A new research study found that the loss of CHD1, one of the most commonly mutated genes in prostate tumors, may be a potential biomarker for targeted prostate cancer therapy.
In the study, “Loss of CHD1 causes DNA repair defects and enhances prostate cancer therapeutic responsiveness,” published in EMBO Reports, researchers showed that CDH1 is involved in DNA damage repair mechanisms, and its loss sensitizes human prostate cancer cells to different drugs, including PARP inhibitors like Lynparza (olaparib).
The CHD1 gene is mutated in 15 to 27 percent of all prostate tumors, with mutations in this gene correlating with chromosomal instability and poor prognosis for prostate cancer patients. However, the importance of CHD1 deletion for prostate cancer cells was not known.
In this study, a team of researchers in Germany and Denmark sought to examine the role of CHD1 to understand how its loss was beneficial for prostate cancer cells. By studying human prostate cancer cell lines lacking the CHD1 gene, investigators found that CHD1 was involved in DNA damage repair mechanisms. It functions by loosening the DNA around break sites to facilitate access of DNA repair proteins.
Similar to descriptions of cancer cells with mutations in other proteins involved in DNA repair mechanisms, such as BRCA1 and BRCA2, researchers found that prostate cancer cells lacking CHD1 were particularly more sensitive to chemotherapy drugs that caused DNA damage, such as Mitomycin C, Camptosar (ironotecan), and PARP inhibitors such as Lynparza.
The PARP protein also helps the cells repair damages in their DNA molecules. Inhibition of this protein with PARP inhibitors increases the amount of damages that are not repaired, ultimately inducing cell death. PARP inhibitors have also shown promise in cancers exhibiting mutations in other DNA repair proteins, and Lynparza is already approved for patients with BRCA-mutated ovarian cancers.
“I am very excited about the translational potential of the study, and we are getting into contact with pharmaceutical companies to try to translate these findings into clinical development,” Steven Johnsen, a professor at the University Medical Center Göttingen in Germany, the study’s lead author, said in a press release.
Researchers are now testing PARP inhibitors in the treatment of prostate cancer. A Phase 2 clinical trial of Lynparza has been demonstrating increased radiologic progression-free survival in patients with metastatic prostate cancer who display genomic abnormalities indicative of DNA repair defects.
“A retrospective analysis of the CHD1 gene in these samples may reveal the potential utility of CHD1 as a biomarker for improved prostate cancer patient stratification and targeted therapy with PARP inhibitors,” Johnsen said.