Problem Statement: The use of pulsed electric fields (PEFs) as a tumor treatment modality is receiving increased traction. A typical clinical procedure involves insertion of a pair of electrodes into the tumor and administration of PEFs (amplitude: ~1 kV/cm; pulse-width: 100 μs). This leaves a zone of complete cell death and a sub-lethal zone where a fraction of the cells survive. There is substantial evidence of an anti-tumor systemic immune profile in animal patients treated with PEFs. However, the mechanism behind such immune profile alterations remains unknown, and the effect of PEFs on cell signaling within sub-lethal zones remains largely unexplored. Moreover, different values of a PEF pulse parameter, for e.g. the pulse-widths of 100 μs and 100 ns, may have different effects on cell signaling. Thus, the challenge of answering the mechanistic questions is compounded by the large PEF parameter space consisting of different combinations of pulse-widths, amplitudes, and exposure times.
Intellectual merit: This Ph.D. research provides proof that sub-lethal PEFs can enhance anti-tumor signaling in triple negative breast cancer cells by abrogating thymic stromal lymphopoietin signaling and enhancing stimulatory proteins such as the tumor necrosis factor. Furthermore, experimental evidence produced during this Ph.D. research demonstrates that PEFs may not directly impact the intracellular mitochondrial membrane at clinically relevant field amplitudes. As demonstrated in this work, PEFs may influence the mitochondria via an indirect route such as disruption of the actin cytoskeleton and/or alteration of ionic environment in the cytoplasm due to cell membrane permeabilization. Thus, a reductionist approach to understanding the influence of PEFs on cell signaling is proposed by limiting the study to membrane dynamics. To overcome the problem of investigating the entire PEF parameter space, this Ph.D. research proposes a first-principle thermodynamic approach of scaling the PEF parameter space such that an understanding developed in one regime of PEF pulse parameter values can be used to understand other regimes of the parameter space. Demonstration of the validity of this scaling model is provided by coupling Monte-Carlo methods for density-of-states with the steepest-entropy-ascent quantum thermodynamic framework for the non-equilibrium prediction of the lipid membrane dynamics. / Ph. D. / A complete cure for cancer is still far from being realized despite very promising developments on the front of molecular drug therapy. One promising conceptual approach would be to achieve the ability to re-tune the cancerous signals that drive disease progression. To overcome current challenges in tuning cancerous signaling a paradigm change in cancer treatment is necessary. For example, a treatment strategy to alter cell signaling which leverages both the physical and chemical properties that accompany malignancy may be required. Electric fields, be it in the form of low-amplitude steady state fields or high-amplitude pulsed electric fields (PEFs), can induce distinct physical and chemical effects on cells. Hence, the use of electric fields as a clinical tumor treatment modality is receiving increased traction. However, the effect of these electric fields on cell signaling and cell behavior remains largely unexplored. This Ph.D. work provides experimental evidence that PEFs can directly impact cancerous cell signaling towards a less inflammatory and possibly less cancerous state. Although a noteworthy finding, the data poses another challenging question, i.e., how does the electric field impact cell behavior? Answering this mechanistic question is essential for FDA approval and a broader clinical use of the electric field modalities. An impediment to answering this question is the vast parameter space of electric fields (e.g., amplitude, pulse width, and number of pulses), which makes performing experimental mechanistic studies untenable. It is argued via experimental evidence gathered during this work that applying scaling laws applicable to lipid membranes may provide a solution to reducing the candidate PEF parameters to a manageable number. A non-equilibrium thermodynamic model is proposed that allows studying the behavior of lipid species using scaled electric field parameters. Thus, the v understanding gained via the proposed model can direct the next level of extensive biological assays and animal studies and eventually lead to effective cancer treatments.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/97564 |
| Date | 16 October 2018 |
| Creators | Goswami, Ishan |
| Contributors | Mechanical Engineering, Verbridge, Scott, von Spakovsky, Michael R., Allen, Irving C., Paul, Mark R., Qiao, Rui, Davalos, Rafael V. |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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