Personalized Treatment Combo for Prostate Cancer

Researchers at the University of Chicago Medicine Comprehensive Cancer Center achieved “proof-of-concept” for a new therapy method that effectively treated a mouse model of the most aggressive kinds of prostate cancer. In a mouse model of advanced prostate cancer, the treatment demonstrated full tumor suppression and long-term survival without adverse effects.

The researchers concluded that their findings, which were published online on September 18, 2023 in Clinical Cancer Research, warrant further examination in human clinical trials.

Strategies for Overcoming Resistance
Prostate cancer in the metastatic setting is a hormonally driven disease, and thus is typically treated with androgen deprivation therapy to lower testosterone levels,” said Akash Patnaik, MD, PhD, MMSc, senior author of the study and an internationally recognized expert in prostate cancer research and treatment. “Although this form of treatment has been shown to have significant anti-cancer responses in patients, the majority will become resistant to hormonal therapy, or castrate-resistant.”

Patients with advanced prostate cancer who do not react to normal hormone therapy, chemotherapy, or immunotherapy have few options. Researchers are striving to discover much-needed treatments for these aggressive malignancies, referred collectively as metastatic castration-resistant prostate cancer (mCRPC).

Patnaik’s lab creates focused techniques to boost prostate cancer’s response to immunotherapy. They revealed that the immune system frequently promotes cancer growth rather than preventing it by recruiting aberrant tumor-associated macrophages that express PD-1 (a checkpoint molecule that inhibits an anti-cancer immune response) into the tumor microenvironment.

Patnaik and colleagues discovered that co-targeting the PI3K and PD-1 pathways enhanced the antitumor effects of hormone therapy in PTEN-deficient prostate cancer, an aggressive form of advanced prostate cancer caused by the loss of a gene that regulates cell growth.

However, they discovered that 40% of the mice in the research remained resistant to the therapy. Further research indicated that activating the Wnt/-catenin pathway restored lactate generation in treatment-resistant tumors. Lactate, the researchers discovered, can interact with macrophages and change them through a process known as histone lactylation. This mutation makes macrophages immunosuppressive, promoting cancer growth.

A paradigm change
Patnaik’s team discovered that resistance to PI3K inhibitors is mediated via Wnt/-catenin and MEK signaling pathways in the current study. They changed their strategy to co-target PI3Ki/MEK signaling pathways, which resulted in an 80% response rate. Similar to prior investigations, they discovered that non-responders showed Wnt/-catenin signaling feedback activation.

They then examined a therapeutic regimen that included three medicines that targeted the PI3K, MEK, and Wnt/-catenin signaling pathways. This strategy resulted in a 100% response rate.

“We were concerned about toxicity with continuous drug administration over the long-term, as is often the case with drug combinations in patients, so we did survival studies in mice with intermittent dosing of the same three drugs,” he explained.

The researchers were ecstatic to learn that the intermittent dosing schedule resulted in total tumor control and greatly longer survival – without the long-term damage associated with constant medication treatment.

According to Patnaik, their findings demonstrate “proof-of-concept” that targeting lactate limits the progression of PTEN/p53-deficient prostate cancer and deserves further exploration in clinical trials.

Furthermore, the hypothesis that the medications can disrupt signaling pathways in cancer cells that influence metabolic output and cross-talk with tumor-promoting macrophages opens up hitherto unexplored treatment avenues.

“We don’t necessarily need to use targeted therapies to kill cancer cells but instead harness their ability to flip the switch in macrophages,” Patnaik said in a statement. “Now the macrophages can eat the cancer cells and control the cancer.”

Patnaik stated that the next step in this research would be to test this concept in the clinic: “We would develop a phase 1 clinical trial looking at testing an intermittent dosing approach to see if we can achieve a similar immune-activating and anti-tumor response as we’ve seen in our mouse model.”

The study, “Suppression of tumor cell lactate-generating signaling pathways eradicates murine PTEN/p53-deficient aggressive-variant prostate cancer via macrophage phagocytosis,” was funded by the Prostate Cancer Foundation Izzy Englander Challenge Award and the National Cancer Institute.

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