Sydney
Hollingsworth
Sponsor: Alan Lombard, Ph.D. MED: Biochem & Molecular Med Targeting tumor cells with defects in homologous recombination using poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) has significantly improved the treatment of several cancers including that of the prostate. However, resistance development is common leading to progression and treatment failure. Preliminary data suggest that prolonged exposure to PARP inhibition induces prostate tumor cell adoption of a drug-tolerant persister (DTP) state that enables survival under therapeutic pressure and which promotes resistance. The emergence of DTP cells is a major obstacle to long-term treatment effectiveness, as these cells can serve as reservoirs for disease relapse. We hypothesize that the DTP state is a conserved cellular response across cancer types and that defining shared features of this state may reveal therapeutic opportunities. Building on prior research characterizing PARPi induced prostate cancer DTP cells, this project investigates breast, ovarian, and pancreatic cancer DTP cells. We identify phenotypic and molecular features associated with the DTP state using cell growth assays, colony formation assays, microscopy, and western blotting. By evaluating similarities and differences in DTP characteristics across cancer models, this work aims to assess the generalizability of the DTP state to support future efforts to target vulnerabilities specific to drug-tolerant tumor cells. Chemotherapy Agent Intercalation Mechanism Characterization via Electron Paramagnetic Resonance Spectroscopy
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Authors:
Sydney Hollingsworth
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DNA intercalating agents proposed for chemotherapy disrupt the structure of DNA and prevent malignant cell replication. However, the mechanism for this process is difficult to observe. A subset of these intercalators incorporates paramagnetic transition metals, making them detectable by Electron Paramagnetic Resonance (EPR) Spectroscopy. EPR is a powerful tool for DNA research because data can be obtained for non-crystallized molecules, closely reflecting the behavior of DNA in living cells. This study demonstrates a proof of concept of the feasibility of using EPR spectroscopy to characterize the intercalation behavior of DNA intercalators; specifically, the copper complex Phen-Acac-Cu(II) (PAC), a representative planar DNA intercalator. Continuous Wave EPR spectra of free Cu(II), free PAC, and PAC bound to DNA confirm that the intercalation process does not induce dissociation of the PAC complex. Electron Spin Echo Envelope Modulation EPR spectroscopy was used to quantify changes in water coordination upon intercalation. Calibration curves were established using fully hydrated and fully chelated free Cu(II). The ESEEM EPR spectra indicate six waters coordinated to free Cu(II), one to free PAC, and zero for intercalated PAC, as expected. These results demonstrate that EPR is a viable technique for exploring DNA intercalation chemotherapies. Graham McNeill's Fulgrim and Gendered Artistic Non-Conformity within the Warhammer Community Kaitlyn Holt
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UC Davis / Chemistry / 2026
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Sydney Hollingsworth