PLK1 Inhibitor Response Prediction via TCTP Phosphorylation in AML
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Solution Overview
Problem
There is a need for a method to enrich for the subset of subjects that have a greater likelihood of responding to PLK1 inhibitors, as existing methods do not effectively predict the efficacy of PLK1 inhibitors in cancer treatment.
Innovation Solution
Determine the phosphorylation of serine 46 of translational control tumor protein (TCTP) in cancer samples before and after exposure to the PLK1 inhibitor onvansertib, and select patients for treatment if phosphorylation is decreased, specifically for acute myeloid leukemia (AML).
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PLK1 inhibitors are administered to cancer patients, then antitumor activity is achieved, but the ability to predict treatment efficacy is insufficient
Solution Approach 1:
The patent applies preliminary action by measuring TCTP phosphorylation status before administering PLK1 inhibitors to predict treatment response. This pre-treatment biomarker assessment allows clinicians to identify patients likely to respond to therapy, enabling informed treatment decisions before the actual therapeutic intervention occurs.
Solution Approach 2:
The patent implements feedback by measuring changes in TCTP phosphorylation levels after PLK1 inhibitor administration and using this information to predict treatment efficacy. The phosphorylation status serves as a feedback signal that indicates whether the drug is effectively inhibiting its target, allowing for real-time assessment of treatment response.
2Reliability
If TCTP phosphorylation is measured before and after onvansertib exposure, then treatment response can be predicted, but additional testing time and complexity are required
Solution Approach 1:
The patent measures TCTP phosphorylation status as a preliminary step before initiating full treatment, allowing for rapid identification of responsive patients. This upfront biomarker assessment prevents time loss by identifying non-responders early, avoiding prolonged ineffective treatment and subsequent treatment switching.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This method allows for the early identification of patients likely to respond to onvansertib treatment by measuring the inhibition of TCTP phosphorylation, predicting treatment efficacy and enabling targeted therapy.
Implementation Method 1
Onvansertib (also known as PCM-075, NMS-1286937, NMS-937, 'compound of formula (1)' in U.S. Patent 8,927,530; IUPAC name 1-(2-hydroxyethyl)-8-{[5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy) phenyl] amino}- 4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide) is the first PLK1 specific ATP competitive inhibitor administered by oral route to enter clinical trials with proven antitumor activity in different preclinical models
Implementation Method 2
determining phosphorylation of serine 46 of translational control tumor protein (TCTP) in a cancer sample obtained from a patient
Data Source
Figure 1A~1B
Figure 2A~2B
Figure 2C
AI summary
Provided is a method comprising determining polo-like kinase 1 (PLK1) activity in a cancer in a patient by measuring phosphorylation of a PLK1 target (a) prior to treatment of (i) the patient or (ii) a cancer sample from the patient with a PLK1 inhibitor, and (b) after the treatment. Also provided is a method comprising determining polo-like kinase 1 (PLK1) activity in a cancer in a patient by measuring phosphorylation of a PLK1 target without treatment with a PLK1 inhibitor.