New subtype of prostate cancer discovered
Scientists have identified a new subtype of prostate cancer that occurs in about seven per cent of patients with advanced disease.
The subtype is characterised by loss of the gene CDK12. It was found to be more common in metastatic prostate cancer compared to early stage tumours that had not spread. Tumours in which CDK12 was inactivated were responsive to immune checkpoint inhibitors, a type of immunotherapy treatment that has overall had limited success in prostate cancer. "Because prostate cancer is so common, seven per cent is a significant number. The fact that immune checkpoint inhibitors may be effective against this sub-type of prostate cancer makes it even more significant," said Arul Chinnaiyan, from University of Michigan in the US. "This is an exciting prospect for patients who have CDK12 alterations and may benefit from immunotherapy," said Chinnaiyan.
Researchers will lead a multisite clinical trial to assess checkpoint inhibitors as a treatment for metastatic prostate cancer with CDK12 loss.
In the study, published in the journal Cell, researchers looked at DNA and RNA sequencing data from 360 tumour samples from patients with metastatic castration-resistant prostate cancer. This is an aggressive, advanced form of the disease in which cancer has spread throughout the body and no longer responds to traditional hormone-based treatments.
Researchers found a loss of CDK12 in only about one per cent of early prostate cancer samples. That jumped to seven per cent for metastatic cancer, which indicates a more aggressive form of the disease. "It suggests that those early-stage patients who have CDK12 loss are the ones who will develop metastatic disease. This could be a harbinger in early cancer," Chinnaiyan said.
By following the mechanism of how CDK12 loss impacts the cell, researchers found a process in which cells create neoantigens that are foreign to the immune system. This boosts immune-fighting T-cells, which may explain why these patients benefit from immune checkpoint blockade.
This suggests that a precision medicine approach to prostate cancer could help better direct immunotherapy treatment. It could also explain why some prostate cancer patients have had exceptional responses to immunotherapy while the treatment has had lacklustre results overall in prostate cancer.
The team had first recognized a possible role for CDK12 in a 2015 paper that evaluated the genomic landscape of advanced prostate cancers. CDK12 has also been linked to ovarian cancer. Little is known about CDK12 on a molecular basis but scientists do know that CDK12 regulates several critical cellular processes and is essential for development. Eliminating it is likely lethal to most cell types.
Researchers suspect cancer must inherit something that allows it to grow in the face of CDK12 loss. More study is needed to understand this, researchers said.