KIF18A Inhibition Guided by SAC and Ploidy Biomarkers for Cancer Treatment

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Solution Overview

Problem

Current cancer treatments targeting the mitotic kinesin KIF18A face challenges due to high cytotoxicity and lack of biomarkers for identifying patient populations, necessitating the identification of determinants of KIF18A dependency to improve drug development.

Innovation Solution

A method for determining sensitivity to KIF18A inhibitor treatment by assaying Spindle Assembly Checkpoint (SAC) activity, ploidy, whole genome doubling (WGD), and Anaphase Promoting Complex (APC/C) activity, followed by administering a KIF18A inhibitor to subjects with increased SAC signaling, high ploidy, or low APC/C activity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If KIF18A inhibitor is administered to treat cancer, then tumor regression is achieved, but cytotoxicity increases affecting cycling tissues

Engineering Contradiction:

Improvetumor regression efficacyVSAvoidcytotoxicity to cycling tissues

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by identifying specific molecular characteristics (SAC activity levels, ploidy status, WGD events, APC/C activity) that distinguish cancer cells from normal cycling tissues. This allows the KIF18A inhibitor to selectively affect cancer cells with these specific qualities while sparing normal tissues, thereby achieving tumor regression with reduced cytotoxicity to healthy cycling tissues

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent utilizes parameter changes by measuring and comparing specific biochemical parameters (SAC signaling activity, ploidy level, genome doubling status, APC/C activity) to identify cancer cells that are dependent on KIF18A. By targeting cells with specific parameter profiles rather than all cycling cells, the treatment achieves selective efficacy with reduced off-target cytotoxicity

Inventive Principle:

Principle #35Parameter changes

2Reliability

If KIF18A inhibitor is used to treat cancer, then tumor proliferation is inhibited, but lack of biomarkers prevents identification of responsive patient populations

Engineering Contradiction:

Improvetreatment efficacyVSAvoidabsence of biomarkers for patient selection

Core Design Contradiction:

ReliabilityVSLoss of information

Solution Approach 1:

The patent applies preliminary action by performing biomarker assessment (SAC activity, ploidy, WGD, APC/C activity) on patient samples before administering the KIF18A inhibitor. This preliminary characterization of the cancer cells' molecular profile allows clinicians to identify patients most likely to respond to treatment, ensuring that the inhibitor is given only to those with KIF18A-dependent tumors, thereby improving treatment efficacy while avoiding unnecessary exposure in non-responsive patients

Inventive Principle:

Principle #10Preliminary action

Data Source

PatentUS20250325527A1KIF18a inhibition for treatment of cancer

Publication Date: 2025.10.23 AMGEN INC

AI summary

Provided herein are methods of determining a treatment for a subject having a neoplastic disease, said method comprising assaying a sample obtained from the subject for (a) SAC activity, (b) ploidy, (c) WGD, (d) APC/C activity, or (e) a combination thereof. In exemplary embodiments, the treatment determined for the subject comprises, consists essentially of, or consists of a KIF18A inhibitor, when the sample is positive for (a) increased SAC activity, (b) high ploidy, (c) WGD, (d) low APC/C activity, (d) or a combination thereof.