Chinese scientists have been the first to show that combining anti-cancer poly [ADP-ribose] polymerase (PARP) inhibitors with radiotherapy may be effective for treating ependymoma CNS tumors expressing elevated levels of the protein chromosome X open reading frame 67 (CXorf67).
In children, 90% of ependymomas arise intracranially, with two-thirds occurring as posterior fossa group A (PFA) tumors, the most common and aggressive of three distinct disease subtypes, which has particularly limited treatment options.
Ependymomas get their start in the lining of the brain's ventricles and spinal canal. They are often resistant to chemotherapy, and thus at present, the standard therapy for intracranial ependymomas is surgical resection combined with radiotherapy, but PFA tumors are often difficult to completely resect surgically.
Therefore, together with the lack of chemotherapeutic options, PFA patients, especially those with recurrent tumors, generally have very poor clinical outcomes.
CXorf67 is an uncharacterized protein with a poorly understood function, although previous studies have indicated a possible role of CXorf67 in low-grade endometrial stromal sarcoma and prostate cancer in humans.
CXorf67 is normally expressed at a low level in all human tissues and was recently reported to be specifically upregulated in PFA ependymoma.
"To examine whether CXorf67 may play a role in tumorigenesis, we analyzed its expression among different tumors, which showed that CXorf67 upregulation was most pronounced in PFA ependymomas," said study co-leader Lin Li.
"Another group had previously shown CXorf67 to be specifically unregulated in PFA ependymomas, but its exact role in PFA ependymomas was unclear, prompting our study reported in the November 12, 2020, online edition of Cancer Cell," said Li, a professor in the Chinese Academy of Sciences (CAS) Centre for Excellence in Molecular Cell Science at the CAS in Shanghai.
In that study, researchers co-led by Li, Hao Li, a professor in the Department of Neurosurgery at the Children's Hospital of Fudan University in Shanghai, and Dianqing Wu, a professor in the Department of Pharmacology at Yale School of Medicine, showed that elevated CXorf67 expression suppressed homologous recombination (HR)-mediated DNA repair.
"Using various assays, we found that knockdown of CXorf67 significantly increased HR repair efficiency, whereas CXorf67 overexpression significantly inhibited it," Li told BioWorld Science. "However, neither CXorf67 overexpression nor knockdown had any apparent effect on the efficiency of non-homologous end-joining (NHEJ)," he said, referring to the pathway for repairing double-strand breaks in DNA.
"Examination of CXorf67 levels in PFA cells showed that the inhibitory effect of CXorf67 on HR was correlated with its expression levels and that when CXorf67 expression was increased to certain levels, its effect on HR was comparable to that of breast cancer 2 (BRCA2) knockdown," explained Li.
Mechanistically, CXorf67 was shown to inhibit HR repair by interacting with partner and localizer of breast cancer 2 (PALB2) and inhibiting the interaction of PALB2 with BRCA2.
"PALB2 plays an important role in maintaining genome integrity through its role in the HR DNA repair pathway," Li said.
"Since its identification as a BRCA2 interacting partner, PALB2 has emerged as a pivotal tumor suppressor protein associated with hereditary breast cancer susceptibility."
Importantly, the researchers demonstrated that PFA tumor cells with elevated CXorf67 expression could be selectively killed by PARP inhibitors, especially when combined with ionizing radiation (IR).
"We evaluated the effect of the PARP inhibitors Taizenna (talazoparib tosylate; Pfizer), Lynparza (olaparib; AstraZeneca), Zejula (niraparib tosylate monohydrate; Tesaro) and IR in combination in multiple systems including cell lines, primary PFA tumor cells, an orthotopic transplantation tumor model, and in a PDX model," said Li.
"The data from these experiments consistently demonstrated that when combined with IR, the IC50 (half maximal inhibitory concentration) of PARP inhibition was dramatically decreased by approximately 20-fold to a nanomolar level for tumor cells with high CXorf67 expression."
Together, these study findings have revealed a role of CXorf67 in HR repair and suggest that combining PARP inhibitors with radiotherapy could be an effective treatment option for PFA ependymomas.
Finally, because the three PARP inhibitors have already been approved for various clinical applications by the FDA, PARP inhibitor/IR combinations can proceed rapidly to clinical trials, Song told BioWorld Science.
"Before clinical trials, we need to file a clinical new drug procurement application, a new drug clinical trial application, and apply for ethical approval, which together may take just 2 weeks or so." (Han, J. et al. Cancer Cell 2020, Advanced publication).