Why is it that some men’s immune systems can be whipped up into a frenzy and can attack metastatic cancer, causing it to melt away?
Some men with widely metastatic prostate cancer have had spectacular results on immunotherapy drugs like pembrolizumab. Other men – whose scans show very similar metastases, whose Gleason and PSA numbers are the same – aren’t helped much at all.
Why is it that some men’s immune systems can be whipped up into a frenzy and can attack metastatic cancer, causing it to melt away? The secret doesn’t lie in what pathologists can see in prostate tissue or a lab test. It’s much smaller than that: it’s in the genes. Specifically, it’s on the number of mutations a cancer has, or its “mutational burden.”
This means, basically, that the cancer has so much baggage – think of a whale , with barnacles all over it – that it looks different enough to cause the immune system to take notice. All the immune system needs, in this case, is a little kickstart – the immunotherapy drug – and it’s ready for battle. “Hypermutation is thought to be caused by inactivation of DNA mismatch repair genes – genes like MSH2,” explains Brady scientist Paula Hurley, Ph.D., “It’s the normal job of these genes to fix damaged DNA.”
“We hypothesize that some men with metastatic castration resistant prostate cancer (CRPC) have resistance to antiandrogen drugs – enzaludamide and abiraterone – because they have many mutations,” says Hurley. Now she wants to prove it. With co-investigator Brian Simons, D.V.M., Ph.D., she will be looking at the genes of men with metas tatic CRPC before they start on androgen receptor drugs and later, if their cancer stops responding to these drugs.
“These studies will provide critical information on how mutational burden leads to resistance to androgen receptor drugs, and will help determine who might respond well to immunotherapy.