OnCo
ideasIdea

Detect tumours changing cell type from RNA in the blood

Some cancers escape treatment by changing into a different kind of cell that the drug no longer affects. Tumour RNA in blood could show this shift months before a biopsy would.

Lineage plasticity (adenocarcinoma to small cell or neuroendocrine transformation in EGFR-mutant lung and prostate cancer) is a DNA-invisible resistance mechanism, usually diagnosed by biopsy late. Cell-free RNA and nucleosome footprinting can infer transcriptional state from plasma. The proposal is a plasma neuroendocrine transformation score monitored in patients at genetic risk (RB1 and TP53 loss) so that the switch to platinum-etoposide or a DLL3 bispecific is made early.

Hypothesis
A plasma-derived lineage score rises at least three months before histological confirmation of neuroendocrine transformation and enables an earlier treatment switch that improves survival in this subgroup.
Rationale
Transformation is frequent in RB1/TP53-altered EGFR-mutant and castration-resistant disease; cfDNA fragmentomics has already discriminated neuroendocrine from adenocarcinoma prostate cancer in small studies.
What would test it
Serial plasma in 200 RB1/TP53-altered patients on TKI or androgen-receptor therapy, blinded scoring, comparison with clinically indicated biopsies.
Maturity
speculative
Who has to act
research
Cost to try
Medium ($1M to $50M)
Years to first evidence
4
Bottlenecks it attacks

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