In this regard, we and other have shown that the expression levels and sub-cellular localization of the tissue-specific homeobox protein, NKX3.1, helps to distinguish men who are at high risk for developing lethal prostate cancer. Reduced expression of NKX3.1, prevalent in early-stage prostate cancer, renders the prostatic epithelium more susceptible to the tumor-promoting effects of oxidative stress. However, when NKX3.1 is present under such conditions, it localizes to the mitochondria, where it protects against aberrant oxidative stress and conversely, its loss or reduction is associated with impaired mitochondrial function and adverse disease outcome.2 Taking that into consideration, we asked whether metformin could overcome the adverse consequences of NKX3.1 loss for prostate cancer and, if so, whether metformin could be used to prevent disease progression in prostate cancer patients.3
We focused our efforts on metformin, a widely-used anti-diabetic drug with known anti-cancer effects related to its mitochondrial activity. Given that the clinical benefit of metformin for prostate cancer has thus far been inconclusive, we hypothesized that targeting patients with low NKX3.1 expression and impaired mitochondria could repurpose metformin in a precision cancer intervention paradigm. Indeed, our co-clinical studies demonstrate a functional and correlative association between low NKX3.1 expression, mitochondrial dysfunction, and metformin intervention in prostate cancer. In particular, we found that metformin restores mitochondrial function and suppresses cancer progression in the prostates of mice lacking Nkx3.1, human prostate cancer cells and tissue organotypic assays. Additionally, preliminary studies identified a potential role for metformin in inhibiting metastasis using our recently established in vivo syngeneic model of prostate cancer metastasis.4 We show that metformin treatment may act to reduce liver metastases of NKX3.1-deficient prostate cancer cells, signifying the relevance of context-dependent metformin treatment in more advanced stages of prostate cancer as well.3
Furthermore, our correlative analyses in several independent human prostate cancer cohorts show that only patients with low NKX3.1 expression and mitochondrial impairment benefit from taking metformin. Patients with low NKX3.1 and taking metformin had significantly improved biochemical recurrence (BCR)-free survival compared with those not taking metformin. Interestingly, patients classified as high risk according to European Association of Urology (EAU) guidelines exhibited significantly increased probability for BCR only when low NKX3.1 expression was taken into account whereas, metformin was shown to consistently reduce BCR probability only in patients with low NKX3.1 expression, indicating that EAU risk alone may not be sufficient to stratify patients and to accurately determine treatment options. In the active surveillance setting, analysis of Gleason grade in initial versus repeat biopsies revealed that all patients with low NKX3.1 on metformin treatment (3/3) were downgraded, whereas 3/4 patients not taking metformin were upgraded. In contrast, 14/16 with high NKX3.1 had no change in Gleason grade regardless of whether they were taking or not taking metformin.
Our functional and correlative data suggest that prostate cancer patients with low NKX3.1 are likely to benefit most from metformin treatment to delay disease progression in a precision interception paradigm (Fig. 1). These findings may help us to identify those patients who are at greatest risk of progressing to lethal prostate cancer and how metformin treatment can be tailored to minimize risk and improve outcomes. This is particularly relevant for American men of African descent, a patient population known to develop aggressive and lethal prostate cancer at very high rates. Taking this knowledge further, we are now working towards establishing new prospective clinical trials with metformin in the active surveillance setting, where precision intervention can be the most effective to reduce overtreatment and delay prostate cancer progression.
Written by: Alex Papachristodoulou1 and Cory Abate-Shen1,2,3,4,5
Departments of 1Molecular Pharmacology and Therapeutics, 2Pathology & Cell Biology, 3Urology, 4Systems Biology, 5Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA.
References:
- Papachristodoulou, A. and Abate-Shen, C. (2022). Precision intervention for prostate cancer: Re-evaluating who is at risk. Cancer Lett 538: 215709. PMID: 35490919. PMCID: PMC9136709.
- Papachristodoulou, A., Rodriguez-Calero, A., Panja, S., Margolskee, E., Virk, R. K., Milner, T. A., Pina Martina, L., Kim, J. Y., Di Bernardo, M., Williams, A. B., Maliza, E. A., Caputo, J. M., Haas, C., Wang, V., De Castro, G. J., Wenske, S., Hibshoosh, H., McKiernan, J. M., Shen, M. M., Rubin, M. A., Mitrofanova, A., Dutta, A. and Abate-Shen, C. (2021). NKX3.1 localization to mitochondria suppresses prostate cancer initiation. Cancer Discov PMID: 33893149
- Papachristodoulou, A., Heidegger, I., Virk, R. K., Di Bernardo, M., Kim, J. Y., Laplaca, C., Picech, F., Schafer, G., De Castro, G. J., Hibshoosh, H., Loda, M., Klocker, H., Rubin, M. A., Zheng, T., Benson, M. C., McKiernan, J. M., Dutta, A. and Abate-Shen, C. (2023). Metformin Overcomes the Consequences of NKX3.1 Loss to Suppress Prostate Cancer Progression. Eur Urol PMID: 37659962
- Arriaga, J. M., Panja, S., Alshalalfa, M., Zhao, J., Zou, M., Giacobbe, A., Madubata, C. J., Kim, J. Y., Rodriguez, A., Coleman, I., Virk, R. K., Hibshoosh, H., Ertunc, O., Ozbek, B., Fountain, J., Jeffrey Karnes, R., Luo, J., Antonarakis, E. S., Nelson, P. S., Feng, F. Y., Rubin, M. A., De Marzo, A. M., Rabadan, R., Sims, P. A., Mitrofanova, A. and Abate-Shen, C. (2020). A MYC and RAS co-activation signature in localized prostate cancer drives bone metastasis and castration resistance. Nat Cancer 1: 1082-1096. PMID: 34085047. PMCID: PMC8171279.