Researchers at the University of Chicago Medicine Comprehensive Cancer Center have made a significant breakthrough in the treatment of aggressive forms of prostate cancer. In a recent study published in Clinical Cancer Research, they established a “proof-of-concept” for a new treatment approach that effectively controlled tumors and improved survival rates in a mouse model of advanced prostate cancer.
Prostate cancer in its metastatic stage is driven by hormones and is typically treated with androgen deprivation therapy (ADT) to lower testosterone levels. However, many patients develop resistance to hormonal therapy, known as castrate-resistant prostate cancer (CRPC). This form of cancer is particularly difficult to treat, leaving patients with limited options.
The researchers focused on improving the responsiveness of prostate cancer to immunotherapy. They discovered that abnormal tumor-associated macrophages expressing PD-1 (a checkpoint molecule that suppresses anti-cancer immune responses) are recruited into the tumor microenvironment, promoting cancer growth instead of suppressing it.
Previous studies by the team showed that co-targeting the PI3K and PD-1 pathways enhanced the antitumor effects of ADT in PTEN-deficient prostate cancer. However, some mice remained resistant to the therapy. Further investigation revealed that the resistance was driven by the activation of the Wnt/β-catenin pathway, which restored lactate production and tumor-promoting properties in macrophages.
To overcome this resistance, the researchers co-targeted the PI3K and MEK signaling pathways, resulting in an 80% response rate. To achieve a 100% response rate, they tested a treatment regimen that included three drugs targeting the PI3K, MEK, and Wnt/β-catenin pathways.
What is particularly promising is that the researchers found that intermittent dosing of the drugs, rather than continuous administration, resulted in complete tumor control and prolonged survival without the long-term toxicity associated with conventional drug combinations.
This breakthrough provides proof-of-concept that targeting lactate as a macrophage phagocytic checkpoint can effectively control the growth of aggressive prostate cancer. Further clinical trials are needed to validate these findings, and the researchers are planning to develop a phase 1 clinical trial to test the intermittent dosing approach in humans.
This research opens up new therapeutic opportunities and highlights the potential of harnessing the immune system to control cancer growth. Instead of directly killing cancer cells, the strategy involves activating macrophages to eat and control the cancer cells.
Source: University of Chicago Medicine Comprehensive Cancer Center, Clinical Cancer Research
Definition:
– Hormonally driven disease: A disease that is influenced by hormones and their effects on various bodily systems.
– Androgen deprivation therapy (ADT): Treatment that aims to lower testosterone levels to combat the growth of hormone-driven cancers.
– Castrate-resistant prostate cancer (CRPC): Prostate cancer that does not respond to standard hormone-based therapy.
– Metastatic: Referring to cancer that has spread from its original location to other parts of the body.
– Immunotherapy: A type of cancer treatment that aims to boost the body’s immune system to fight and control cancer.
– Macrophages: A type of immune cell that engulfs and destroys foreign substances, including cancer cells.
– PI3K and MEK signaling pathways: Cellular pathways involved in cell growth, division, and survival. Inhibition of these pathways can have anti-cancer effects.
– Wnt/β-catenin pathway: A cellular pathway involved in various physiological processes, including cell growth and proliferation. Dysregulation of this pathway is associated with cancer development and progression.
