Poster Presentation NSW State Cancer Conference 2023

Targeting anti-androgen resistance in prostate cancer using physiologically relevant models (#111)

Michelle Devadason 1 , Yi Fang Guan 2 , Kanu Wahi 2 , Swati Irani 3 , Margaret Centenera 4 , Kristin Brown 5 , Luke Selth 6 , Lisa Butler 4 , Jeff Holst 2
  1. School of Clinical Medicine , UNSW , Sydney , NSW , Australia
  2. School of Biomedical Sciences, UNSW, Sydney , NSW, Australia
  3. School of Medicine , University of Adelaide, Adelaide , South Australia , Australia
  4. Freemason's Foundation Centre for Men's Health, University of Adelaide , Adelaide , South Australia , Australia
  5. Peter MacCallum Cancer Centre, Melbourne , Victoria , Australia
  6. Flinders Health and Medical Research Institute, Flinders University, Bedford Park, Adelaide , Australia

Objective/rationale

Prostate cancer (PCa) is the second leading cause of male cancer-related death worldwide1. A hallmark of PCa is its critical dependence on male androgen hormones, which regulate cellular metabolism and growth. The main therapy for advanced disease aims to block the production or action of these androgens. However, resistance to these anti-androgen therapies such as Enzalutamide (Enz) is inevitable as it leads to a lethal and incurable form of PCa2. The onset of Enz resistance in PCa is associated with changes to metabolic pathways, which may provide novel therapeutic targets.

However, therapeutic development is challenged by poor clinical translation of anti-cancer therapies, which might be due to a lack of preclinical models that mimic the in vivo environment3. In vitro models traditionally use culture media containing nutrient levels disproportionate to physiological levels in human plasma. This could induce artificial metabolic pathways, which may substantially alter therapeutic responses in vitro4,5. As such, we set out to test whether physiological nutrient levels in the culture media may provide a better preclinical model for testing anti-cancer therapies.

Design/method

Cell viability assays were used to compare growth rates of the PCa cell lines LNCaP, V16D and MR49F in traditional and physiological media +/- Enz, UCPH-101 (EAAT1 transporter inhibitor) and Leflunomide (DHODH inhibitor). Targeted metabolomics with 13C-glutamine was used to profile these 2D cell lines and 3D patient-derived explants in traditional and physiological media +/- Enz.

Results

Targeted metabolomics showed significant metabolic changes in physiological media for both 2D and 3D models, such as decreased aspartate levels with Enz treatment. This may be mediated by androgen receptor-regulated enzymes of aspartate metabolism such as DHODH, ARG1, ASRGL1 and GOT1. Inhibiting both the intracellular uptake of aspartate (EAAT1) and its downstream metabolism (DHODH) had an additive effective in Enz sensitive and resistant PCa cell lines cultured with physiological media.

Conclusions

Culturing 2D and 3D models of PCa with physiological media revealed novel metabolic features in response to Enz, which were absent in traditional media. A combination therapy targeting these metabolic vulnerabilities had an additive effect with physiological media on Enz sensitive and resistant cell lines. Future directions include testing this combination therapy using 3D explant models (xenografts and patient-derived) cultured with traditional and physiological media.

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