Uses of labeled HSP90 inhibitors

Patent metadata

Field	Value
Publication number	US-9555137-B2
Application number	US-201214131423-A
Country	US
Kind code	B2
Filing date	Jul 6, 2012
Priority date	Jul 8, 2011
Publication date	Jan 31, 2017
Grant date	Jan 31, 2017

Abstract

The disclosure provides evidence that the abundance of this particular “oncogenic HSP90” species, which is not dictated by HSP90 expression alone, predicts for sensitivity to HSP90 inhibition therapy, and thus is a biomarker for HSP90 therapy. The disclosure also provides evidence that identifying and measuring the abundance of this oncogenic HSP90 species in tumors predicts of response to HSP90 therapy. “Oncogenic HSP90” is defined herein as the HSP90 fraction that represents a cell stress specific form of chaperone complex, that is expanded and constitutively maintained in the tumor cell context, and that may execute functions necessary to maintain the malignant phenotype. Such roles are not only to regulate the folding of overexpressed (i.e. HER2), mutated (i.e. mB-Raf) or chimeric proteins (i.e. Bcr-Abl), but also to facilitate scaffolding and complex formation of molecules involved in aberrantly activated signaling complexes (i.e. STATS, BCL6).

First claim

The invention claimed is:

1. A method for determining whether a patient with a blood cancer will likely respond to therapy with an HSP90 inhibitor which comprises:
(a) contacting a sample containing blood cancer cells and non-cancerous blood cells from the patient with a cell permeable fluorescently labeled HSP90 inhibitor that binds directly and preferentially to a cancer-specific form of HSP90 present in the cancer cells of the patient;
(b) measuring the amount of fluorescently labeled HSP90 inhibitor bound to HSP90 protein in the cancer cells and non-cancer cells in the sample; and
(c) comparing the amount of the fluorescently labeled HSP90 inhibitor bound to the cancer cells with the amount of the fluorescently labeled HSP90 inhibitor bound to the non-cancer cells,

wherein a greater amount of fluorescently labeled HSP90 inhibitor bound to the cancer cells than the non-cancer cells indicates presence of the cancer specific form of HSP90 in the cancer cells; thereby determining that the blood cancer will likely respond to therapy with the HSP90 inhibitor.

2. The method of claim 1 , wherein the non-cancer cells are lymphocytes.

3. The method of claim 1 , wherein said measuring is conducted by flow cytometry.

4. The method of claim 1 , wherein the greater the amount of fluorescently labeled HSP90 inhibitor bound to the cancer cells measured in step (b) as compared with the fluorescently labeled HSP90 inhibitor bound to the non-cancer cells, the greater the magnitude of the likely response to the HSP90 inhibitor therapy.

5. The method of claim 1 , wherein the blood cancer is a leukemia.

6. The method of claim 5 , wherein the leukemia is chronic myeloid leukemia.

7. The method of claim 1 , wherein the sample comprises live cells.

8. The method of claim 1 , wherein the sample comprises a biological fluid.

9. The method of claim 8 , wherein the biological fluid is blood or bone marrow.

10. The method of claim 8 , wherein the biological fluid is blood.

11. The method of claim 1 , wherein the sample comprises disrupted tumor cells.

12. The method of claim 1 , wherein the sample comprises frozen cells.

13. The method of claim 1 , wherein the sample comprises fixed and permeabilized cells.

14. The method of claim 1 , further comprising the step of administering to the patient an HSP90 inhibitor as therapy, wherein the fluorescently labeled HSP90 inhibitor is a labeled form of the HSP90 inhibitor to be administered as therapy.

15. The method of claim 14 , wherein the HSP90 inhibitor to be administered as therapy is PU-H71 or an analog, homolog or derivative of PU-H71.

16. The method of claim 15 , wherein the HSP90 inhibitor is PU-H71.

17. The method of claim 1 , wherein the fluorescently labeled HSP90 inhibitor is a form of PU-H71 or of an analog, homolog, or derivative of PU-H71.

18. The method of claim 1 , wherein the fluorescently labeled HSP90 inhibitor is a form of PU-H71.

19. The method of claim 1 , wherein the fluorescently labeled HSP90 inhibitor is PU-H71-FITC2.

20. The method of claim 1 , wherein the fluorescently labeled HSP90 inhibitor is PU-H71-NBDI.

21. The method of claim 1 , wherein the blood cancer is a hematologic malignancy.

22. The method of claim 1 , further comprising the step of administering to the patient an HSP90 inhibitor.

Assignees

• Chiosis Gabriela
• Taldone Tony
• Alpaugh Mary L
• Gomes-Dagama Erica M
• Guzman Monica L
• Zong Hongliang
• Sloan-Kettering Inst For Cancer Res
• Univ Cornell

Inventors

• Chiosis Gabriela
• Taldone Tony
• Alpaugh Mary L
• Gomes-Dagama Erica M
• Guzman Monica L
• Zong Hongliang

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• G01N33/57557 Primary

  of other specific parts of the body, e.g. brain · CPC title

• G01N33/57505

  of the blood, e.g. leukaemia · CPC title