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.

2021 Grantees

Spencer J. Collis, PhD

Spencer J. Collis, PhD

Reader 
University of Sheffield 
Sheffield, United Kingdom 
TTFields-based DDRi combinations to overcome spatiofunctional heterogeneity 

Research
DNA damaging chemoradiotherapy is standard of care treatment for post-surgical management of patients with glioblastoma. The recent discovery that TTFields modulates DNA damage response (DDR) processes presents a critical opportunity to develop more effective, rationally-designed TTFields-based therapeutic strategies. However, such strategies need to overcome extensive interpatient and intratumoural heterogeneity, which includes diversity in DDR processes and inherently treatment resistant glioblastoma stem-like cell (GSC) subpopulations known to upregulate key aspects of the DDR. Dr. Collis’s group has recently developed novel clinically and surgically relevant ex vivo glioma stem-like (GSC) models that reflect spatiofunctional heterogeneity and post-surgical residual disease. In this project, he aims to establish 1) whether functionally and spatially distinct glioblastoma cell populations liberated from patient tumors demonstrate differential responses to TTFields therapy and 2) universal therapeutic vulnerabilities amongst tumor subclones and vulnerabilities specific to difficult-to-treat populations.

Biography
Dr. Collis a molecular and cell biologist with over 20 years’ research experience in DNA damage response and genome stability. Following his PhD at Cancer Research UK (CRUK)’s Paterson Institute, he carried out his postdoctoral training at the Johns Hopkins University and CRUK’s London Research Institute. In 2009, he established his own laboratory at the University of Sheffield and was subsequently awarded a prestigious CRUK Senior Cancer Research Fellowship. He is currently a reader in genome stability.

Acknowledgment of Support
The AACR-Novocure Tumor Treating Fields Research Grant will be instrumental in allowing us to further define how TTFields therapy interacts with the various subpopulations within tumors, as well as the postsurgical resistant stem cell niche responsible for tumor recurrence. This will help us to identify potential drug combinations that could further improve its clinical effectiveness.

Maurizio D’Incalci, MD

Maurizio D’Incalci, MD

Laboratory Head 
Humanitas University 
Rozzano, Italy 
TTFields in mesothelioma: mechanisms and novel rational drug combinations

Research
Although Tumor Treating Fields (TTFields) have shown activity in combination with standard chemotherapy in mesothelioma (MPM) patients, the molecular mechanisms which elicit these effects have not been fully elucidated. Based on his preliminary data, Dr. D’Incalci is set to investigate whether the sensitivity of MPM to TTFields is related to down-regulation of genes/pathways involved in cell cycle regulation, cell survival, and DNA repair. Mechanistic insights can help identify synergistic combinations of TTFields with specific chemotherapeutics. Using drugs currently used to treat MPM or those with a mechanism of action which hints at potential additive or synergistic effects with TTFields (such as DNA repair inhibitors like PARP inhibitors, inhibitors of cell cycle checkpoints and mitosis as well as epigenetic modulators including BET inhibitors), Dr. D’Incalci aims to identify drugs that can synergize with TTFields in vitro and in vivo.

Biography
Dr. D’Incalci obtained his medical degree cum laude from the University of Milan. He then specialized in pharmacology and in oncology. He subsequently worked in the Molecular Pharmacology Laboratory of the National Cancer Institute. He has been chief of the Cancer Chemotherapy Laboratory and of the Oncology Department at the Mario Negri Institute, Italy. Currently, he is a professor at the Humanitas University and head of the Cancer Pharmacology Laboratory at the Humanitas Research Hospital.

Acknowledgment of Support
The AACR-Novocure Tumor Treating Fields Research Grant will allow my research group to investigate the mode of action of TTFields and to identify mechanism-based effective combinations of TTFields with antitumor drugs against malignant pleural mesothelioma potentially applicable in the clinic.

Chang-Young Jang, PhD

Chang-Young Jang, PhD

Professor 
Sookmyung Women’s University 
Seoul, South Korea 
Identification of new target of TTFs in mitosis for therapeutic application

Research
Tumor treating fields (TTFs) therapy impacts mitotic cells by disrupting microtubule (MT) polymerization and cytokinesis. Dr. Jang’s team preliminary data suggest that Aurora B and MCAK may be involved in mediating TTF’s effects on mitosis. In this project, he aims to elucidate the mechanism underlying TTFs-induced Aurora B activation.

Biography
Dr. Jang received his PhD in biochemistry from Korea University, South Korea. His postdoctoral research at Stanford University focused on deeper mechanistic understanding of mitotic progression. Dr. Jang is currently a professor in the College of Pharmacy at Sookmyung Women’s University. His current research is focused on the communication between DNA damage response and mitotic exit checkpoint and the role of mitotic structures in mitotic catastrophe.

Acknowledgment of Support
I am very honored to receive the AACR-Novocure Tumor Treating Fields Research Grant. This support will enable my group to translate our basic science discoveries into new treatment strategies and improve the efficacy of TTFs treatment in glioblastoma and other cancer patients.

Sara G.M. Piccirillo, PhD

Sara G.M. Piccirillo, PhD

Assistant Professor 
University of New Mexico 
Albuquerque, New Mexico 
The impact of Tumor-Treating Fields on residual disease in glioblastoma 

Research
Residual disease in glioblastoma has been difficult to detect. Dr. Piccirillo previously contributed to the development of a multiple-sampling scheme that allows objective identification of the residual disease in the sub-ventricular zone (SVZ) of GBM patients. Her work revealed that in 65% of cases the SVZ contains treatment-resistant cancer stem-like cells. Thus, investigating residual disease in this area may hold the key to developing a valid therapeutic target for many patients. In this study, Dr. Piccirillo and her research group are set to examine the impact of Tumor Treating Fields (TTFields) on treatment-resistant cancer stem-like cells isolated from the SVZ of GBM patients using single-cell transcriptomics and functional phenotyping analysis.

Biography
Dr. Piccirillo received her PhD in translational and molecular medicine from the University of Milan-Bicocca, Italy. She pursued postdoctoral training at the University of Cambridge, U.K. She is currently a tenure-track assistant professor in the Department of Cell Biology and Physiology at the University of New Mexico Health Sciences Center, and a full member of the Comprehensive Cancer Center.

Acknowledgment of Support
I am extremely honored to receive the 2021 AACR-Novocure Tumor Treating Fields Research Grant. This support will provide us with the necessary resources to examine the impact of TTFields on mechanisms contributing to the ability of cancer stem-like cells to overcome treatment and seed the recurrent tumor in GBM patients.

Claudio E. Tatsui, MD

Claudio E. Tatsui, MD

Associate Professor 
University of Texas MD Anderson Cancer Center 
Houston, Texas 
Tumor Treating Fields in the therapy of spinal metastases 

Research
Dr. Tatsui’s group aims to investigate the therapeutic potential of tumor treating fields (TTFs) in 3D cultures derived from cell lines and fresh surgical specimens of spinal metastasis. His group plans to 1) identify the most effective inhibitory frequencies for different types of spinal tumors, 2) evaluate if increased electrical conductivity induced by metal improves the antiproliferative effect of TTFs, and 3) validate the most effective inhibitory TTF frequency in vivo.

Biography
Dr. Tatsui obtained his medical degree at Federal University of Parana, Brazil. He completed clinical fellowships in complex spine reconstructive surgery at the University of Miami and in neurosurgical oncology at the MD Anderson Cancer Center. He currently holds the position of associate professor in the Department of Neurosurgery at MD Anderson Cancer Center. His practice and research focus on the development of innovative treatments for patients suffering from spinal metastasis.

Acknowledgment of Support
I am very grateful to receive the 2021 AACR-Novocure Tumor Treating Fields Research Grant. Tumor growth remodels the bony microenvironment, creating changes in tissue anisotropic properties thus far never explored in the context of TTFields application. This research support will allow build up knowledge to develop new treatment strategies for spinal metastasis.

Suhe Wang, MD, PhD

Suhe Wang, MD, PhD

Research Associate Professor 
University of Michigan 
Ann Arbor, Michigan 
Natural electrical fields treatment to induce immune modulation in NSCLC

Research
Dr. Wang hypothesizes that Tumor Treating Fields therapy can induce the release of neoantigens from tumors, modulate the tumor microenvironment, and elicit anti-tumor immune responses against lung epithelial cells that have undergone lung adenocarcinoma-specific mutations. She is set to interrogate this hypothesis in a mouse model of inducible lung adenocarcinoma with KRAS activating mutations.

Biography
Dr. Wang obtained her MD and PhD from Fujian Medical University, China, and the University of Strathclyde, Scotland, respectively. She completed her post-doctoral training at King’s College London, U.K., and at the University of Michigan. Her main research interest is the application of nano-medicine to vaccines, cancers, and autoimmune diseases. Her research has been widely published and supported by the DOD, NIH, and US Thyroid Research Council.

Acknowledgment of Support
Tumor Treating Fields (TTFs) invented by Novocure have not been applied to KRAS-mutated NSCLC, a subtype of lung cancer with a poor prognosis. By completing this study, we hope that TTFs can be added as an effective treatment against KRAS-mutated NSCLC.

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

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.