Louisiana Research Day Program Book 2025

Biomedical Research: Section 1

Biomedical Research: Section 1

Grace Lee, OMS-II, Berony Geneste, OMS-II, Dalal Dawud, B Pharm; Zakaria Y Abd Elmageed, PhD Department of Biomedical Science, Discipline of Pharmacology, VCOM-Louisiana 7 REPURPOSING ATYPICAL ANTIPSYCHOTICS FOR PROSTATE CANCER THERAPY: EVALUATING THEIR EFFECTS ON CELL PROLIFERATION, MIGRATION, AND ER STRESS INDUCTION

Jedidiah Lim, OMS; Victoria Lucas, OMS; Samreen Shah, OMS; Sherine Thomas, OMS; Meredith Gwin, PhD; Dara W. Frank, PhD; Samir Gauta, MD, PhD; Melissa Lipsmeyer, PhD; Rebekah Morrow, PhD; K. Adam Morrow, PhD; Sarah Voth, PhD 1 VCOM-Louisiana; 2 Section of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, CT; 3 Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI; 4 VCOM-Louisiana 6 PSEUDOMONAS INDUCED ARDS PROMOTES COAGULOPATHY SECONDARY TO CYSTATIN-C DEPLETION

Rationale: Pseudomonas aeruginosa is a predominant agent of pneumonia and infection induced acute respiratory distress syndrome (ARDS). Strains responsible for acute infection utilize a type III secretion system (T3SS) to inject toxic exoenzymes directly into host cells. The T3SS toxin expressed by ~ 90% of clinical strains is exoenzyme Y (ExoY). Intoxicated cells are afflicted with tau hyperphosphorylation, cytoskeletal collapse, and the release of pathogenic tau into the extracellular space. In the absence of ExoY-elicited release of cytotoxic tau, endothelial amyloids including amyloid beta (A β ) are cytoprotective, antimicrobial, and contribute to regulation of the coagulation cascade. Cytotoxic tau disrupts the innate function of endothelial amyloids, suppresses antimicrobicity, and may promote infection induced hypercoagulability, a devastating complication of ARDS. Cystatin C (CysC), a ubiquitous cysteine protease inhibitor, plays a pivotal role in amyloid homeostasis. In critically ill patients, blood and urine proteomics indicate that serum CysC is markedly depleted through ARDS-induced inflammatory proteinuria, yet no cause, remedy, or mechanism of this critical care phenomenon has been identified.

Here, we sought to determine whether CysC depletion via inflammatory proteinuria promotes hypercoagulability during ExoY induced pneumonia. Methods: Male and female wildtype C57BL/6J mice (10-12 weeks old) were infected intratracheally with either vehicle or 1 x 105 colony forming units (CFU) of bacteria in 40 µl of PBS. P. aeruginosa strain ExoY+ (secretes only ExoY in host cells) was used for infections. Weight, urine, and PT/INR were collected daily and survival was tracked. At 48 hours post-infection, surviving mice were sacrificed. Urine was collected via cystocentesis, blood was collected via cardiac puncture, and the brain, kidneys, heart, and lungs were fixed for histological analysis. CysC levels of the blood and urine were measured via ELISA. Amyloid and tau levels were assessed via immunoblotting and thioflavin T.

Background & Aim: Repurposing atypical antipsychotics for untreated metastatic castration-resistant prostate cancer (mCRPC) therapy is an intriguing area of research. Several studies have shown that some antipsychotic drugs, originally developed to treat psychiatric disorders, exhibit anticancer properties. This study aimed to evaluate atypical antipsychotics anticancer properties for treatment of mCRPC by reducing cellular proliferation and migration while inducing endoplasmic reticulum (ER) stress, with fewer side effects compared to first generation antipsychotics. Methods: This study explored the anticancer potential of four atypical antipsychotics: cariprazine, xanomeline, pimavanserin, and iloperidone. Cytotoxic assay was performed to determine the half-maximal inhibitory concentration IC50 values of these drugs in mCRPC cells. Colony formation assay was also used to assess the ability of cells to inhibit clonogenic survival. Transwell migration assay was conducted to evaluate the impact of these agents on cell migration. To elucidate the underlying molecular mechanisms, immunoblotting analysis was conducted to

evaluate pimavanserin’s role in inducing ER stress by quantifying protein markers such as CHOP, BiP, calnexin, PDI, and PERK. Results: We found that MTT assay identified a wide range of IC50 values for the tested antipsychotics, with pimavanserin demonstrating the highest potency in reducing cell viability. Therefore, pimavanserin was selected for further investigation due to its superior efficacy and tolerability profile. Colony formation assay further confirmed pimavanserin’s superior ability to impair clonogenic survival. The transwell migration assay revealed significant inhibition of mCRPC cell migration by all four drugs, with pimavanserin exhibiting the strongest effect. These results highlight pimavanserin as a promising candidate for mCRPC therapy. Western blot analysis will validate whether pimavanserin induces ER stress by upregulating markers such as CHOP, BiP, calnexin, PDI, and PERK, which are critical components of the unfolded protein response. Conclusion: Repurposing atypical antipsychotics offers a promising approach to cancer treatment. Among the tested agents,

pimavanserin displayed the most potent effects in reducing mCRPC cell proliferation, clonogenic survival, migration, and positioning it as a leading candidate for further research. Ongoing studies will focus on elucidating the molecular mechanisms underlying its anticancer activity, particularly its capacity to induce ER stress. These results support the potential development of pimavanserin for preclinical and clinical trials. Keywords: mCRPC, atypical antipsychotic agents, cel proliferation, colony formation, migration

Results: TBD

Conclusions: TBD

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2025 Research Recognition Day