Zoledronic Acid and Thymosin α1 in prostate cancer

Prostate Cancer continues to be one of the most common types of cancer worldwide. The American Cancer Association calculates that in 2023 the estimated number of new prostate cancer cases in the United States is 288,300 cases, the first cause of cancer in the male population.

Despite the efforts to create new treatments and therapies for advanced or metastatic prostate cancer, it is still an incurable malignancy with a poor prognosis; that may be because Prostate cancer is a cold immune tumor, meaning that it is a tumor that is not likely to trigger a robust immune response, with limited T-cell infiltration in the microenvironment of the tumor. Evidence demonstrates that “turning up” the heat in cold tumors can promote a response to immune checkpoint inhibitors.

Zoledronic acid is a third-generation bisphosphonate that many studies have reported also participates in immune regulation, promoting the biological functions of macrophages and cells. Thymosin α1 is a thymic hormone associated with immunomodulatory activity on T cells, natural killer cells, and macrophages.

With this information, a retrospective analysis study was made by Sheng Want et al. They found that combining Androgen Deprivation Therapy with Zoledronic Acid and Thymosin α1 improves therapeutic outcomes in patients with advanced or metastatic Prostate cancer and suppresses prostate cancer tumor progression in mouse models that may be attributed to the enhanced frequency of cytotoxic CD8+ T cells. In the statistical analysis results for 14 of 20 patients with Prostate cancer, the serum levels of PSA and PAP were decreased after combination treatment with ADT and ZA plus Tα1, and their levels remained relatively low for more than four months. Also, the results showed that combination treatment with ZA and Tα1 resulted in a significant reduction in prostate cancer tumor growth compared to the effect of each treatment alone.

Zoledronic Acid and Thymosin α1 treatment also decreased the percentage of anti-inflammatory Tumor-associated macrophages. Still, they increased the number of pro-inflammatory tumor-associated macrophages in prostate cancer tumors, demonstrating that Zoledronic acid and Thymosin α1 stimulated cytotoxic T cells directly or indirectly via the immune plasticity of macrophages and Prostate cancer cells. These findings preliminarily revealed and elucidated the mechanisms underlying the complex and integrated interplay among Prostate cancer cells, macrophages, and T cells mediated by ZA plus Tα1 therapy that turned immune cold prostate cancer tumors into T-cell-inflamed tumors.

The study concluded by demonstrating that Androgen Deprivation Therapy and Zoledronic Acid plus Thymosin α1 therapy inhibits disease progression in patients with advanced or metastatic prostate cancer and suppresses tumor progression in an allograft mouse model. The antineoplastic mechanisms of ZA and Tα1 are associated with the blockade of MyD88/NF-κB signaling in prostate cells. Still, activating this axis in macrophages and T cells leads to increased infiltration of cytotoxic T cells and enhanced tumor inflammation.

Reference: Rebecca L. Siegel MPH, Kimberly D. Miller MPH, Nikita Sandeep Wagle MBBS, MHA, PhD, Ahmedin Jemal DVM, PhD, 12 January 2023, Cancer statistics, 2023, https://acsjournals.onlinelibrary.wiley.com/doi/10.3322/caac.21763