Methods and systems for treating disease using an ATR/Chk1 signaling pathway inhibitor
Inventors
Blume-Jensen, Peter • Dunyak, James • Masson, Kristina • Murshid, Ayesha • Shipitsin, Michail • Wigerup, Caroline Maria
Assignees
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Publication Number
US-12433888-B1
Publication Date
2025-10-07
Expiration Date
Abstract
Provided herein are methods and systems for determining and/or validating response to a checkpoint kinase 1 (Chk1) inhibitor, a Wee1 inhibitor, an ATR inhibitor, or a combination thereof, and methods of administering a Chk1 inhibitor, a Wee1 inhibitor, an ATR inhibitor, or a combination thereof to a subject determined to be responsive to said therapy.
Core Innovation
The invention relates to methods of treating cancer by administering a therapeutic agent to a subject whose cancer cell tissue sample is determined to exhibit a Response-Predictive Signature. The signature includes a first biomarker score, a second biomarker score, and a third biomarker score, each compared to a respective predictive threshold, or in a composite form to a composite threshold.
The signature biomarkers are Ser296 phosphorylated Chk1, Ser473 phosphorylated Kap1, and total cyclin E1. The biomarker scores can be determined using scoring schemes including percent positive cells and weighted intensity distribution, with detection involving nuclear localization in cells from the cancer tissue sample and measured biomarker responses from tissue, including regions of interest and biomarker measurement using multiplex protein-based assays.
For one treatment approach, the therapeutic agent is prexasertib or a pharmaceutically acceptable salt thereof, and the cancer is selected from ovarian cancer, endometrial cancer, or bladder cancer. For an alternative treatment approach, the therapeutic agent is an inhibitor of expression or activity of a protein in an ATR/Chk1 signaling pathway, again in a subject whose cancer tissue sample exhibits the Response-Predictive Signature.
Claims Coverage
The document includes two independent claims that define treatment of cancer using a Response-Predictive Signature based on three biomarkers, with either individual predictive thresholds or a composite threshold. The claims also specify two therapeutic approaches and, for one claim, the cancers ovarian cancer, endometrial cancer, or bladder cancer.
Response-predictive signature with predictive thresholds for Chk1, Kap1, and cyclin E1
Administering prexasertib or a pharmaceutically acceptable salt to a subject whose cancer cell tissue sample exhibits a Response-Predictive Signature comprising a first biomarker score for Ser296 phosphorylated Chk1 greater than or equal to a first predictive threshold, a second biomarker score for Ser473 phosphorylated Kap1 greater than or equal to a second predictive threshold, and a third biomarker score for total cyclin E1 greater than or equal to a third predictive threshold.
Composite-score response-predictive signature for ATR/Chk1-pathway inhibition
Administering a therapeutic agent that is an inhibitor of expression or activity of a protein in an ATR/Chk1 signaling pathway to a subject whose cancer tissue sample exhibits a Response-Predictive Signature comprising a composite score greater than or equal to a composite threshold, wherein the composite score comprises a first biomarker score for Ser296 phosphorylated Chk1, a second biomarker score for Ser473 phosphorylated Kap1, and a third biomarker score for total cyclin E1, and wherein the cancer is selected from ovarian cancer, endometrial cancer, or bladder cancer.
Treatment eligibility is determined by the Response-Predictive Signature defined by Ser296 phosphorylated Chk1, Ser473 phosphorylated Kap1, and total cyclin E1, using either individual biomarker predictive thresholds or a composite score threshold, followed by administration of prexasertib or an ATR/Chk1-pathway inhibitor.
Stated Advantages
Documented Applications
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