Predictive biomarker for hypoxia-activated prodrug therapy
Inventors
ELENBAAS, BRIAN A. • Gualberto, Antonio • Hart, Charles Praray
Assignees
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Publication Number
US-10760130-B2
Publication Date
2020-09-01
Expiration Date
Abstract
Enolase levels are predictive of the probability that a cancer patient will respond favorably to cancer therapy involving administration of hypoxia-activated achiral phosphoramide mustards.
Core Innovation
The invention relates to treating cancer in a patient by determining that an enolase RNA or protein level in a cancer sample isolated from the patient exceeds a predetermined level, and then administering to the patient a hypoxia-activated prodrug of formula (I). The predetermined level of enolase is equal to or greater than 1.8 ng/ml. The determination of enolase RNA or protein levels is used to select patients for HAP therapy.
The hypoxia-activated prodrug of formula (I) is characterized by selecting Z3 and defining X4 as Cl or Br, or a physiologically acceptable salt thereof. The document identifies hypoxia-activated prodrugs including TH-302 and TH-281 as examples of the prodrug class used in the disclosed treatment approach. Related diagnostic, predictive, and monitoring uses involve enolase isoenzymes and measurement of enolase RNA or protein from sample types such as serum, plasma, or tumor biopsies.
The document describes that enolase levels, including ENO1 and ENO2, in a patient’s sample correlate with treatment response, including progression-free survival and overall survival. It also covers enolase isoenzymes EN01, EN02, and EN03, and combination with a non-hypoxia-activated anticancer drug.
Claims Coverage
The document includes one independent claim directed to a cancer-treatment method, plus dependent refinements that specify particular hypoxia-activated prodrugs, enolase isoenzymes, assay modalities for RNA and protein, and combination with a non-hypoxia-activated anticancer drug. The core inventive features center on using a predetermined enolase RNA or protein threshold to select patients, and administering a hypoxia-activated prodrug of formula (I).
Enolase-threshold patient selection
Determining that an enolase RNA or protein level in a cancer sample isolated from the patient exceeds a predetermined level
Hypoxia-activated prodrug administration by enolase threshold
Administering to the patient a hypoxia-activated prodrug of formula (I) when the predetermined enolase level is met or exceeded
Predetermined enolase threshold of at least 1.8 ng/ml
Wherein the predetermined level of enolase is equal to or greater than 1.8 ng/ml
Formula (I) prodrug definition with halogen selection
Selecting Z3 from the group consisting of specified options and wherein X4 is Cl or Br, or a physiologically acceptable salt thereof
Specific hypoxia-activated prodrug examples
Using a hypoxia-activated prodrug selected as either TH-302 or TH-281
Enolase isoenzyme targeting by EN01, EN02, and EN03
Performing the method using enolase isoenzymes EN01, EN02, and/or EN03
Enolase RNA and protein measurement modalities
Determining enolase RNA levels using PCR-based methods including qRT-PCR, multiplex qPCR, and/or in-situ hybridization, and/or determining enolase protein levels using immunoassay and immunostaining-based methods including immunohistochemistry, histochemistry, western blot, FACS, immunofluorescence staining, bead-based suspension immunoassay, Luminex technology, and a proximity ligation assay
Combination with a non-hypoxia-activated anticancer drug
Administering the hypoxia-activated prodrug together with an anticancer drug that is not a hypoxia-activated prodrug
Overall claim coverage is directed to treating cancer by selecting patients based on enolase RNA or protein levels exceeding a predetermined threshold equal to or greater than 1.8 ng/ml, followed by administering a hypoxia-activated prodrug of formula (I) defined by selected structural parameters, with refinements specifying TH-302 and TH-281 examples, enolase isoenzymes, allowed RNA and protein assay modalities, and possible combination with a non-hypoxia-activated anticancer drug.
Stated Advantages
Improved clinical outcomes associated with higher enolase levels, including progression-free survival and overall survival correlations in pancreatic cancer patients treated with gemcitabine ± TH-302
Provides a predetermined enolase level threshold to select patients for HAP therapy
Documented Applications
Predictive use: using enolase RNA or protein levels in a cancer patient sample to select patients for hypoxia-activated achiral phosphoramide mustard prodrug therapy, including TH-302 and TH-281
Monitoring and predictive diagnostic use: measuring enolase RNA or protein from serum, plasma, or tumor biopsy samples and using the results to relate to treatment response
Therapeutic combination context: treating pancreatic cancer patients with gemcitabine in combination with or in relation to TH-302 (gemcitabine ± TH-302)
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