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Targetunrated confidence 0 of 5: unrated

Volasertib against PLK1: a differential window claimed in infant-type cells, on a target every dividing cell needs

also called volasertib · BI 6727 · PLK1 inhibition

Volasertib blocks PLK1 and did little for adults with this leukaemia. One group reports that infant-type cells respond much better, which would make it a drug for the wrong age group tested in the wrong one.

The same thing, for a scientist

The therapeutic claim is DIFFERENTIAL SENSITIVITY, not selectivity: volasertib had limited success in adults, PLK1 marks an infant MLLr signature, and in a cord-blood versus bone-marrow CRISPR model the dose-dependent antiproliferative effect is most pronounced in the infant arm. The adult arm answers the drug by upregulating PLK1 and AURKA, and adding the Aurora A inhibitor alisertib overcomes the poor response.

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What would have to be true for this to be a paediatric drug

Three things, none of which is established. A window: PLK1 is required by every proliferating cell, so the claim needs a dose at which infant blasts die and infant marrow does not — and an infant's marrow is the most proliferative tissue in the body. A biomarker: PLK1 expression tracks proliferation everywhere, so a high-PLK1 signature may select fast-cycling disease rather than infant biology. A trial: the contrast the paper draws is with adult volasertib experience, and there is no paediatric PLK1-inhibitor experience in this disease to contrast it with.

How this could bite us back
  • PLK1 is required for mitosis in every dividing cell. In an infant, the marrow, gut epithelium and growing tissues are all highly proliferative, so the on-target toxicity is broader than in an adult, not narrower.
  • Volasertib's adult clinical record includes myelosuppression as the dominant dose-limiting toxicity, which is the same compartment the leukaemia occupies.
  • The proposed escape from the adult model's resistance is to ADD alisertib, an Aurora A inhibitor - a second antimitotic. A two-antimitotic combination in an infant compounds exactly the toxicity that limits each one alone.
  • The biomarker is expression of a proliferation-associated kinase. Selecting patients on it risks selecting the most proliferative disease rather than the age group the hypothesis is about.
Still open
  1. What is the dose-limiting toxicity of volasertib in children, and has any paediatric PLK1 inhibitor study been registered?
Every source behind this entry (1)
  1. E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    Volasertib, blocking PLK-1, exhibited limited success in adults; PLK-1 characterises an infant MLLr signature; and in a CRISPR/Cas9 MLLr model in CD34+ cells from human cord blood and adult bone marrow, volasertib induced a significant dose-dependent decrease in proliferation and cell-cycle arrest, most pronounced in the infant model.

    PMID 39684470DOI
    What this evidence cannot show

    Abstract read; full text not read. 'Limited success in adults' summarises prior clinical experience the paper cites rather than a comparison run inside it.

    Evidence that argues against this (2)
    • Proliferation and cell-cycle arrest in culture are the endpoints a mitotic kinase inhibitor cannot fail on. What distinguishes a drug from a cytotoxic is the ratio between malignant and normal, and a cord-blood-derived model supplies no normal comparator from the same donor at the same cycling rate. Oncofusion knowledge graph (internal analysis) 2026
    • Pan-essentiality is the finding and it argues against the target rather than for it. This gene is depleted in more than 94% of all DepMap lines, which leaves almost no dynamic range in which selectivity could appear, so the small index-versus-comparator difference is uninterpretable rather than small. For a therapeutic claim this matters more than for a biological one: PLK1 at 99.9% of lines depleted is the profile of a cytotoxic target, and volasertib's adult clinical record is consistent with that. Oncofusion knowledge graph (internal analysis) 2026
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