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New Therapeutic Approach for Prostate Cancer Targets Tumour Microenvironment

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Prostate cancer (PCa) remains one of the most common malignancies among men worldwide, with significant mortality rates. Despite advancements in treatment, particularly for localised PCa, metastatic PCa continues to pose therapeutic challenges.

A growing body of research highlights the crucial role of the tumour microenvironment (TME) in PCa progression and therapeutic resistance. The tumour microenvironment (TME), which is made up of TAMs (tumour-associated macrophages), CAFs (cancer-associated fibroblasts), and MDSCs (myeloid-derived suppressor cells), is becoming more and more known as a key area for new treatments.

The findings were published in the journal Prostate Cancer.

TAMs are a significant component of the TME in PCa. They are broadly categorised into M1-type (pro-inflammatory) and M2-type (anti-inflammatory) macrophages. Most of the time, M2-type TAMs are found in the PCa TME. They are connected to tumour growth and metastasis, and are not responding to treatments like ADT. Studies have shown that a lot of M2-type TAMs in the blood of PCa patients is linked to a bad prognosis and an early biochemical recurrence. TAMs have shown promise in preclinical models, especially when they are stopped from recruiting macrophages or changed from M2-type to M1-type, which fights tumours.

CAFs, which make up a substantial part of the tumour stroma, play a pivotal role in supporting tumour growth and metastasis. They are classified into myofibroblastic CAFs (myCAFs), inflammatory CAFs (iCAFs), and antigen-presenting CAFs (apCAFs). Each subtype contributes to the tumorigenic process through different mechanisms, such as extracellular matrix remodelling and immunosuppression. CAFs are also implicated in therapeutic resistance, making them a compelling target for novel therapies. Strategies to target CAFs include direct depletion, blocking their secreted factors, or reprogramming them into a quiescent state resembling normal fibroblasts.

MDSCs are another key player in the TME, contributing to immunosuppression and tumour progression. They can be divided into polymorphonuclear (PMN-MDSCs) and monocytic (M-MDSCs) subsets. These cells inhibit T cell function, promote regulatory T cell expansion, and support angiogenesis, thereby fostering an environment conducive to tumour growth. Targeting MDSCs involves strategies to reduce their infiltration, inhibit their immunosuppressive functions, or promote their differentiation into less harmful cell types.

Therapeutic strategies and clinical trials

Recent advancements have led to several therapeutic strategies targeting TAMs, CAFs, and MDSCs:

  • TAM targeting. CCR2 inhibitors can be used to stop TAMs from recruiting, and zoledronic acid and antibodies that target phosphatidylserine can be used to change M2-type TAMs into M1-type ones.
  • CAFs targeting. Using fibroblast activation protein (FAP) inhibitors to reduce the number of CAFs, blocking CAF-secreted factors like NRG1 and CXCL12, and all-trans retinoic acid to normalise the number of CAFs are all possible strategies.
  • MDSCs targeting. VEGFR inhibitors, such as cabozantinib, are used to stop MDSCs from entering the body, STAT3 inhibitors are used to stop their functions, and agents, such as curcumin, are used to help them differentiate.

Several clinical trials are underway to evaluate these strategies. For instance, cabozantinib combined with immunotherapy has shown promising preliminary results in mCRPC patients. Similarly, clinical trials targeting FAP with talabostat and MDSCs with curcumin and β-glucan are ongoing.

Despite the promising preclinical outcomes, translating these therapies into clinical success has been challenging. The primary obstacles include the heterogeneity of the TME, the dynamic nature of cellular components, and the lack of reliable biomarkers for patient selection. Future research should focus on identifying specific biomarkers to stratify patients who are most likely to benefit from these therapies. Additionally, rigorous clinical trials are needed to validate the safety and efficacy of these novel approaches.

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