Cancer--Treatment

Significant efforts are being made to understand and treat cancer, though methods are costly, invasive, and detrimental to healthy surrounding tissues. Techniques in optical imaging assess cancer cells’ state in response to treatments. The purpose of this study is to employ non-ionizing radiation as a potential safer therapeutic option and use timelapse fluorescence microscopy to monitor and quantify treatments to lung cancer cells. This thesis (1) measures and visualizes effects of a combinatory repurposed drug treatment through monitoring cellular metabolic state with time-lapse fluorescence microscopy and (2) develops a non-ionizing electromagnetic radiation system as a possible therapy modality. Results obtained demonstrate the effectiveness of a combinatory drug treatment and promising capability of non-ionizing radiation treatment, determined by an increase in fluorescence intensity correlated with metabolic state. In the future, different irradiation doses and drug combinations will be used for additional cancer cell lines, such as prostate and breast cancer.

With the advent of newly and more reliably designed targeted therapy methods in the past several years, targeted radionuclide therapy has attracted more attentions around the world as a more reliable treatment modality in combination with other well established traditional cancer treatments i.e., external beam radiotherapy and chemotherapy. Alpha particles have a high relative biological effectiveness (RBE) due to their high linear energy transfer (LET). However, to utilize them for therapeutic purposes, precise human body dosimetry calculation is required. The measurement of their uptake and biodistribution can be quite challenging. Also, due to the complex biology of different types of cells, their shapes and functions, there is not a simple and clear understanding of the mechanism of action that fits all. This study aims to estimate and compare the human organ dosimetry of the alpha emitter, 212Pb, from animal data assuming that it is conjugated with three different types of commonly used targeting nanoparticles. For this purpose, the pre-published animal data of three different radionuclide labeled peptide, antibody, and small molecule carriers were selected and converted to human data. Then a compartmental model was designed for each of them to fit the model to the human data with 212Pb, half-life of 10.64 hours. Once each model reached the desired fit, the area under the curves were extracted then the estimated human organ dosimetry calculations took place via the MIRD scheme. The organ dosimetry results for 212Pb + three different carriers are presented in Tables 14, 17, and 20.

According to U.S. Breast Cancer Statistics, about 1 in 8 U.S. women will develop invasive breast cancer during their lifetime. Chemotherapeutics that are used on patients currently often lead to tumor resistance, bone marrow suppression and cachexia. This study evaluated a novel combination of three non-mutagenic compounds for their effectiveness against mammary tumor cells, toxicity towards immune cells, ability to provoke the expression of immunogenic cell death (ICD) markers, and killing in 3D tumor models. Methotrexate (MTX), 2-deoxyglucose (2DG), and wogonin (WGN) were combined at doses well below their EC50 values yet effectively killed human and mouse breast cancer cells. The combination inhibited cancer cell colony formation and induced a high degree of cell death in multiple malignant tumor cell lines. Importantly, the combination did not significantly inhibit the viability of peripheral-blood mononuclear cells (PBMCs), even when employed at 3X the concentration that killed cancer cells. In marked contrast, low-dose doxorubicin, a common therapeutic for breast cancers, significantly decreased PBMC viability and increased the percentage of cell death. Our novel combinatorial therapy (Trifecta) elicited the significant expression of three ICD hallmarks: calreticulin surface expression, ATP secretion, and HMGB-1 release. In all cases, Trifecta elicited an equal or greater degree of ICD-marker expression compared to doxorubicin, a known inducer of ICD. We show significant efficacy of Trifecta against human and mouse mammary 3D tumor models grown in Matrigel® ECM-complex containing culture medium, and reaffirm the marked resistance of tumorspheres towards the conventional chemotherapeutic doxorubicin. The effectiveness of Trifecta in an acceptable surrogate model for mouse studies bodes well for translation of our findings to the clinic. In conclusion, Trifecta has proven highly effective against tumor cells grown either as monolayers or tumorspheres, without significant cytotoxic effects towards proliferating immune cells. Furthermore, treatment with this combination elicits ICD, which has the potential to prime an adaptive immune response against tumor cells and prevent future relapse. The drugs chosen for our combination target metabolic pathways that cancer cells are heavily dependent upon and do not interact with or induce mutations in DNA. These properties place Trifecta at the forefront of developing anticancer therapies.

Due to the difficulty of a complex commissioning technique for a multi energetic, multi-modality linear accelerator, I perform all the commissioning and acceptance testing for a TrueBeam linear accelerator with 4 megavoltage (MV) energies of which 2 are flattening filter-free (FFF) and 6 electron energies varying from 6 MeV to 20 MeV.
A 2 dimensional (2D) water tank was used for scanning all the required field sizes for all the energies. The one dimensional (1D) water tank was used to collect all the output factors for all the photon fields sizes small to medium electron field sizes. For the large electron fields sizes, we had to use the 2D water tank. All the collected data was converted into a file type accepted by the planning system (Eclipse) and subsequently imported there. Treatment plans were generated using multiple forms of planning to verify the viability and quality of the beam data commissioned.