Established and novel pathway targets in ovarian cancer
Cancer cells rely on their ability to exploit many pathways to survive13
Changes in these pathways enable cancers to13:
Multiple pathways are being investigated for maintenance in ovarian cancer, including1,14-17:
- DNA-damage repair
- Immune checkpoints
PARP inhibition leverages the DNA damage–repair pathway18
PARP enzymes, and homologous recombination repair (HRR) proteins such as BRCA, are involved in DNA-damage repair.18
In tumor cells with a compromised DNA damage–repair pathway (for example, mutations in HRR genes), PARP inhibition causes an excessive accumulation of DNA damage and, thus, tumor-cell death.19,20
Angiogenesis is driven through increased production of VEGF20,21
VEGF ligands and their receptors (VEGFRs) have been shown to play major roles in tumor-cell angiogenesis.22
Inhibition of VEGF or VEGFR activity interferes with neovascularization, leading to cancer-cell death.22
Avoidance of immune destruction, which may be modulated by the PD-1 and PD-L1 pathways23
Binding of the PD-L1 protein to the PD-1 receptor protein found on T cells inhibits immune-mediated anti-tumor activity. Inhibition of this interaction results in the restoration of anti-tumor immune responses.24
Combination strategies may regulate multiple mechanisms that lead to cancer by targeting non-overlapping pathways14-17
Simultaneous inhibition of various pathways involved in cancer-cell survival may13,25,26:
- Impede tumor-cell survival
- Prevent resistance to pathway inhibition
- Maximize the effects of targeting different pathways
Combination strategies include inhibition of the DNA damage–repair pathway through PARP.
These combinations target14-17:
- DNA-damage repair + angiogenesis
- DNA-damage repair + immune checkpoints
- DNA-damage repair + angiogenesis + immune checkpoints
Hallmarks of her tumor
When any mechanism regulating DNA-damage repair is impaired or deficient, tumorigenesis may occur13,27
BRCAm is the most well-known cause of impaired DNA damage-repair in ovarian cancer.28 However, other genetic mutations in homologous recombination repair (HRR) genes, promoter methylation, and unidentified causes can cause DNA damage–repair dysfunction, resulting in a homologous recombination deficiency (HRD) phenotype. This inability to repair DNA damage leads to genomic instability.29,30
Because multiple mechanisms of DNA damage–repair deficiency can result in genomic instability,* a biomarker of HRD, even women without a BRCA mutation may still harbor tumors with an HRD phenotype.31
*Genomic instability assays are also commonly referred to as “genomic scar” assays.
Identification of the biomarkers of
HRD can reveal tumor reliance on the DNA damage–repair pathway
Key genotypic biomarkers of HRD in tumor cells include13,28:
- BRCA mutations
- Mutations in other specific homologous recombination repair (HRR) genes
- Other causes of altered gene expression (eg, epigenetic alterations)
The HRD phenotype may be detected by measuring genomic instability through the following:
- Loss of heterozygosity
- Telomeric allelic imbalance
- Large-scale state transitions
Recurrence is an ever-present threat to women undergoing treatment for advanced ovarian cancer. Treatment strategies that include maintenance therapy at the earliest possible opportunity are critical for delaying recurrence.
The baseline knowledge that cancer cells rely on their ability to modulate many pathways to survive has led to research in combination pathway inhibition. Consider biomarkers of HRD, including BRCAm, at diagnosis to know the hallmarks of her tumor.
BRCAm=BReast CAncer susceptibility gene mutation; HRD=homologous recombination deficiency.
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