Outsmarting treatment-resistant prostate cancers

Aggressive prostate tumors can rapidly evolve to resist PARP inhibitors, but it may be possible to detect resistance early enough to counteract.


Protein_PARP1_PDB_1uk0Two views of the structure of the DNA-repair protein PARP1

It was a surprising discovery that opened up a new avenue for treating prostate cancer. In recent years, studies have revealed that gene mutations long associated with breast and ovarian cancers – BRCA1 and BRCA2 – also play a significant role in driving aggressive prostate cancers

Men with these mutations (about 20 percent of prostate cancer patients with metastatic tumors) have shown very high response rates to a new class of drugs called PARP inhibitors, three of which have already gained FDA approval for use in ovarian cancer.

The bad news: Prostate cancers can rapidly evolve to resist PARP inhibitors.

The good news: It may be possible to detect the emergence of resistant cancer cells with just a blood test, researchers have now found, and that could provide earlier information about PARP inhibitor resistance and important clues about how to overcome resistance.

“Understanding when resistance is developing, and how that is happening is really critical to understanding how we can overcome it,” says oncologist Joshi Alumkal, M.D., co-first author of the paper describing the findings in the journal Cancer Discovery.

Alumkal is an associate professor in the OHSU School of Medicine and co-leader of the prostate cancer research program at the OHSU Knight Cancer Institute. His collaborators include co-first author David Quigley, Ph.D., at the University of California San Francisco.

Repairing DNA

BRCA genes encode proteins that help to mend damaged DNA. Mutations that inactivate BRCA genes can allow DNA damage to go unrepaired, which makes cells vulnerable to the transformation that leads to cancer. But BRCA mutations are double-edged swords in cancer cells.

High mutation rates in tumors mean that cancer cells can lose all functioning copies of a BRCA gene, thus losing that pathway for fixing broken DNA. Such cancer cells can still maintain their DNA integrity enough to survive by relying on a backup repair system involving a protein called PARP1.

PARP inhibitors knock out the backup system, which is lethal to cancer cells that lack a functional BRCA repair pathway.

“It’s worth pointing out there are pretty dramatic effects seen with PARP inhibitors in prostate cancer,” Alumkal says. In the study, he and co-authors closely monitored the effects of PARP inhibitor therapy in two men with prostate cancer that had spread to other organs after relapse from first-line treatments. “These were patients who had really run out of options,” Alumkal says.

The men agreed to participate in biomarker studies exploring the value of profiling the genetic makeup of tumor cells. Testing confirmed the presence of BRCA2 mutations that made them candidates for experimental use of a PARP inhibitor.

After starting the treatment, the men’s tumors stopped growing or shrank and they experienced improvements in functioning. One, who had become debilitated enough to need a wheelchair, began gaining weight and stopped using the wheelchair.

It was a temporary reprieve. Within seven months, the cancer rebounded in both men. Neither survived much longer. Given their altruistic participation in research, Alumkal says he felt a duty to learn as much as possible from their experience.

Evolving a work-around

Importantly, both subjects had agreed to blood collection for circulating tumor DNA sequencing. By sequencing circulating tumor DNA from these patients prior to treatment and again when the cancer progressed, the researchers were able to find a likely explanation for why PARP inhibitors stopped working. The circulating tumor DNA in both subjects at progression showed new mutations in the BRCA2 gene.

“Many of these new BRCA2 gene mutations were able to restore the normal sequence or structure of the gene,” Alumkal says. “These tumors had figured out a work-around to repair DNA double strand breaks despite or perhaps because of PARP inhibitor therapy.”

That the mutations indicative of drug resistance could be detected in tumor DNA circulating in the blood is significant because blood can be sampled repeatedly and with far less risk than attempting to obtain tumor samples directly.

“Our results suggest that monitoring levels of DNA repair mutations in the blood could be useful to tell you if a patient is responding to treatment with a PARP inhibitor,” Alumkal says. Blood tests might also provide an early warning of treatment resistance – earlier than is possible with PSA testing, the standard biomarker used today.

The findings call out the possibility of finding early on when prostate cancer becomes resistant to PARP inhibitors. Further research will be needed to define the most effective cancer drugs or drug combinations to turn to when that occurs.

“If we can understand more about the process by which treatment-resistant cancer cells with BRCA2 reversion mutations emerge and we can block that process,” says Alumkal, “we may be able to extend the benefit of PARP inhibitors.”

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Analysis of Circulating Cell-free DNA Identifies Multi-clonal Heterogeneity of BRCA2 Reversion Mutations Associated with Resistance to PARP Inhibitors by David Quigley, Joshi J Alumkal, Alexander W. Wyatt, Vishal Kothari, Adam Foye, Paul Lloyd, Rahul Aggarwal, Won Kim, Eric Lu, Jacob Schwartzman, Kevin Beja, Matti Annala, Rajdeep Das, Morgan Diolaiti, Colin C. Pritchard, George V THOMAS, Scott A. Tomlins, Karen E. Knudsen, Christopher J. Lord, Charles J Ryan, Jack Youngren, Tomasz M. Beer, Alan Ashworth, Eric J. Small and Felix Y. Feng, Cancer Discovery (April 27, 2017)

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