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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.

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

Scientific Statement of Research
TTFields are low-intensity intermediate-frequency alternating electric fields used to treat cancer patients. Clinical trials have demonstrated the effectiveness of TTFields in patients with glioblastoma. TTFields may interfere with the proper formation of the mitotic spindle, eventually activating the spindle assembly checkpoint (SAC) and triggering apoptosis. More recent data suggests that TTFields may also affect the replication fork integrity and inhibition of ionizing radiation-induced DNA damage repair. These observations are cell cycle phase dependent, but the impact of TTFields on the cell cycle distribution is not fully elucidated. More research is needed to investigate the underlying mechanism of how TTFields relate to cell cycle changes. This proposed research into the cell cycle effect and the connection to the earlier observations is important for developing novel strategies that will increase the efficacy of TTFields.

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 ICR in London, where he studied the effect of radiotherapy induced G2 cell cycle arrest abrogation. After his training he did 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

Scientific Statement of 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. Identifying effects of TTFields on TNTs in contextually relevant environments provides opportunity for novel therapeutic combinations of TTFields with TNT-targeting drugs.

Biography
After completing undergraduate studies in biochemistry at the State University of New York (SUNY) College at Geneseo, Dr. Lou received his MD and PhD degrees (microbiology and immunology) from SUNY Upstate Medical University in Syracuse, New York in 2004. 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 in 2010. He completed an additional fellowship in neuro-oncology at the Preston Robert Tisch Brain Tumor Center at Duke. Dr. Lou, a diplomate of the American Board of Internal Medicine, is board certified in medical oncology and internal medicine. He is also board certified in neuro-oncology through the United Council for Neurologic Subspecialties. He joined the faculty in the Division of Hematology, Oncology and Transplantation in 2011 and is 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

Scientific Statement of Research
Tumor Treating Fields (TTFields) is an FDA-approved therapy for glioblastoma (GBM). The electrical fields used in this therapy disrupt cytoskeletal microtubules, preventing cell division and 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. This project will improve understanding of how GBM cells resist TTFields and whether specific adjuvant therapies increase TTFields efficacy.

Biography
Dr. Sarkisian completed his BS degree in biological sciences at Clemson University. After working as a research assistant in neurology at Children’s Hospital in Boston, he completed his PhD in physiology and neurobiology at the University of Connecticut, Storrs. He did his postdoctoral training in neurobiology at Yale University and was recruited to 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

Scientific Statement of Research
This research hypothesizes that a major mechanism by which TTFields exerts its anti-tumor effect, other than by disrupting mitosis, is through the downregulation of DNA repair pathways and the initiation of DNA replication stress, resulting in DNA damage, the generation of R-loops, and collapsed replication forks leading to mitotic catastrophe. Agents that interfere with replication fork maintenance or DNA repair may be more lethal when combined with TTFields given the downregulation of specific DNA repair, chromosome maintenance, and cell cycle checkpoint pathways, amongst other altered signaling pathways deleterious to cancer cells. Combinatorial therapies using agents that target or enhance replication stress, applied concomitantly with TTFields and in combination with radiation, will be tested in models of lung and pancreatic cancers using in vitro and ex vivo models to provide evidence for novel clinical strategies empowered through the combinatorial use of TTFields.

Biography
Dr. Story took his PhD at Colorado State University, Fort Collins in 1989. He was a post-doctoral fellow at the UT MD Anderson Cancer Center and was subsequently promoted to assistant professor. In 2004 he 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. He is also the director of the UTSW Pre-Clinical Radiation Core Facility and 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.