Using oxidative cell death to target RB1-deficient prostate cancer

Unmet Need

In the first quarter of 2023, there were approximately 288,300 Americans diagnosed with prostate cancer, accounting for about 15% of all new cancer diagnoses. The five-year survival rate of patients with prostate cancer is 97.1%, but this drops significantly to 34% for those with metastatic disease. The tumor suppressor gene retinoblastoma (Rb1) is often mutated in prostate cancer, small cell lung cancer, as well as breast and bladder cancers. This mutation fuels uncontrolled proliferation of cancerous cells and is frequently present in therapy-resistant cancers including those resistant to hormone receptor antagonists and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. This consequently leads to lower survival rates for patients with metastatic prostate cancer. Rb1 is mutated in approximately 12% of metastatic prostate cancer cases, which equates to over 2,000 patients a year in the U.S. There is a need for new methods of overcoming therapy resistance and improving patient survival.

Technology

Duke inventors have identified a new target for therapy-resistant prostate cancer. This treatment would be administered by physicians treating Rb1-deficient metastatic prostate cancer patients for whom conventional treatments fail. Specifically, Duke inventors demonstrated that Rb1-deficient cancer cells are particularly sensitive to an oxidative cell death called ferroptosis, which can be induced by several chemical compounds as potential treatment. By selectively depleting retinoblastoma protein (RB), the inventors observed sensitization of prostate cancer cells to induction of ferroptosis. Depleting RB from Rb1-intact cancer cell lines from a range of other histological origins, including the lung, liver, and breast in vitro also sensitized them to ferroptosis. The same result was observed in vivo with cell-derived xenograft models. In pre-clinical mouse models, the inventors demonstrated minimal toxicity of ferroptosis inducer JKE-1674 and specificity for Rb1-deficient tumors. They also reported therapeutic efficacy of ferroptosis induction in PTEN/Rb1 double knockout mice – a genotype commonly observed in late-stage human prostate cancer such as castration-resistant prostate adenocarcinoma and treatment-emergent neuroendocrine prostate cancer.

Other Applications

This technology could be used against other Rb1-deficient cancers. It may also be useful in combination with conventional chemotherapy. Ferroptosis is known to be a form of immunogenic cell death, and so could potentially be used in combination with immunotherapies to boost anti-tumor immunity.

Advantages

• New way to target Rb1-deficient prostate cancer
• Potentially applicable to other therapy-resistant cancers
• Particular strategy for the specific indication of therapy-resistant metastatic prostate cancer could make FDA approval easier to acquire
• Minimal to no off-target effects in other organs