By Stephen Beech via SWNS
A potential new treatment for an aggressive form of prostate cancer has shown promise in lab tests.
American scientists have shown how a gene alteration drives the disease and have also discovered a potential “degrader” that stops it.
They have managed to destroy tumors in mice.
However, the team says the treatment is still at a “pre-clinical” stage and further tests are needed before human trials can take place.
When researchers at the University of Michigan Rogel Cancer Center first identified a new subtype of aggressive prostate cancer, they knew they needed to understand how the genetic alteration was driving cancer and how to target it with treatment.
In two new papers, both published in the journal Cell Reports Medicine, the team describes the mechanisms of how alterations in the CDK12 gene drive prostate cancer development and reports on a promising degrader that targets CDK12 and a related gene to destroy tumors.
Researchers previously found loss of the CDK12 gene in about 7% of patients with metastatic prostate cancer, suggesting the alteration may be linked to a more aggressive form of the disease.
That was discovered from DNA and RNA sequencing from patient tumor samples. CDK12 also plays a role in some ovarian cancers.
To understand how CDK12 loss impacts cells on a molecular level, the Michigan researchers created a mouse model to try to parallel the genetic alterations they were seeing in human prostate cancers.
Senior author Professor Arul Chinnaiyan said: “What was quite surprising was when we created CDK12 loss in a mouse prostate, this caused precursor lesions to form in the mouse prostate.
“Then, when we added loss of the p53 oncogene, the mice developed bona fide invasive prostate cancer.
“It will be an addition to the field to have a genetically engineered mouse model that parallels what we see in human prostate cancer.”
With the mouse model, researchers then discovered the mechanism of how CDK12 loss induces DNA damage.
They explained that the loss of the gene activates other known cancer-driver genes, causing them to be overexpressed at a high level while also causing DNA to be replicated very rapidly.
The collision of the two processes leads to DNA damage.
Chinnaiyan said: “These back-to-back studies taken together are quite impressive.
“We created an animal model and then deciphered the mechanisms of how CDK12 loss actually drives prostate cancer.”
The Michigan team also found that a partner gene, CDK13, is important in targeting the alteration therapeutically.
They developed a potential therapy designed to degrade CDK12 and CDK13.
Testing in cell lines and mice showed the degrader specifically binds to CDK12 and CDK13 and stops the growth of cancer cells over normal cells.
The researchers say the degrader can be absorbed orally and would not need to be delivered intravenously.
That is notable as most protein degraders are too large to be absorbed orally, which has limited their potential in drug development.
The team also found that knocking down CDK12/13 activated the AKT pathway, which plays a role in cancer development.
Combining the CDK12/13 degrader with existing therapies targeting AKT resulted in a “synergistic” effect in destroying cancer cells.
The researchers suggest the potential to combine a CDK12/13 degrader with other approved therapies.
Chinnaiyan said: “It’s well known that single therapies for cancer treatment have been challenging.
“Often times patients develop resistance. If we can find the right combination, we could prevent resistance mechanisms from occurring.
“That’s one of the benefits of finding an FDA-approved agent to combine with CDK12/13 degraders.”
He added: “This study also highlights an international collaboration with Doctor Ke Ding, a medicinal chemist at the Shanghai Institute of Chemistry, in the development of orally bioavailable CDK12/13 degraders.”
The team plan to further develop the CDK12/13 degrader with the goal of moving to a clinical trial.
The causes of prostate cancer are largely unknown, but certain factors increase the risk of developing the condition.
The chances of developing prostate cancer increase as you get older, with most cases in men aged over 50.
More than 52,000 men are diagnosed with prostate cancer every year on average in the UK.
Over 12,000 men dies from prostate cancer every year in the UK, one every 45 minutes.
One in eight men will be diagnosed with prostate cancer in their lifetime.
