AACR-Novocure Tumor Treating Fields Research Grants

The AACR-Novocure Tumor Treating Fields Research Grants represent a joint effort to promote and support innovative research focused on Tumor Treating Fields (TTFields), which are intermediate frequency, low intensity, alternating electric fields that disrupt cell division in cancer cells. These grants are intended to provide a deeper understanding of the mechanisms of action of this novel anti-cancer treatment modality and to accelerate the development of new treatment strategies to advance therapeutic options for cancer. The research proposed for funding must be focused on the preclinical application of TTFields in cancer and may be basic or translational in nature.

2020 Grantees

Carsten Hagemann, PhD

Carsten Hagemann, PhD

Privatdozent (Assistant Professor)
Universitätsklinikum Würzburg
Würzburg, Germany
Overcoming the blood brain barrier drug delivery hurdle with TTFields

Research
Many potential drugs are unable to reach the brain due to the blood-brain barrier (BBB). Dr. Hagemann and his research group previously demonstrated the feasibility of transiently opening the BBB and, consequently, increasing permeability via TTFields. In this study, they are elucidating the mechanisms by which TTFields open up the BBB. Using 2D, 3D, and organotypic tissue models, they are exploring the potential clinical application of this TTFields effect on the BBB.

Biography
Dr. Hagemann’s PhD was awarded for work on Raf mediated signaling by the Julius-Maximilians-University Würzburg, Germany. During his postdoctoral training at Leicester University, his research expanded to stress activated kinases. He subsequently became head of the Tumor Biology Research Laboratory in the Department of Neurosurgery, University Hospital Würzburg. He is Privatdozent (assistant professor equivalent) for experimental neurosurgery, focusing on molecular growth mechanisms of glioblastoma multiforme, developing new drug delivery systems and TTFields.

Acknowledgement of Support
Our engagement in TTFields research led to the discovery of potential of TTFields to transiently open the blood-brain barrier. Support by the AACR-Novocure Tumor Treating Fields Research Grant enables us to translate this observation into future clinical practice, offering a solution to the current CNS drug delivery problem to treat brain tumors and other diseases.

Sandeep Mittal, MD, FRCSC, FACS

Sandeep Mittal, MD, FRCSC, FACS

Professor
Virginia Tech
Roanoke, Virginia
Epigenetic modifications induced by TTFields in patient-derived GBM cells

Research
Epigenetic modifications in cancer cells (e.g. methylation or acetylation of DNA or proteins) induced by TTFields remain unknown and may serve as prognostic or therapeutic response markers (e.g. hypermethylation of the MGMT promoter in GBM). Dr. Mittal and his research group are set to determine whether TTFields decrease the prevalence of epigenetic markers of TMZ resistance using patient-derived GBM cell lines. They plan to pursue the following aims: 1) determine if in vitro TTFields regulate the expression of MGMT by altering transcriptional activity of the MGMT gene; and 2) determine if in vitro TTFields alteration of cell morphology and the actin cytoskeleton is associated with changes in global histone acetylation, and if it can be manipulated with HDAC inhibitors.

Biography
Dr. Mittal received his medical degree from McGill University in Canada and completed a neurosurgery residency and a postdoctoral research fellowship at the Montreal Neurological Institute at McGill University. He subsequently completed a fellowship in epilepsy surgery, followed by another fellowship in neuro-oncological surgery. He is professor and chief of neurosurgery at Virginia Tech Carilion School of Medicine and Carilion Clinic. He also directs the Translational Neurosurgery Research Laboratory located at the Fralin Biomedical Research Institute at Virginia Tech. His primary clinical and research interests are related to developing novel therapies for brain tumors and epilepsy.

Acknowledgement of Support
The 2020 AACR-Novocure Tumor Treating Fields Research Grant will allow us to investigate an important aspect of TTFields that has largely remained unexplored thus far. That is, do TTFields delay the development of temozolomide resistance in patients with glioblastoma? We thank the AACR and Novocure for supporting this valuable and highly clinically relevant research.

Debabrata Saha, PhD

Debabrata Saha, PhD

Associate Professor
UT Southwestern Medical Center
Dallas, Texas
Evaluating efficacy of TTFields and radiotherapy in preclinical tumor model

Research
In this study, Dr. Saha and his research group aim to test the therapeutic potential of using TTFields with stereotactic ablative radiotherapy (SAbR) and an immune stimulatory drug (anti-PD-L1 antibody) in preclinical immune-competent models of lung and pancreatic tumor. They plan to pursue the following aims: 1) optimize the sequence of delivery of TTFields and SAbR for maximum tumor control in mouse syngeneic lung and pancreatic cancer models, and 2) optimize the sequence of delivery of TTFields, radiation and an immuno-stimulatory agent (anti-PD-L1 antibody) for synergistic tumor growth inhibition in mouse syngeneic lung cancer model.

Biography
Dr. Saha received his PhD in chemistry from the University of Nebraska, Lincoln. As a postdoctoral fellow at Vanderbilt Medical Center in Nashville, he carried out research on cell signaling and radiation therapy. After joining UT Southwestern Medical Center, Dr. Saha further expanded his research in the field of cancer radiotherapy in preclinical cancer models.

Acknowledgement of Support
I am extremely grateful to receive the 2020 AACR-Novocure Tumor Treating Fields Research Grant. Because cancers can rarely be controlled by single therapy modality, TTFields can be more effective in a combinatorial regimen because of its impact on multiple signaling pathways. I will be testing the efficacy of TTFields with radiation and anti PD-L1 therapy.

David D. Tran, MD, PhD

David D. Tran, MD, PhD

Associate Professor
University of Florida 
Gainesville, Florida 
Molecular mechanism of resistance to Tumor Treating Fields in glioblastoma

Research
Tumor-treating fields (TTF) were recently approved for the treatment of GBM and mesothelioma. TTF are low-intensity alternating electric fields that disrupt chromosomal segregation leading to apoptosis. Unfortunately, treatment resistance develops in most TTF responders; these resistance mechanisms remain largely unexplored. The research team has previously identified the Prostaglandin E2 Receptor (PTGER3) as a master regulator of TTF resistance. With this grant, they are set to determine the mechanism by which PTGER3 regulates TTF resistance.

Biography
Dr. Tran received his MD-PhD degrees from the Mayo Clinic College of Medicine in 2005 and completed his oncology and neuro-oncology fellowship at Washington University School of Medicine in St. Louis in 2011. He is currently associate professor, chief of the Division of Neuro-Oncology, and associate director of the Preston A. Wells, Jr. Brain Tumor Center at the McKnight Brain Institute of the University of Florida. He serves as the PI of several national trials in brain tumors.

Acknowledgment of Support
It is my distinct honor to receive this prestigious award. It will provide my team with the necessary resources to investigate the mechanism of how tumor cells develop resistance to this novel cancer therapeutic modality and to identify methods to overcome it.

Christopher Douglas Willey, MD, PhD

Christopher Douglas Willey, MD, PhD

Professor 
The University of Alabama at Birmingham 
Birmingham, Alabama 
Exploring Novo-TTF in advanced patient derived GBM models with multi-omics 

Research
Glioblastoma (GBM) research has relied on highly artificial models that select for highly proliferative tumors and no longer resemble the patient’s tumor. In contrast, Dr. Willey’s research group uses patient-derived models of cancer (PDMC) coupled with comprehensive molecular profiling to develop reliable models. In this AACR-Novocure project, they are set to investigate the impact of tumor microenvironmental (TME) stressors (hypoxia and nutrient deprivation) on TTF efficacy against derivative PDMCs (spheroids and 3D matrix-embedded tumors).

Biography
Dr. Willey completed a bachelor’s degree at Duke University, where he majored in biomedical engineering. He obtained his MD/PhD degrees through the Medical Scientist Training Program (MSTP) at the Medical University of South Carolina. After his internship, he completed a radiation oncology residency at Vanderbilt University in the American Board of Radiology Leonard B. Holman Pathway Fellowship Program. As a tenured professor in radiation oncology at the University of Alabama at Birmingham, his research is focused on cancer cell biology and kinase signaling in patient-derived models of cancer.

Acknowledgment of Support
I am honored to receive this AACR-Novocure Tumor Treating Fields Research Grant that will investigate TTF-resistance mechanisms in advanced patient-derived models of glioblastoma. This support will allow us to identify new targets and biomarkers to enhance the efficacy of Tumor Treating Fields and improve outcomes in this terrible disease.

2019 Grantees

Gerben R. Borst, MD, PhD

Gerben R. Borst, MD, PhD

Clinician Scientist
The Netherlands Cancer Institute
Amsterdam, Netherlands
Uncovering and exploiting interphase effects of Tumor Treating Fields

Research
TTFields are thought to specifically target dividing cells by interfering in various processes that regulate mitotic progression. Nevertheless, more recent data suggests that TTFields may also affect replication fork integrity and ionizing radiation-induced DNA damage repair. Although these observations are cell cycle phase dependent, the impact of TTFields on cell cycle distribution is not fully elucidated. Dr. Borst and his research group are set to study the interphase effects of TTF and exploit clinically relevant TTF sensitization strategies.

Biography
Dr. Borst trained as a radiation oncologist at the Netherlands Cancer Institute. During this training he obtained his PhD and performed a fellowship at the Institute of Cancer Research in London, where he studied the effect of radiotherapy induced G2 cell cycle arrest abrogation. He subsequently pursued a postdoctoral fellowship at the Princess Margaret Cancer Centre in Toronto, studying the effect of PARP inhibition on radiotherapy outcome. Currently, he treats patients with primary brain tumors and brain metastasis. His research group focuses on combining different modalities to increase the effect of cancer treatment.

Acknowledgement of Support
This AACR-Novocure Tumor Treating Fields Research Grant will allow me to clarify the working mechanism of Tumor Treating Fields. This support is of upmost importance in finding new ways to increase the efficacy of Tumor Treating Fields and thereby improve the treatment outcome for cancer patients.

Emil Lou, MD, PhD

Emil Lou, MD, PhD

Assistant Professor
University of Minnesota
Minneapolis, Minnesota
ECM-mimicking platform for testing TTFields and intercellular communication

Research
The influence of TTFields on vital processes such as cell-cell communication is unknown. Understanding the role of ultrafine actin-based tunneling nanotubes (TNTs) in bridging cells to allow cell-cell communication and facilitate cancer invasion is continuously evolving. Studies evaluating TNT-driven communication between cells cultured in 3D ECM-mimicking fibrous environments would elucidate factors regulating 1D, 2D, and 3D migrational plasticity. The goal of this project is to determine the effects of TTFields on cell proliferation and TNT-mediated intercellular communication in 3D ECM-mimicking fibrous environments.

Biography
Dr. Lou received his MD and PhD degrees (microbiology and immunology) from SUNY Upstate Medical University in Syracuse, New York. He performed his residency training in internal medicine at Duke University Medical Center and then subsequently completed his medical oncology and hematology fellowship at the Memorial Sloan Kettering Cancer Center. He completed an additional fellowship in neuro-oncology at the Preston Robert Tisch Brain Tumor Center at Duke. He is a member of the faculty in the Division of Hematology, Oncology and Transplantation, and a member of the Masonic Cancer Center, University of Minnesota.

Acknowledgement of Support
I extend my gratitude to the AACR and Novocure for this award. This grant affords the opportunity to bridge cancer cell migrational plasticity with the role of tunneling nanotubes in invasive cancers and to explore TTFields-driven strategies to overcome drug resistance.

Matthew R. Sarkisian, PhD

Matthew R. Sarkisian, PhD

Associate Professor
University of Florida
Gainesville, Florida
Enhancing TTFields therapy for glioma by dual inhibition of HDAC6 and SIRT2

Research
The electrical fields used in TTFields disrupt cytoskeletal microtubules, preventing cell division and glioblastoma (GBM) growth. Dr. Sarkisian proposes that the efficacy of TTFields therapy can be enhanced by combining TTFields with other therapies that disrupt microtubules. Normally histone deacetylase 6 (HDAC6) and sirtuin2 (SIRT2), which target microtubules, promote glioma cell proliferation and regulate primary cilia, microtubule-based cellular “antennas” that may increase the resistance of GBM to TTFields therapy. Treatment of human GBM cells with HDAC6 inhibitors and TTFields is more toxic to these cells than either treatment alone, potentially because HDAC6 inhibitors disrupt primary cilia. Dr. Sarkisian hypothesizes that combining TTFields with HDAC6/SIRT2 inhibitors will increase the effectiveness of TTFields as a therapy for GBM.

Biography
Dr. Sarkisian completed his PhD in physiology and neurobiology at the University of Connecticut, Storrs. He did his postdoctoral training in neurobiology at Yale University and subsequently joined the University of Florida as an assistant professor in the Department of Neuroscience. He is currently an associate professor with tenure at the University of Florida. His laboratory explores how primary cilia signaling affects the growth and behavior of normal neurons and glioma cells in the brain.

Acknowledgement of Support
My goal is to better understand why glioblastoma cells resist current therapies, resulting in such an aggressive and difficult to treat cancer. The AACR-Novocure Tumor Treating Fields Research Grant will allow me to investigate new strategies aimed at making tumor cells more receptive to therapy and thereby prolonging patient survival.

Michael D. Story, PhD

Michael D. Story, PhD

Professor
University of Texas Southwestern Medical Center at Dallas
Dallas, Texas
Exploiting the conditional vulnerabilities caused by TTFields exposure

Research
Dr. Story hypothesizes that aside from disrupting mitosis, TTFields downregulate DNA repair pathways and initiate DNA replication stress, resulting in DNA damage, the generation of R-loops, collapsed replication forks, and eventual mitotic catastrophe. Agents that interfere with replication fork maintenance or DNA repair may be more lethal when combined with TTFields. Thus, he sets out to test combinatorial therapies involving agents that target or enhance replication stress, TTFields and radiation, in in vitro and ex vivo models of lung and pancreatic cancers.

Biography
Dr. Story obtained his PhD at Colorado State University, Fort Collins. He pursued post-doctoral training at the UT MD Anderson Cancer Center, subsequently being promoted to assistant professor. He then moved to UT Southwestern Medical Center, Dallas as an associate professor, ultimately rising to full professor. He is currently chief of the Division of Molecular Radiation Biology and vice-chair of the Department of Radiation Oncology, and director of the UTSW Pre-Clinical Radiation Core Facility. He holds the David M. Pistenmaa MD, PhD distinguished chair in radiation oncology.

Acknowledgement of Support
I am grateful for this AACR-Novocure grant as it will allow my laboratory to continue to develop a better understanding of TTFields effects on cancer cells and how we can ultimately exploit that knowledge for clinical benefit.