotherapy. Myeloid cells are cells of the immune system that are supposed to defend the body against foreign invaders, including cancer cells.

We recently found an antibody that binds to myeloid cells in the tumor. We propose to attach a radioactive element to that antibody to kill tumor myeloid cells, and also deliver radiation to the tumor. Non-invasive imaging will be used to monitor tumor shrinkage and/or progression. We believe this novel approach can be a safe and highly effective way to increase the power of immunotherapy to treat glioma in adults and children.

2019 - 2021 Ongoing Projects

Research Collaboration Grant

The Research Collaboration Grant is a two-year, $200,000 grant, designed to support a multi-PI, multidisciplinary project that can accelerate advances in the understanding and treatment of brain tumors through collaborative team science.

Justin Lathia, PhD

Institution: Cleveland Clinic

Co-Pl: Joshua Rubin, MD, PhD

Co-Pl Institution: Washington University in St. Louis

Tribute: In memory of Victor Perez Maldonado

Advances in medicine emerge from prospective clinical trials, which allow patients with a given disease and meeting specific eligibility criteria to access studies that provide a controlled assessment of a therapy. This eligibility practice, while controlled, has largely ignored the possibility that female and male patients with glioblastoma, a highly malignant form of brain cancer, differ in incidence rates and outcome.

In the present era of Precision Medicine, sex of the patient, which is linked to incidence and survival, is not used to personalize care for glioblastoma.

Our preliminary and published studies uncovered a remarkably better response to standard care in female glioblastoma patients than in male patients as well as sex-specific differences in signaling networks and interactions in the tumor microenvironment.

In this project, we will utilize animal models that allow us to distinguish between the contribution of sex hormones and that of sex chromosomes to determine changes in signaling pathways and alterations in microenvironmental interactions by using a real-time in vivo imaging platform.

Our studies will demonstrate a paradigm for sex-specific approaches to personalized medicine in glioblastoma. Progress in our studies will establish a model approach for future studies that take into account sex as a biological variable in cancer care.

Basic Research Fellowship

The Basic Research Fellowship is a two-year, $100,000 grant, awarded to post-doctoral fellows who are mentored by established and nationally-recognized experts in the neuro-oncology field.

Javier Ganz, PhD

Institution: Children’s Hospital Boston

Mentor: Christopher A. Walsh, MD, PhD

Tribute: In honor of Joel A. Gingras, Jr.

Understanding how brain cancer starts requires studying the brains of normal people, and trying to figure out where and how the earliest mutations arise that might lead to cancer years later. Our preliminary data suggest that young healthy people already harbor cells in their brain showing mutations that we know drive brain cancer. How do these early mutations arise? Such somatic mutations can be acquired during prenatal development or later in life, but are usually not inherited from the parents. Acquisition of these mutations by normal cells can lead to microscopic abnormalities starting years before detectable tumors appear. By studying the occurrence of early cancer mutations in normal brains, we will establish a roadmap of early-occurring processes that precedes cancer initiation. Brain tumors in general are derived mostly from glial cells, astrocytes and oligodendrocytes, but not neurons. We developed a method that, for the first time, is able to study the complete genome of glial cells and see how they accumulate somatic mutations, starting from fetal life and through older stages. By studying this at the single cell level, will give us a unique opportunity to obtain information with unprecedented resolution, no attainable by any other means. This research will be the first of its kind, improving our understanding of brain tumor initiation but also in providing the basis for developing sensitive methods for detecting incipient tumors where no manifestation is evident.

Maria Garcia Fabiani, PhD

Institution: University of Michigan

Mentor: Maria Castro, PhD

Tribute: In memory of Bruce and Brian Jackson

This project relates to a sub-type of pediatric malignant glioma (pHGG) that is currently incurable. This tumor is found predominantly in the adolescent population and patients have a median survival of 18 months post diagnosis. The extrapolation of tested chemotherapeutics and targeted agents from adult HGG failed to improve the clinical outcome in the pediatric population, so the availability of a reliable experimental model is imperative for the testing of new therapies specifically designed for this type of tumor. The experiments proposed will shed light on many aspects of the tumor’s biology. We are interested in studying: 1) the role that the immune system plays in tumor progression and malignancy 2) and how we could harness it to test therapeutic modalities. To achieve this, we have developed a pHGG mouse model that mirrors the human disease and is a valuable tool to complete the proposed experiments. Having a mouse model to study this disease will allow us to explore many aspects of this type of tumor and possible therapies. The lab where I work has a strong background in brain cancer research and immune-therapeutics of cancer and offers an extraordinary working environment that will allow me to unravel key aspects of this tumor which currently remain unknown. We expect to provide compelling evidence to gain new insights on the biology of this subtype of pHGG which will lead to the development of novel immune-mediated targeted therapies.

Albert Kim, MD

Institution: Massachusetts General Hospital

Mentor: Elizabeth Gerstner, MD

Tribute: In honor of Paul Fabbri

Brain metastases (BM) are the most common tumor within the brain and carry a poor prognosis due to limitations in current treatment options. This is a critical unmet need, as the incidence of BM is rising as treatment for systemic cancer improves. Recent promising studies demonstrate that immune checkpoint inhibitors (ICI) can induce objective intracranial response. This response is unpredictable and often not durable. Further compounding this conundrum is the difficulty in accurately assessing response, as an increase in contrast enhancement on standard post-contrast MRI can be seen in treatment-related changes and true tumor progression. These challenges highlight the need for noninvasive biomarkers that reflect the biological response to ICI, as it is not feasible to obtain serial brain biopsies to understand why some patients benefit and others do not. Here, we leverage two novel, complementary approaches – perfusion MRI and circulating tumor DNA from blood and CSF – to understand the longitudinal changes within the tumor environment as a result of ICI. Our proposal is an unprecedented opportunity specifically tailored to patients with BM in which we will obtain detailed tumor blood vessel changes and the genomic basis for such changes during treatment. We seek to identify reasons why ICI ultimately fail, and specific patterns that predict response to ICI. This will result in optimization and better patient selection for these promising treatments.

Thi Thu Trang Nguyen, PhD

Institution: Columbia University

Mentor: Markus Siegelin, MD

Tribute: In memory of Katie Monson

Glioblastoma is the most common primary brain tumor with a current life expectancy of 12-15 months. In this proposal, the applicants propose a novel treatment strategy for glioblastoma. Using preclinical models, the investigators are evaluating a combination therapy of two clinically validated drug compounds, BH3-mimetics as well as a certain class of cholesterol lowering compounds that were recently shown to be efficacious in model systems of GBM. We are studying the mechanism by which this drug combination works, which has informed and led us to the proposed strategy. Using the most advanced model system resembling human disease, we will be studying this drug combination in “patient-derived xenograft” model systems. The results of these studies will allow us to propose clinical studies, involving this novel drug combination. In this context, it is noteworthy that both compounds have already entered clinical testing, enabling quicker access to patient application.

Jan Remsik, PharmD, PhD

Institution: Memorial Sloan-Kettering Cancer Center

Mentor: Adrienne Boire, MD, PhD

Tribute: Supported by an Anonymous Corporate Partner

Leptomeningeal metastasis (LM) or spread of cancer cells into the spinal fluid is increasingly common and results in rapid neurologic disability and death. Colonization of leptomeningeal space by cancer cells can take years or even decades after primary cancer diagnosis. The molecular basis of this process remains virtually unknown. Working from our observations from patient samples and unique experimental mouse models, we will dissect the mechanism of cancer cell entry to the spinal fluid using cutting-edge technologies. Moreover, the presence of fully functional immune system in our novel syngeneic mouse models enables us to target immune pathways essential for development and progression of LM. Our approach will rationalize the application of immune therapies, employing the patient’s own immunity as an active weapon against disseminated cancer cells.

Anh Tran, PhD

Institution: Northwestern University

Mentor: Craig Horbinski, MD, PhD

Tribute: In honor of Ned Smith and Team Smith Strong

Glioblastoma (GBM) is an aggressive form of brain cancer with no cure and few treatment options. Increased activation of receptor tyrosine kinases (RTKs), especially epidermal growth factor receptor, (EGFR) has been well-characterized in GBM. However, drugs that only targeting RTKs have limited efficacy on GBM patients. Our preliminary data show that tissue factor (TF), a protein normally involved in blood clotting, is increased in GBM and can activate many RTKs, even with RTK inhibitor treatment. TF does this through another protein called protease-activated receptor 2 (PAR2), and we found that we could block TF and PAR2 with drugs to decrease GBM malignancy. Furthermore, blocking these proteins also suppress brain tumor-initiating cells, which were known to cause therapeutic resistance and recurrence in GBM. In this study, we will: 1. Investigate how TF and PAR2 interact with and activate RTKs, with the goal to understand how they can help GBM tumors to evade treatments. 2. Determine how TF and PAR2 promote brain tumor initiating cells and test if this effect could be blocked by getting rid of either protein. We will also find the connection between TF, PAR2, RTKs, and tumor-initiating cells. This research will reveal novel targets for GBM therapy and extend our knowledge on the regulation of different factors that contribute GBM malignancy.