Abstract
Glioblastoma multiforme (GBM) is the most common primary brain cancer. GBMs commonly acquire resistance to standard-of-care therapies. Among the novel means to sensitize GBM to DNA-damaging therapies, a promising strategy is to combine them with inhibitors of the DNA damage repair (DDR) machinery, such as inhibitors for poly(ADP-ribose) polymerase (PARP). PARP inhibitors (PARPis) have already shown efficacy and have received regulatory approval for breast, ovarian, prostate, and pancreatic cancer treatment. In these cancer types, after PARPi administration, patients carrying specific mutations in the breast cancer 1 (BRCA1) and 2 (BRCA2) suppressor genes have shown better response when compared to wild-type carriers. Mutated BRCA genes are infrequent in GBM tumors, but their cells can carry other genetic alterations that lead to the same phenotype collectively referred to as ‘BRCAness’. The most promising biomarkers of BRCAness in GBM are related to isocitrate dehydrogenases 1 and 2 (IDH1/2), epidermal growth factor receptor (EGFR), phosphatase and tensin homolog (PTEN), MYC proto-oncogene, and estrogen receptors beta (ERβ). BRCAness status identified by accurate biomarkers can ultimately predict responsiveness to PARPi therapy, thereby allowing patient selection for personalized treatment. This review discusses potential biomarkers of BRCAness for a ‘precision medicine’ of GBM patients.
Highlights
Accepted: 21 July 2021Glioblastoma multiforme (GBM) has a radically altered genome and epigenome [1,2], which partially explains its aggressiveness
We reviewed data from the most promising candidate biomarkers of BRCAness in GBM, namely mutate isocitrate dehydrogenases 1 and 2 (IDH1/2), epidermal growth factor receptor (EGFR) mutated variant (EGFR vIII), phosphatase and tensin homolog (PTEN), MYC oncogene, and the estrogen receptors beta (ERβ)
A better understanding of the cancer biology of GBM has brought into attention the DNA damage repair (DDR) cascade with the central role of PARP1 as a therapeutic target, opening up the opportunity for the use of PARP inhibitors (PARPis) in GBM therapy
Summary
Glioblastoma multiforme (GBM) has a radically altered genome and epigenome [1,2], which partially explains its aggressiveness. These modifications comprise point mutations, changes in the gene copy number, complete rearrangements, and epigenetic alterations [3] Part of these genetic aberrations arise from the dysregulation of one or more molecular pathways responsible for recognizing and repairing DNA damage. While genomic instability contributes to the poor prognosis for GBM patients [5], the damaged DNA offers a target for pharmacological approaches that induce cancer cell death by a mechanism called synthetic lethality. This killing process occurs only if two molecular pathways are simultaneously deficient in one cell, whereas the isolated defect is innocuous [6]. We examine here the value of biomarkers that indicate the BRCAness status in GBM as an objective decision-making criterion for adding PARPi in the current glioma therapy
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