A breakthrough in prostate cancer treatment

Introduction

Prostate cancer is a devastating disease that affects millions of men worldwide. Despite advancements in treatment options, aggressive forms of the disease, such as metastatic castrate-resistant prostate cancer (mCRPC), remain a major challenge. However, a recent study conducted by researchers at the University of Chicago Medicine Comprehensive Cancer Centre has established a promising "proof-of-concept" for a new treatment approach that could revolutionize the field.

The study, published in Clinical Cancer Research, demonstrated the remarkable effectiveness of this novel treatment in a mouse model of advanced prostate cancer. The researchers achieved complete tumour control and long-lasting survival without any side effects. These ground-breaking findings have paved the way for further investigation in human clinical trials.

Finding the exact cancer cell and then destroying it but leaving the healthy tissue untouched. In theory, it could be like aiming and shooting at someone in the video game but real world is a bit different, isn’t it?

Overcoming Resistance to Hormonal Therapy

Hormonal therapy, specifically androgen deprivation therapy (ADT), is the standard treatment for metastatic prostate cancer. However, the majority of patients eventually develop resistance to this therapy, leading to castrate-resistant prostate cancer. This resistance poses a significant challenge for clinicians and leaves patients with limited treatment options.

Dr. Akash Patnaik, an accomplished physician-scientist and renowned expert in prostate cancer research and treatment, and his team at the University of Chicago Medical Centre have been exploring new strategies to overcome this resistance. Their research focuses on harnessing the immune system's ability to combat cancer cells.

Targeting Macrophages to Control Cancer Growth

Dr. Patnaik's team discovered that macrophages, a type of immune cell, play a crucial role in promoting the growth of prostate cancer. These macrophages express a molecule called PD-1, which suppresses the anti-cancer immune response. By targeting these macrophages, the researchers aimed to control the growth of the cancer.

In a previous study, the team found that co-targeting the PI3K and PD-1 pathways enhanced the effects of hormonal therapy in PTEN-deficient prostate cancer, a particularly aggressive form of the disease. However, a significant portion of the mice remained resistant to this therapy. Further investigations revealed that the activation of the Wnt/β-catenin pathway restored lactate production in these treatment-resistant cancers, leading to macrophages promoting tumour growth.

A Novel Therapeutic Approach 

Building on their previous findings, Dr. Patnaik and his team developed a novel therapeutic approach. By co-targeting the PI3K, MEK, and Wnt/β-catenin signalling pathways, they achieved an impressive 80% response rate in mouse models. However, a small percentage of the mice still showed resistance due to the restoration of lactate production in the treatment-resistant cancers. This led the researchers to investigate further and uncover the mechanism behind this resistance. They discovered that lactate can interact with macrophages and modify them through a process called histone lactylation, making the macrophages immunosuppressive and promoting cancer growth. In their latest study, the researchers found that targeting lactate as a macrophage phagocytic checkpoint can effectively control the growth of PTEN/p53-deficient prostate cancer. Through intermittent dosing of the three drugs, they achieved complete tumor control and significantly prolonged survival without the long-term toxicity associated with continuous drug administration.

These groundbreaking findings provide "proof-of-concept" for a new treatment approach that holds great promise for the most aggressive forms of prostate cancer. The researchers believe that their strategy of harnessing the ability of macrophages to eliminate cancer cells could revolutionize cancer therapy. By flipping the switch in macrophages, the cancer cells can be effectively controlled and eliminated.

The next step for Dr. Patnaik and his team is to translate these findings into clinical trials. They plan to develop a phase 1 clinical trial to test the efficacy of the intermittent dosing approach in human patients. If successful, this approach could potentially offer a new therapeutic option for patients with metastatic castrate-resistant prostate cancer, who currently have limited treatment options. The potential of this novel therapeutic approach extends beyond prostate cancer. The researchers have also uncovered new therapeutic opportunities by perturbing signaling pathways in cancer cells that affect the metabolic output of the cancer cell and its interaction with tumor-promoting macrophages. This opens up new avenues for research and the development of targeted therapies for various types of cancer.

Conclusion

The research conducted by Dr. Patnaik and his team has demonstrated the effectiveness of co-targeting multiple signaling pathways in treating aggressive forms of prostate cancer. Their findings provide a solid foundation for further investigation in human clinical trials and offer hope for patients with limited treatment options. This novel therapeutic approach has the potential to revolutionize cancer therapy and pave the way for more targeted and effective treatments in the future.

Written by Sara Maria Majernikova

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References:

Chaudagar, K., et al. (2023) Suppression of tumor cell lactate-generating signaling pathways eradicates murine PTEN/p53-deficient aggressive-variant prostate cancer via macrophage phagocytosis. Clinical Cancer Research. doi.org/10.1158/1078-0432.CCR-23-1441

Chetta, P., Sriram, R. and Zadra, G. (2023) ‘Lactate as key metabolite in prostate cancer progression: What are the clinical implications?’, Cancers, 15(13), p. 3473. doi: https://doi.org/10.3390/cancers15133473. 

Mathieu (2023) Revolutionary breakthrough in prostate cancer treatment at the University of Bern, Greater Geneva Bern area. Available at: https://ggba.swiss/en/revolutionary-breakthrough-in-prostate-cancer-treatment-at-the-university-of-bern/(Accessed: 29 September 2023).