FRAGMENT OF SECRETED HEAT SHOCK PROTEIN-90ALPHA (Hsp90ALPHA) AS VACCINES OR EPITOPE FOR MONOCLONAL ANTIBODY DRUGS OR TARGET FOR SMALL MOLECULE DRUGS AGAINST A RANGE OF SOLID HUMAN TUMORS
The invention provides methods for treating HIF-1α-overexpressing human tumors, inhibiting HIF-1α-overexpressing tumor invasion and preventing tumor metastasis, and/or promoting tumor prophylaxis, using various types of inhibitors against the Hsp90α from the tumors.
1 . An isolated peptide comprising the sequence set forth in SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 or SEQ ID NO: 6.
2 . A nucleic acid molecule encoding the peptide of claim 1 .
3 . A cDNA molecule of claim 2 .
4 . A vector comprising the cDNA molecule of claim 3 .
5 . A host-vector system comprising the vector of claim 4 transfected into a compatible host cell.
6 . The host-vector system of claim 5 , wherein the compatible host cell is a prokaryotic cell or a eukaryotic cell.
7 . An antibody which recognizes and binds an epitope comprising the sequence set forth in SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 and/or SEQ ID NO: 6.
8 . The antibody of claim 7 , wherein the antibody is a monoclonal antibody or fragment thereof, a polyclonal antibody or a fragment thereof, chimeric antibodies, humanized antibodies, human antibodies, or a single chain antibody.
9 . A pharmaceutical composition comprising the antibody of claim 7 and a pharmaceutical carrier.
10 . A vaccine comprising the isolated peptide of claim 1 .
11 . A method for treating HIF-1α-overexpressing cancer in a subject in need thereof comprising:
(a) providing a composition comprising an inhibitor of Hsp90α; and
(b) administering a therapeutically effective amount of the composition to the subject so as to treat HIF-1-positive cancer in the subject.
12 . A method for inhibiting HIF-1α-overexpressing cancer in a subject in need thereof comprising:
(a) providing a composition comprising an inhibitor of Hsp90α; and
(b) administering a therapeutically effective amount of the composition to the subject so as to inhibit HIF-1-positive cancer in the subject.
13 . A method for preventing metastasis of HIF-1α-overexpressing cancer in a subject in need thereof comprising:
(a) providing a composition comprising an inhibitor of Hsp90α; and
(b) administering a therapeutically effective amount of the composition to the subject so as to prevent metastasis of HIF-1-positive cancer in the subject.
14 . The method of claim 11 , 12 or 13 , wherein the inhibitor of Hsp90α targets the amino acids of Hsp90α as set forth in SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 and/or SEQ ID NO:6.
15 . The method of claim 11 , 12 or 13 , wherein the inhibitor of Hsp90α is selected from the group consisting of a small molecule, a peptide, an antibody or a fragment thereof and a nucleic acid molecule.
16 . The method of claim 11 , 12 or 13 , wherein the inhibitor of Hsp90α is an inhibitor of Hsp90α receptor and is selected from the group consisting of a small molecule, a peptide, an antibody or a fragment thereof or a nucleic acid molecule.
17 . The method of claim 15 or 16 , wherein the nucleic acid molecule is a siRNA molecule.
18 . The method of claim 15 or 16 , wherein the antibody is selected from the group consisting of monoclonal antibody or fragment thereof, a polyclonal antibody or a fragment thereof, chimeric antibodies, humanized antibodies, human antibodies, and a single chain antibody.
19 . A method for treating, inhibiting or preventing metastasis of HIF-1α-overexpressing cancer in a subject in need thereof comprising:
(a) providing a composition comprising sensitized antigen presenting cells, wherein the antigen presenting cells are sensitized with peptides having the amino acid sequence set forth in SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4 and/or SEQ ID NO:5; and
(b) administering a therapeutically effective amount of the composition to the subject so as to treat, inhibit or prevent metastasis of HIF-1α-overexpressing cancer in the subject.
20 . The method of any one of claim 11 , 12 or 13 , wherein the Hsp90α inhibitor is administered intravenously, intramuscularly, intraperitonealy, orally or via inhalation.
21 . A method of any one of claim 11 , 12 or 13 , wherein the effective amount of the inhibitor of Hsp90α or fragments thereof is about 1-5 mg/day, 5-10 mg/day, 10-50 mg/day, 50-100 mg/day, 100-150 mg/day, 150-200 mg/day, 100-200 mg/day, 200-300 mg/day, 300-400 mg/day, 400-500 mg/day, 500-600 mg/day, 600-700 mg/day, 700-800 mg/day, 800-900 mg/day, 900-1000 mg/day, 1000-1100 mg/day, 1100-1200 mg/day, 1200-1300 mg/day, 1300-1400 mg/day, 1400-1500 mg/day, 1500-1600 mg/day, 1600-1700 mg/day, 1700-1800 mg/day, 1800-1900 mg/day, 1900-2000 mg/day, 2000-2100 mg/day, 2100-2200 mg/day, 2200-2300 mg/day, 2300-2400 mg/day, 2400-2500 mg/day, 2500-2600 mg/day, 2600-2700 mg/day, 2700-2800 mg/day, 2800-2900 mg/day or 2900-3000 mg/day.
22 . A method for identifying inhibitors of Hsp90α comprising:
(i) contacting the Hsp90α in a Hsp90α positive cell with a molecule of interest, and
(ii) determining whether the contact decreases or inhibits the binding of Hsp90α to its receptor, a decrease or inhibition in binding being indicative that the molecule of interest is an inhibitor of Hsp90α.
23 . A method for identifying inhibitors of Hsp90α comprising:
(i) contacting LRP-1 in LPR-1 positive cell with a molecule of interest, and
(ii) determining whether the contact decreases or inhibits the binding of Hsp90α to LRP-1, a decrease or inhibition in binding being indicative that the molecule of interest is an inhibitor of Hsp90α.
24 . The method of claim 22 or 23 , wherein the Hsp90α inhibitor is selected from the group consisting of a small molecule, a peptide, an antibody or a fragment thereof and a nucleic acid molecule.
25 . A screening method according to claim 22 or 23 , which comprises separately contacting each of a plurality of samples to be tested.
26 . The screening method of claim 25 , wherein the plurality of samples comprises more than about 10 4 samples.
27 . The screening method of claim 25 , wherein the plurality of samples comprises more than about 5×10 4 samples.
28 . The method of any one of claim 11 , 12 or 13 , wherein the subject is selected from the group consisting of human, non-human primate, monkey, ape, dog, cat, cow, horse, rabbit, mouse and rat.
29 . A kit for the treating, inhibiting or preventing metastasis of HIF-1α-overexpressing cancer in a subject in need thereof, comprising:
(i) a composition comprising a Hsp90α inhibitor; and
(ii) instructions for use of the composition for treating, inhibiting or preventing metastasis of HIF-1α-overexpressing cancer.