Predictive biomarker for hypoxia-activated prodrug therapy

1. A method for treating cancer in a patient, comprising the steps of determining that an enolase RNA or protein level in a cancer sample isolated from said patient exceeds a predetermined level and administering to said patient a hypoxia-activated prodrug of formula (I)

wherein Z 3 is selected from the group consisting of:

 and

X 4 is Cl or Br, or a physiologically acceptable salt thereof;

wherein the predetermined level of enolase is equal to or greater than 1.8 ng/ml; and

wherein the hypoxia-activated prodrug is administered in an amount of about 100 mg/m 2 to about 700 mg/m 2 to the patient in need of cancer therapy.

2. The method according to claim 1 , wherein the hypoxia-activated prodrug comprises (2-bromoethyl)({[(2-bromoethyl)amino][(2-nitro-3-methylimidazol-4-yl)methoxy]phosphoryl})amine (TH-302) or (2-chloroethyl)({[(2-chloroethyl)amino][(2-nitro-3-methylimidazol-4-yl)methoxy]phosphoryl})amine (TH-281).

3. The method of claim 1 , wherein the cancer patient is suffering from pancreatic cancer.

4. The method of claim 1 , wherein the enolase is EN01 (α-enolase), EN02 (γ-enolase) and/or EN03 (β-enolase).

5. The method of claim 1 , wherein the hypoxia-activated prodrug is administered intravenously in an amount of about 240 mg/m 2 to about 340 mg/m 2 to the patient in need of cancer therapy.

6. The method of claim 1 , wherein the hypoxia-activated prodrug is administered in combination with an anticancer drug that is not a hypoxia-activated prodrug.

7. The method of claim 1 , wherein the patient sample is one or more of a serum sample, plasma sample, whole blood sample, pancreatic juice sample, tissue sample, tumor sample or tumor lysate.

8. The method of claim 1 , wherein the enolase RNA level is determined by a method comprising PCR, qRT-PCR, multiplex qPCR or in-situ hybridization, or the enolase protein level is determined by a method comprising immunohistochemistry, histochemistry, western blot, FACS, immunofluorescence staining, a bead-based suspension immunoassay, Luminex technology or a proximity ligation assay.

9. The method of claim 1 , wherein the hypoxia-activated prodrug is administered in combination with gemcitabine.