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Promising Personalized Targeted/Immunotherapy Combination Treatment Identified For an Aggressive Form of Advanced Prostate Cancer

The majority of prostate cancers are diagnosed at an early stage, such that patients can be closely monitored without treatment, or are cured with local treatment. However, recurrent and metastatic disease often progresses to an advanced stage and becomes resistant to therapy, known as metastatic castration-resistant prostate cancer (mCRPC): nearly 35,000 patients are projected to die of prostate cancer in 2023. Novel approaches to treatment are urgently needed.

Now, research funded by the 2016 Izzy Englander – PCF Challenge Award has defined a mechanism that prostate cancers use to reprogram the immune system, thus allowing them to grow unchecked. PCF Challenge Award recipient, Akash Patnaik, MD, PhD, MMSc, (University of Chicago) and team identified a promising immunotherapy-based combination treatment to prevent the cancer cells from developing this ability. These findings were recently published in the journal Clinical Cancer Research.


Genetic and immune system factors in tumors lead to aggressive cancer

Over the past decade, much progress has been made in understanding genetic changes in advanced prostate cancer. Approximately 50% -75% of mCRPC patients have a mutation in a “tumor suppressor” gene called PTEN. PTEN’s function is to prevent cells from growing too rapidly. When this gene does not function properly, the risk of aggressive cancer increases.

Normally, the immune system also works to identify and destroy cancer cells. In patients with PTEN-mutated tumors, the normal anti-tumor immune response is often suppressed, and immunotherapy clinical trials have shown limited benefit in advanced cancer patients harboring PTEN mutations. Co-occurrence of mutations in a gene called p53 is present in 56% of PTEN-deficient advanced prostate cancer patients, which also suppresses the immune response within the tumor. Given the aggressive nature and poor response of PTEN/p53-mutant advanced prostate cancer to standard-of-care hormonal therapies, chemotherapies and immunotherapy, a deeper understanding of immune escape mechanisms is critical for the discovery of new personalized therapeutic options for these patients.

Combination therapy increases survival in mouse studies

Patnaik and colleagues performed a series of laboratory experiments and utilized mouse models of PTEN/p53-mutated prostate cancer. One set of experiments tested a novel drug called copanlisib. This drug is designed to work by blocking a cancer-causing pathway called PI3K/AKT that PTEN normally acts to suppress. However, in mice and patients without a properly-functioning PTEN gene, treatment with a combination of hormone therapy + PI3K/AKT targeted therapies is minimally effective.

Patnaik and colleagues discovered that upon treatment with hormonal therapy and PI3K-targeted therapy, PTEN/p53-mutated prostate cancer had developed a way to force macrophages (a type of immune cells with tumor-promoting and anti-tumor dual functions in cancer) into a “tumor-promoting” mode by expressing a protein called PD-1 on their surface. The researchers hypothesized that adding a third drug to block PD-1 would unleash the power of the macrophages to kill the cancer.

The triplet combination of hormone therapy + copanlisib + a PD-1 blocker was then tested in mouse models. While the response rate among mice treated with one- or two-drug combinations was not significantly greater than for untreated mice, the 60% response rate for triple combination-treated mice was significantly higher than untreated control mice. These data demonstrate that the three-drug approach is needed to overcome resistance to treatment in PTEN/p53-mutated prostate cancer.

 The road ahead to clinical trials

As part of the PCF Challenge Award, a phase 1b clinical trial is being planned to test the safety and efficacy of PI3K/AKT pathway-blocking medicines in combination with an anti-PD1 drug in patients with PTEN-deficient mCRPC. The effects of this treatment on immune cell activities will be studied. If successful, this project could result in a new precision immunotherapy regimen for patients with PTEN-deficient CRPC.

PCF congratulates the investigators on this groundbreaking work. In identifying a novel mechanism of immune resistance, and a potential therapeutic strategy, Dr. Patnaik and team are moving us closer towards the goal of reducing death and suffering for men with advanced prostate cancer.

What this could mean for patients: Metastatic prostate cancer with mutations in genes called PTEN and p53 is aggressive and resistant to existing therapies. These early studies show that a new combination of three medications may boost the immune system’s ability to kill prostate cancer cells. Next, this combination will be tested in a human clinical trial.