Researchers at University of California Los Angeles identified cell surface targets to treat prostate adenocarcinoma and neuroendocrine prostate cancer, two distinct major subtypes of advanced prostate cancer, and suggested that CAR T cell therapy against one of the targets could help treat neuroendocrine prostate cancer.
The study appeared in Proceedings of the National Academy of Sciences.
Prostate adenocarcinoma constitutes 95% of diagnosed prostate cancers, but can recur as a highly aggressive neuroendocrine prostate subtype due to treatment resistance in castration-resistant prostate cancer (CRPC) patients. Unlike prostate adenocarcinoma, neuroendocrine prostate tumors express low levels of cell surface proteins targeted to treat prostate cancer, including prostate-specific membrane antigen (PSMA; FOLH1; GCPII), and likely will not respond to PSMA-targeted therapies.
The researchers used bioinformatics to identify 7,555 human cell surface proteins from protein and gene expression databases, then evaluated data from patient-derived prostate cancer samples to compare differential expressions between the two prostate cancer subtypes. They found each subtype expresses hundreds of different cell surface genes at levels fourfold or more than the other subtype.
Further profiling using transcriptome and proteomic analyses of eight prostate cancer cell lines revealed several cell surface proteins with enriched expression in each subtype, including FXYD domain containing ion transport regulator 3 (FXYD3) in prostate adenocarcinoma and carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5; CD66e) in neuroendocrine prostate cancer.
As a proof of concept, the UCLA team engineered CAR T cells targeting CEACAM5 to evaluate if they would kill neuroendocrine prostate cancer cells. In two CEACAM5-expressing neuroendocrine prostate cancer cell lines, the CAR T cells induced expression of effector cytokine interferon (IFN) gamma and cell death.
The authors wrote that future research should evaluate whether it is possible to safely engineer dual or bispecific CAR T therapies against PSMA and CEACAM5 to treat CRPC regardless of prostate cancer subtype.