Cancer Biology & Treatment

At the Center for Bioelectrics we are applying to biomedical targets very high electric fields — megavolts per meter — for very short times — nanoseconds. These electric fields are stronger and shorter than had ever been used in the biology lab or the clinic... or in nature. Since cells and organisms have never in the history of life on earth seen this kind of electrical excitation, they have evolved no specific defense, regulatory, or signaling mechanisms that might be induced by this new kind of stimulation.

After initial nanosecond pulsed electric fields (nsPEF) experiments demonstrated success at decontaminating bacteria, researchers at the Center turned their attention to cancer. At that time, apoptosis was a central topic in cell and cancer biology research. Apoptosis is a programmed cell death, in contrast with unprogrammed necrosis, now called accidental death. The first studies to show that nanosecond pulses induce apoptosis, reduce mouse tumor size, and kill human tumor cells were in 2002 and 2003. Since then, studies at ODU have shown that nanosecond pulses can kill many types of tumors and furthermore can induce an immune response in treated animals. Ablation with nsPEF of melanoma, breast, liver, and colorectal cancers initiates an antitumor immune response that both assists tumor eradication and prevents the formation of new tumors. Researchers at the Center are currently characterizing this immune response and exploring the efficacy of combination therapies.

Cold atmospheric plasma (CAP) produces reactive oxygen and nitrogen species, ions, and transient electric field, each exhibiting anticancer activity and together amplifying their individual activities to devastate malignant cells. Its viability as an anticancer therapy is illustrated by recent clinical trials of CAP treatment of patients with head and neck cancers. At the Center for Bioelectrics, we focus on inhibitory effects of CAP on cancer metabolism, proliferative signaling, and inflammation and how they may be exploited to address therapy resistance. For example, we recently discover that CAP at an unexpected low-dose regime can simultaneously suppress multiple supply lines to cancer survival (e.g. metabolism, proliferative signaling, angiogenesis), often known as cancer hallmarks, in therapy-resistant malignant cells, with negligible impact on their healthy counterparts, leading to high-rate apoptotic death of malignant cells in vitro and in clinically relevant in vivo models. Findings such as these are being explored to develop novel strategies that can improve the current options for mitigating the risk of tumorigenesis, overcoming drug resistance, and enhancing prognosis of patients who receive current anticancer therapies.

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Cold Plasma Bioengineering

Cold plasma produces diverse biologically active agents, including reactive species, ions, photons, and will affect transient electric fields that are also produced endogenously by eukaryotic cells. This similarity has fueled extensive exploitation of its benefits to human health, leading to cold plasma-based procedures in clinical utility for coagulation and ablation and in clinical trials for treatment of wounds, head and neck cancers, and autoimmune skin disorders. Here at the Center for Bioelectrics, investigators engineer cold plasma chemistry to replicate and leverage beneficial biological effects of endogenous reactive species and ions for novel solutions that can improve the prognosis of patients with cancer (e.g. pancreatic, leukemia, breast, skin cancers), infection, and injured organs. Through multidisciplinary collaboration, we focus on (1) dose-controlled delivery of cold plasma and plasma-activated solution; (2) their effects on the mammalian host's immune response and energy requirement; (3) their molecular and cellular targets in pathological or regenerative tissues; (4) their benefits as a monotherapy for cancer, infection and injury or as a drug-delivery method for gene immunotherapy; and (5) their synergy with other bioengineering platforms such as pulsed electric field. Furthermore, investigators at the Center are interested in cold plasma-based infection control in agriculture and environment settings.

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Microbial Disinfection

Microorganisms are known to be vulnerable to oxidative stress and membrane poration induced by cold plasma and pulsed electric field (PEF), respectively. With cold plasma and PEF being developed into two complimentary bioengineering technologies in the Center for Bioelectrics, they are being advanced toward patient benefits. Against antibiotic resistance, investigators at the Center have developed a plasma activated solution (PAS) to achieve a 7-log10 reduction of pandrug-resistant bacteria and fungi without harming mammalian cells. This is significant given that these pathogens are resistant to all current antibiotics. Further, PAS is engineered to dismantle bacterial biofilm formed inside lumens of gastrointestinal endoscope channels and central venous catheters. Recognizing the current lack of effective eradication of in vivo microbial biofilm, implicated in diabetic foot ulcers and chronic obstructive pulmonary disease, investigators at the Center developed a PAS-based wound dressing therapy and demonstrated its efficacy and safety in disrupting MRSA wound biofilms, the culprit responsible for life-threatening bacteremia. Further, these discoveries are being expanded to meet the challenge of disinfection beyond medicine, for example PEF-reduced biofouling control of liquid food (e.g., orange juice), PAS-enhanced animal food safety, and PAS-based control of COVID spread by inactivating SARS-CoV-2 binding with human cells.

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Cold Plasma-Based Regenerative Medicine

Of diverse reactive species and ionic species produced by cold plasma, hydrogen peroxide and nitric oxide are known to promote cell proliferation and angiogenesis, respectively. These contribute to the basis of multiple successful clinical studies of cold plasma for wound healing. Interestingly, cold plasma activates, in a dose-dependent fashion, major signaling pathways important in regenerative medicine, for example Nrf2 for abatement of excessive oxidative stress common in injured tissues, Wnt for migration of stem cells, and HIF-1 alpha for angiogenesis. These studies suggest that cold plasma may be applicable beyond skin wounds. As an example, investigators at the Center for Bioelectrics discovered that cold plasma elicits neuroprotection against glutamate excitotoxicity by elevating cellular antioxidant capacity, a desirable function for treatment of stroke and spinal cord injury. In the case of vitiligo in which dysregulated T cells attack melanocytes to cause skin depigmentation and for which there is no cure, investigators innovated a gel prepared with cold plasma that disrupts T cell attack on melanocytes, arrests excessive oxidative stress, and promotes re-pigmentation of vitiligo lesion in animal models. This in vivo efficacy is successfully demonstrated in a controlled and randomized clinical trial. Current focus is to improve mechanistic insights and translational readiness.

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HSP90 inhibitors modulate Acute and Chronic Lung Injury

Acute Lung Injury (ALI), acute respiratory distress syndrome (ARDS) and Pulmonary Fibrosis (PF) are major determinates of morbidity and mortality. FDA-approved therapeutic interventions are limited, and new drugs are thus needed. Heat Shock Proteins (HSP) are chaperones that assist a high number of client proteins during their folding, stabilization and/or degradation. HSP90, the most ubiquitous protein of the family, plays a major role during lung injury and inflammation. Indeed, HSP90 is a critical regulator of pulmonary endothelial permeability and modulates key proteins, including RhoA, ROCK1, cofilin and VE-cadherin, thus participating in the development of alveolar edema. Consequently, HSP90 inhibitors control at multiple levels both inflammation and lung injury. Among the >400 client proteins, HSP90 stabilizes Transforming Growth Factor-β (TGF-β), its receptor and Raf, ERK and Smads signaling, that are directly involved in the development of chronic lung injury. HSP90 inhibitors reduce mortality in several animal models of ALI and prevent the development of Pulmonary Fibrosis. Further investigations are required to establish optimal dose strategy, potency, and therapeutic schemes of the various new HSP90 inhibitors.

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