ANTI-ESTROGEN AND IMMUNE MODULATOR COMBINATIONS FOR TREATING BREAST CANCER

• US 20100303825A9
• Filed: 11/13/2002
• Published: 12/02/2010
• Est. Priority Date: 05/10/2000
• Status: Active Grant

• Current Assignee: Signe BioPharma Inc.
• Original Assignee: Signe BioPharma Inc.
• Inventors: Sirbasku, David
• Granted Patent: US 8,119,138 B2
• Time in Patent Office: Days
• US Class Current: 424/155.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/542 oral/gastrointestinal
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• CPC Class Codes: A61K 31/429 condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/5685 having an oxo group in position 17, e.g. androsterone
• CPC Class Codes: A61K 38/1774 Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)
• CPC Class Codes: A61K 39/0008 Antigens related to auto-immune diseases; Preparations to induce self-tolerance
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: C07K 14/70567 Nuclear receptors, e.g. retinoic acid receptor [RAR], RXR, nuclear orphan receptors
• CPC Class Codes: C07K 16/00 Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies antibodies with enzymatic activity, e.g. abzymes C12N9/0002
• CPC Class Codes: C07K 16/065 Purification, fragmentation
• CPC Class Codes: C07K 16/12 against material from bacteria
• CPC Class Codes: C07K 16/26 against hormones ; against hormone releasing or inhibiting factors
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C12N 2500/14 : Calcium; Ca chelators; Calcitonin
• CPC Class Codes: C12N 2500/24 : Iron; Fe chelators; Transferrin
• CPC Class Codes: C12N 2500/25 : Insulin-transferrin; Insulin-transferrin-selenium
• CPC Class Codes: C12N 2500/90 : Serum-free medium, which may still contain naturally-sourced components
• CPC Class Codes: C12N 2501/39 : Steroid hormones
• CPC Class Codes: C12N 2501/392 : Sexual steroids
• CPC Class Codes: C12N 2501/395 : Thyroid hormones
• CPC Class Codes: C12N 2503/02 : Drug screening
• CPC Class Codes: C12N 2510/00 : Genetically modified cells
• CPC Class Codes: C12N 2510/02 : Cells for production
• CPC Class Codes: C12N 2510/04 : Immortalised cells
• CPC Class Codes: C12N 5/0629 : Keratinocytes; Whole skin
• CPC Class Codes: C12N 5/0631 : Mammary cells
• CPC Class Codes: C12N 5/0693 : Tumour cells; Cancer cells
• CPC Class Codes: G01N 2333/70503 : Immunoglobulin superfamily, e.g. VCAMs, PECAM, LFA-3
• CPC Class Codes: G01N 2333/71 : for growth factors; for growth regulators
• CPC Class Codes: G01N 33/5011 : for testing antineoplastic activity
• CPC Class Codes: G01N 33/574 : for cancer
• CPC Class Codes: G01N 33/57415 : of breast
• CPC Class Codes: G01N 33/6854 : Immunoglobulins
• CPC Class Codes: G01N 33/743 : Steroid hormones
• CPC Class Codes: G01N 33/96 : involving blood or serum control standard

Abstract

Compositions for treating cancers of mucosal tissues including breast, prostate, ovary, colon are disclosed which include various combinations of new or conventional anti-estrogen compounds, aromatase inhibitors, immune modulators, immune inhibitors, immune inhibitor mimicking compounds and steroid or thyroid hormones. Methods of predicting susceptibility of a cancer of mucosal origin to treatment with a composition containing an immune inhibitor or an immune inhibitor mimicking compound are also disclosed. Preferred methods include identifying in a specimen of cancer cells the presence of a Poly-Ig (Fc) receptor or Poly-Ig-like (Fc) receptor capable of binding to an immune inhibitor or an immune inhibitor mimicking compound and of mediating immune inhibition of cancer cell growth.

Claims

1. A method of predicting susceptibility of a cancer of mucosal origin to treatment with an immunoglobulin inhibitor mimicking compound, the method comprising:

identifying in a specimen of said cancer cells expression of a Poly-Ig (Fc) receptor or a Poly-Ig-like (Fc) receptor that is capable of binding to said immunoglobulin inhibitor mimicking compound and of mediating immunoglobulin inhibition of cancer cell growth in cancer cells of mucosal origin.

2. The method of claim 1 wherein the Fc region of said identified Poly-Ig (Fc) receptor or Poly-Ig-like (Fc) receptor is capable of binding to said immunoglobulin inhibitor mimicking compound.

3. The method of claim 1 comprising determining whether said cancer cell is at least partially hormone responsive with respect to stimulation of cell growth by said hormone.

4. The method of claim 1 wherein said immunoglobulin inhibitor mimicking compound is tamoxifen.

5. The method of claim 1 wherein said immunoglobulin inhibitor mimicking compound is MER-25 or a chemically modified form thereof.

6. The method of claim 1 wherein said cancer of mucosal origin is from breast, prostate, colon, kidney, bladder, lung, pancreas, nasopharynx, ovarian, endometrial, vaginal or cervical.

7. The method of claim 1 further comprising detecting expression of secretory component in said cancer cells.

8. The method of claim 1 further comprising detecting the presence of ERγ

in said cancer cells.

9. A method of treating breast cancer in an individual in need of such treatment, the method comprising:

in a specimen of breast cancer cells from said individual, determining susceptibility of at least a portion of said cells to cell growth inhibition by an immunoglobulin inhibitor mimicking compound by a method comprising identifying in at least a portion of said cells the expression of a Poly-Ig receptor or Poly-Ig-like receptor, or the Fc receptor region thereof, that is capable of binding to said immunoglobulin inhibitor mimicking compound and mediating immunoglobulin inhibition of breast cancer cell growth; and

administering said immunoglobulin inhibitor mimicking compound to said individual.

10. The method of claim 9 further comprising administering an aromatase inhibitor to said individual.

11. The method of claim 9 further comprising administering a pure anti-estrogen compound to said individual.

12. The method of claim 9 further comprising administering to said individual an enhancer of immunoglobulin production.

13. The method of claim 12 wherein said enhancer comprises levimisole.

14. The method of claim 12 wherein said enhancer comprises imiquimod.

15. The method of claim 12 wherein said enhancer comprises picibanil.

16. The method of claim 12 wherein said enhancer comprises DHEA.

17. The method of claim 9 further comprising transferring a functional Poly-Ig receptor gene or Poly-Ig-like receptor gene to breast cancer cells in said individual.

18. The method of claim 9 further comprising transferring a DNA sequence encoding the Fc portion of a Poly-Ig receptor or Poly-Ig-like receptor to breast cancer calls in said individual.

19. The method of claim 9 comprising administering MER-25 or a chemically modified form thereof, and at least one hormone to said individual.

20. The method of claim 18 wherein said at least one hormone is chosen from the group consisting of pituitary hormones, adrenal hormones, thyroid hormones, cytokines and neurogenic hormones.

21. The method of claim 20 wherein said at least one hormone comprises progesterone.

25. The composition of claim 21 wherein said anti-estrogenic compound comprises a compound chosen from the group consisting of tamoxifen, toremifene, ICI 16384, ICI 182780, EM-800, RU 58688 and EM-139.

26. The composition of claim 21 wherein said hormone is chosen from the group consisting of pituitary hormones, adrenal hormones, thyroid hormones, cytokines and neurogenic hormones.

27. The composition of claim 26 wherein said hormone comprises progesterone.

22. A pharmaceutical composition for treating a cancer of mucosal origin comprising:

an immune inhibitor of steroid hormone reversible cancer cell growth or an immune inhibitor mimicking compound; and

at least one at least one component chosen from the group consisting of;

an anti-estrogen compound,

an aromatase inhibitor,

an agent that enhances immunoglobulin production, and

a hormone,

together with a pharmaceutically acceptable carrier.

23. The composition of claim 22 wherein said agent that enhances immunoglobulin production comprises a compound chosen from the group consisting of Levimisole, Imiquimod, Picibanil and DHEA.

24. The composition of claim 22 wherein said anti-estrogenic compound or said immunoglobulin inhibitor mimicking compound comprises MER-25 or a chemically modified form thereof.

28. A method of screening a compound for anti-estrogenic activity comprising:

culturing a predetermined population of estrogen responsive cancer cells in a nutrient medium comprising a quantity of immunoglobulin inhibitor or immunoglobulin inhibitor mimicking compound sufficient to inhibit cell growth in the absence of an inhibition-reversing amount of estrogen;

adding a defined amount of the substance of interest to the cell culture medium;

adding a defined amount of estrogen to said cell culture medium, said amount being sufficient to stimulate cell growth in the presence of said inhibitor or inhibitor mimicking agent under the same cell culture conditions but in the absence of said substance of interest, to provide a test culture;

incubating said test culture for a predetermined period of time under growth promoting conditions;

testing said substance of interest for cytotoxic effects on said cells;

determining the cell population of the test culture after said predetermined period of time, wherein a lack of increase in the cell population, not attributable to cytotoxic effects of said substance of interest, indicates an anti-estrogenic effect by said substance of interest.