Predictive biomarker for hypoxia-activated prodrug therapy
Inventors
ELENBAAS, BRIAN A. • Shen, Lei
Assignees
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Publication Number
US-10071109-B2
Publication Date
2018-09-11
Expiration Date
Abstract
CYP2W1 levels are predictive of the probability that a cancer patient will respond favorably to cancer therapy involving administration of a hypoxia-activated achiral phosphoramidate mustards.
Core Innovation
The invention provides a predictive biomarker strategy for hypoxia-activated achiral phosphoramidate mustards in cancer treatment by determining CYP2W1 RNA or CYP2W1 protein levels in a cancer sample isolated from a patient. Treatment decisions are based on whether the measured CYP2W1 RNA or protein exceeds a predetermined level.
The strategy is specifically tied to administering the hypoxia-activated prodrug TH-302, including use with TH-281, to a cancer patient suffering from gall bladder cancer or non-small cell lung cancer when the CYP2W1 RNA or protein in the cancer sample meets the predetermined threshold condition.
The document also characterizes a candidate hypoxia-activated prodrug of formula (I) with substituents including Z3 and X4, with examples such as Cl and Br, and physiologically acceptable salts. It further provides diagnostic, predictive, and monitoring approaches by measuring CYP2W1 RNA or protein using multiple modalities, and correlates high CYP2W1 expression with stronger TH-302 antitumor efficacy and complete responses using patient-derived xenograft (PDX) models.
Claims Coverage
The independent claim covers a CYP2W1-guided treatment method using TH-302 for specific cancer types, with one independent claim (clm-00001). The dependent claims further define quantitative determination of CYP2W1 levels, assay platforms for RNA/protein, supported gall bladder and non-small cell lung cancer PDX contexts, acceptable sample types, and an administration amount range for the hypoxia-activated prodrug.
CYP2W1-threshold determination for selecting hypoxia-activated prodrug administration
Determining that a CYP2W1 RNA or protein level in a cancer sample isolated from the patient exceeds a predetermined level, and administering a hypoxia-activated prodrug to the patient when that threshold condition is met.
TH-302 hypoxia-activated prodrug for treating specific CYP2W1-positive cancers
Administering a hypoxia-activated prodrug comprising (2-bromoethyl)({[(2-bromoethyl)amino][(2-nitro-3-methylimidazol-4-yl)methoxy]phosphoryl})amine (TH-302) to a cancer patient suffering from gall bladder cancer or non-small cell lung cancer.
Log2-relative CYP2W1 RNA threshold exceeding a predetermined value
Determining CYP2W1 RNA level relative to a control sample as a Log 2 value with a predetermined value of 5.0 Log 2.
Assay selection for CYP2W1 RNA and CYP2W1 protein measurement
Determining CYP2W1 RNA levels using PCR-based or hybridization methods or determining CYP2W1 protein levels using immunodetection/protein-assay methods.
CYP2W1-threshold context limited to specified PDX models
Limiting the method to cases where the measured level of CYP2W1 RNA or protein is greater than a predetermined level in a gall bladder PDX tumor model GL1208 or in a selected non-small cell lung cancer PDX model from LU1304, LU2505, LU1380, LU0357, LU1235, and LU0387.
Defined patient sample types for CYP2W1 measurement
Configuring the method for patient samples selected from serum, plasma, whole blood, pancreatic juice, tissue, tumor, or tumor lysate.
Administration amount range for the hypoxia-activated prodrug
Administering the hypoxia-activated prodrug in an amount ranging from 100 mg/m2 to 700 mg/m2.
Overall, claim coverage centers on selecting patients for hypoxia-activated prodrug therapy by determining whether CYP2W1 RNA or protein in a cancer sample exceeds a predetermined threshold, and administering TH-302 to patients with gall bladder cancer or non-small cell lung cancer. Dependent claims further specify threshold quantification for CYP2W1 RNA, assay modalities for RNA/protein detection, permitted sample types, constrained model contexts, and an administration amount range.
Stated Advantages
Predictive selection of cancer patients for hypoxia-activated prodrug therapy based on CYP2W1 RNA or protein exceeding a predetermined level.
Improved treatment association shown by linking high CYP2W1 expression to stronger TH-302 antitumor efficacy and complete responses in gall bladder and non-small cell lung cancer PDX models.
Documented Applications
Diagnostic, predictive, and monitoring use cases for measuring CYP2W1 RNA or protein and applying the predetermined threshold condition to support therapeutic administration with hypoxia-activated prodrugs.
Therapeutic use in treating cancer patients suffering from gall bladder cancer or non-small cell lung cancer using TH-302 when CYP2W1 RNA or protein exceeds a predetermined level.
Use of patient-derived xenograft (PDX) model evidence to support correlation between CYP2W1 expression and TH-302 antitumor efficacy/complete responses in gall bladder and non-small cell lung cancer models.
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