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Targeting PLOD2 Suppresses Invasion and Metastatic Potential in Radiorecurrent Prostate Cancer - Beyond the Abstract

The past few decades have been witness to significant strides in diagnostic, therapeutic, and preventative approaches that have resulted in an overall 29% reduction in cancer deaths since their height in the 1990s.1 Despite this promising trend, the 5-year survival rate of patients with metastases deriving from solid tumours remains between 5-30%,2 a bleak prognosis that reflects a critical lack of effective anti-metastatic therapies in the clinical armamentarium.

Prostate cancer is one such disease that has benefitted immensely from strides in prevention, diagnosis (particularly with the PSA blood test), and treatment of localized disease, yet has fallen short with anti-metastatic treatments. One need only look at the outstanding survival rate of patients with localized prostate cancer —between 90-99% survival after 5 years— and compare this to the 5-year survival rate of metastatic prostate cancer patients —between 30-40%— to appreciate the disparity in the effectiveness of therapies for localized versus metastatic disease.3

Radiorecurrent prostate cancer can be a particularly aggressive disease that arises after relapse from radiotherapy, a common treatment modality for localized prostate cancer. Up to 50% of high-risk prostate cancer patients develop distant metastases within five years of radiorecurrent relapse,4 and therefore this provides a clinically relevant model for exploring potential avenues to suppress metastatic disease.

In our study, we identified the procollagen-modifying protein PLOD2 as a negative prognostic factor that promotes the cellular mechanisms of invasion, migration, and extravasation in radiorecurrent prostate cancer. Since invasion and migration facilitate cancer cell motility within the tissue, and extravasation allows cancer cells to exit the circulation and colonize distant tissue, these mechanisms comprise integral steps of the metastatic cascade.

By inhibiting PLOD2 expression with the pharmacological agent PX-478, we were able to effectively suppress these key steps of the metastatic cascade. Although PX-478 suppresses PLOD2 expression by inhibiting its upstream mediator HIF1α, this finding nevertheless shows promise as a proof-of-concept for pharmacologically inhibiting PLOD2 to reduce metastasis in the clinic. While there are currently no specific inhibitors for PLOD2, ongoing work to develop targeted agents against it will undoubtedly yield potential anti-metastatic therapies for testing in clinical trials.6

Could the future development of such PLOD2 inhibitors offer new hope in treating metastatic prostate cancer? This is a question worth asking after decades of preclinical research has yielded few clinically successful anti-metastatic therapies. The troubled clinical history of inhibiting matrix metalloproteinases (MMPs) acts as a useful case study when considering the future of PLOD2 inhibition. MMPs have previously been the subject of intense clinical interest due to their ability to promote invasion through collagen degradation, yet over 50 MMP inhibitors have been tested in clinical trials to date, and all have failed.7 Among the many reasons attributed to these failures, lacking a solid understanding of the complex biology underlying MMPs before embarking on clinical trials appears to be one of the primary causes of failure. Indeed, additional research has revealed that some MMPs have anti-tumour effects, thereby causing their broad-spectrum inhibition to fail in moving the needle toward positive clinical outcomes. In fact, severe side effects caused by some MMP inhibitors were the reason for their respective trial termination8.

This cautionary tale of MMP inhibition must be heeded as we approach the development of PLOD2 inhibitors. In particular, the deleterious effects of reduced PLOD2 expression on vital biological processes should be carefully considered.9-11 Moreover, further studying the role of PLOD2 in all steps of the metastatic cascade must be conducted if it is to succeed as a target in anti-metastatic therapy. Our preclinical results indicate that a PLOD2 inhibitor could target the critical steps of invasion, migration, and extravasation within the metastatic cascade of prostate cancer. Additional research that expands upon our results, or that elucidates the role of PLOD2 in the remaining steps of the cascade, will be essential for broadening our understanding of the complex biology surrounding PLOD2 in cancer progression. Most importantly, if PLOD2 plays a critical role in numerous steps along the metastatic cascade, its inhibitors will be effective in a wider array of patients at various stages of prostate cancer. In such a scenario, a PLOD2 inhibitor might be most effective in locally advanced disease, as it could inhibit further local invasion while suppressing extravasation of any undetected, circulating tumour cells before they can establish distant metastases. Ultimately, if the history of past anti-metastatic inhibitors has taught us anything, it is that further preclinical study of this promising metastatic target is needed to give its future clinical inhibition the best chance at success.


The therapeutic potential of PLOD2 inhibitors to suppress critical steps of the metastatic cascade.

Written by: Gavin Frame, MSc1,2 & Stanley K Liu, PhD, MD1-3

  1. Department of Medical Biophysics, University of Toronto, Toronto, ON
  2. Sunnybrook Research Institute, Toronto, ON
  3. Department of Radiation Oncology, University of Toronto, Toronto, ON
References:

  1. Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2020. CA Cancer J Clin 70, 7-30, doi:10.3322/caac.21590 (2020).
  2. Esposito, M., Ganesan, S. & Kang, Y. Emerging strategies for treating metastasis. Nat Cancer 2, 258-270, doi:10.1038/s43018-021-00181-0 (2021).
  3. Rebello, R. J. et al. Prostate cancer. Nat Rev Dis Primers 7, 9, doi:10.1038/s41572-020-00243-0 (2021).
  4. Philipson, R. G. et al. Patterns of Clinical Progression in Radiorecurrent High-risk Prostate Cancer. Eur Urol 80, 142-146, doi:10.1016/j.eururo.2021.04.035 (2021).
  5. Sandhu, S. et al. Prostate cancer. Lancet 398, 1075-1090, doi:10.1016/S0140-6736(21)00950-8 (2021).
  6. Lee, J. et al. Unleashing the Potential of 1,3-Diketone Analogues as Selective LH2 Inhibitors. ACS Med Chem Lett 14, 1396-1403, doi:10.1021/acsmedchemlett.3c00305 (2023).
  7. Vandenbroucke, R. E. & Libert, C. Is there new hope for therapeutic matrix metalloproteinase inhibition? Nat Rev Drug Discov 13, 904-927, doi:10.1038/nrd4390 (2014).
  8. Winer, A., Adams, S. & Mignatti, P. Matrix Metalloproteinase Inhibitors in Cancer Therapy: Turning Past Failures Into Future Successes. Mol Cancer Ther 17, 1147-1155, doi:10.1158/1535-7163.MCT-17-0646 (2018).
  9. Ha-Vinh, R. et al. Phenotypic and molecular characterization of Bruck syndrome (osteogenesis imperfecta with contractures of the large joints) caused by a recessive mutation in PLOD2. Am J Med Genet A 131, 115-120, doi:10.1002/ajmg.a.30231 (2004).
  10. Kot, A. et al. Loss of the long form of Plod2 phenocopies contractures of Bruck syndrome - osteogenesis imperfecta. Journal of Bone and Mineral Research, doi:10.1093/jbmr/zjae124 (2024).
  11. Kasamatsu, A. et al. Deficiency of lysyl hydroxylase 2 in mice causes systemic endoplasmic reticulum stress leading to early embryonic lethality. Biochem Biophys Res Commun 512, 486-491, doi:10.1016/j.bbrc.2019.03.091 (2019).
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