Written by Charlotte Harrison, Science Writer.
Ovarian cancer is usually diagnosed late and can be difficult to treat. A study published in Cancer Cell shows that high-grade serous carcinoma (HGSC) — a type of ovarian cancer linked to poor prognosis — can be classified into three groups based on genomic changes that reflect how cells within the tumour signal, grow and respond to treatment.
The findings could help HGSC treatments become tailored to a patient’s specific type of tumour.
DECIDER study
The research was performed as part of the EU-funded DECIDER study. A goal of DECIDER is to characterize intra- and inter-tumour heterogeneity in patients with HGSC and investigate if heterogeneity is associated with treatment response.
The researchers used whole-genome sequencing data from 510 samples of 148 patients with HGSC to determine genetic changes that underpin how the tumour evolves, or develops and spreads into new metastases.
Evolutionary states
Their findings showed that tumours could be classified into three evolutionary states depending on their stage of development and pattern of spread: evolving, maintaining and adaptive. Each state had distinct features related to genomics, signalling pathways and morphological phenotypes, as well as treatment response.
For example, the evolving state used signalling pathways involving MAPK and ERBB2, the maintaining state used the PI3K/AKT pathway and the adaptive state used NOTCH and WNT signalling.
Pathway analysis indicated that the three states do not exist independently, but are linked by two evolutionary trajectories.
PI3K/AKT signalling
The researchers then assessed how chemotherapy affected the evolutionary states. Here, they found that for the tumours from the maintaining group, which is linked to poor clinical outcome, PI3K/AKT signalling was not affected by chemotherapy treatments, and remained active in relapsed cases.
This finding indicates that AKT/PI3K signalling has a key role in HGSC tumour progression and chemotherapy resistance.
Several clinically approved PI3K/AKT inhibitors are available, so the author next tested several of these in organoid cell lines that had enriched PI3K/AKT pathways. One particular inhibitor, alpelisib (a PI3Kα inhibitor approved for treating advanced metastatic breast cancer) caused pronounced tumour-cell death.
The study points towards eventual tumour-specific treatments. “Prior studies have not identified generally accepted subgroups of HGSC tumours that would enable targeted treatment in the same way as, for example, in breast cancer. Our study is a step forward in identifying effective targeted therapies,” said lead author Sampsa Hautaniemi in a press release.
