Use of psoralen derivatives and combination therapy for treatment of cell proliferation disorders

Patent metadata

Field	Value
Publication number	US-9439897-B2
Application number	US-201514603539-A
Country	US
Kind code	B2
Filing date	Jan 23, 2015
Priority date	Nov 6, 2007
Publication date	Sep 13, 2016
Grant date	Sep 13, 2016

Abstract

Methods for the treatment of a cell proliferation disease or disorder in a subject, involving applying a psoralen derivative lacking a DNA cross-linking motif to cancer cells, applying a psoralen or a derivative thereof and lapatinib, or applying a psoralen or derivative thereof and neratinib, to a subject and further applying initiation radiation energy form an energy source.

First claim

The invention claimed is:

1. A method of inhibition of ErbB2 signaling in cancer cells comprising applying a psoralen derivative lacking a DNA cross-linking motif to cancer cells and applying initiation radiation energy form an energy source, thereby blocking the ErbB2 signaling,
wherein the psoralen derivative lacking a DNA cross-linking motif is represented by the formula (1):

wherein R 1 is hydrogen, lower alkyl, or lower alkoxy;
R 2 and R 3 are each, independently, hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, or R 2 and R 3 may join to form a substituted or unsubstituted, condensed 5 to 7 membered aliphatic or aromatic ring, optionally containing at least one heteroatom selected from N, S, and O;
R 4 and R 5 are each, independently, hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, or R 4 and R 5 may join to form a substituted or unsubstituted, condensed 5 to 7 membered aliphatic or aromatic ring, optionally containing at least one heteroatom selected from N, S, and O;
with the proviso that at least one of R 2 and R 3 or R 4 and R 5 are joined to form a substituted or unsubstituted, condensed 5 to 7 membered aliphatic or aromatic ring, optionally containing at least one heteroatom selected from N, S, and O.

2. The method of claim 1 , wherein the cancer cells are ErbB2+ breast cancer cells.

3. The method of claim 1 , which comprising, prior to said applying the initiation energy, administering to the subject at least one energy modulation agent that converts the initiation energy to an energy that activates the psoralen derivative.

4. The method of claim 1 , wherein the at least one energy modulation agent is one or more selected from the group consisting of a biocompatible fluorescing metal nanoparticle, fluorescing dye molecule, gold nanoparticle, a water soluble quantum dot encapsulated by polyamidoamine dendrimers, a luciferase, a biocompatible phosphorescent molecule, a combined electromagnetic energy harvester molecule, and a lanthanide chelate capable of intense luminescence.

5. A method of treating a cell proliferation disorder or disease comprising administering a psoralen derivative lacking a DNA cross-linking motif to a subject in need thereof and applying initiation radiation energy form an energy source,
wherein the treatment is caused by inducing apoptosis in diseased cells, thereby blocking ErbB2 signaling in cancer cells,
wherein the psoralen derivative lacking a DNA cross-linking motif is represented by the formula (1):

wherein R 1 is hydrogen, lower alkyl, or lower alkoxy,
R 2 and R 3 are each, independently, hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, or R 2 and R 3 may join to form a substituted or unsubstituted, condensed 5 to 7 membered aliphatic or aromatic ring, optionally containing at least one heteroatom selected from N, S, and O;
R 4 and R 5 are each, independently, hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, or R 4 and R 5 may join to form a substituted or unsubstituted, condensed 5 to 7 membered aliphatic or aromatic ring, optionally containing at least one heteroatom selected from N, S, and O;
with the proviso that at least one of R 2 and R 3 or R 4 and R 5 are joined to form a substituted or unsubstituted, condensed 5 to 7 membered aliphatic or aromatic ring, optionally containing at least one heteroatom selected from N, S, and O.

6. The method of claim 5 , wherein the diseased cells are ErbB2+ breast cancer cells.

7. The method of claim 1 or 5 , wherein the initiation radiation energy is UVA or visible energy.

8. The method of claim 1 or 5 , wherein the initiation radiation energy is applied via a thin fiber optic.

9. The method of claim 1 or 5 , wherein the psoralen derivative is SMSF032310.

10. The method of claim 5 , wherein the cell proliferation disorder or disease is cancer.

11. The method of claim 10 , wherein the cell proliferation disorder or disease is breast cancer.

12. The method of claim 5 , which comprising, prior to said applying the initiation energy, administering to the subject at least one energy modulation agent that converts the initiation energy to an energy that activates the psoralen derivative.

13. The method of claim 5 , wherein the at least one energy modulation agent is one or more selected from the group consisting of a biocompatible fluorescing metal nanoparticle, fluorescing dye molecule, gold nanoparticle, a water soluble quantum dot encapsulated by polyamidoamine dendrimers, a luciferase, a biocompatible phosphorescent molecule, a combined electromagnetic energy harvester molecule, and a lanthanide chelate capable of intense luminescence.

14. A method of treating a cell proliferation disorder or disease comprising administering a psoralen or substituted psoralen and lapatinib to a subject in need thereof and applying initiation radiation energy form an energy source,
wherein the treatment reduces diseased cell growth and/or viability compared to that of diseased cells treated with lapatinib alone, or a combination of lapatinib and the psoralen or psoralen derivative, or a combination of lapatinib and the initiation radiation energy.

15. The method of claim 14 , wherein the treatment reduces tumor cell growth and/or viability in lapatinib resistant tumor cells.

16. The method of claim 15 , wherein the lapatinib resistant tumor cells are HER2+ breast cancer cells.

17. The method of claim 14 , wherein the initiation radiation energy is UVA or visible energy.

18. The method of claim 14 , wherein the psoralen or substituted psoralen is 8-Methoxypsoralen (8-MOP), 4′-aminomethyl-4,5′,8-trimethylpsoralen (AMT), or SMSF032310.

19. The method of claim 14 , wherein the cell proliferation disorder or disease is breast cancer.

20. The method of claim 14 , which comprising, prior to said applying the initiation energy, administering to the subject at least one energy modulation agent that converts the initiation energy to an energy that activates the psoralen derivative.

21. The method of claim 15 , wherein the at least one energy modulation agent is one or more selected from a biocompatible fluorescing metal nanoparticle, fluorescing dye molecule, gold nanoparticle, a water soluble quantum dot encapsulated by polyamidoamine dendrimers, a luciferase, a biocompatible phosphorescent molecule, a combined electromagnetic energy harvester molecule, and a lanthanide chelate capable of intense luminescence.

22. A method of treating a cell proliferation disorder or disease comprising administering a psoralen or substituted psoralen and neratinib to a subject in need thereof and applying initiation radiation energy form an energy source,
wherein the treatment reduces diseased cell growth and/or viability compared to that of diseased cells treated with neratinib alone, or a combination of neratinib and the psoralen or psoralen derivative, or a combination of neratinib and the radiation energy.

23. The method of claim 22 , wherein the diseased cells are tumor cells.

24. The method of claim 23 , wherein the tumor cells are ErbB2+ breast cancer cells.

25. The method of claim 22 , wherein the radiation energy is UVA or visible energy.

26. The meth

Assignees

• Immunolight Llc
• Univ Duke

Inventors

• Xia Wenle
• Gooden David
• Soderblom Erik J
• Toone Eric J
• Spector Neil L
• Beyer Jr Wayne F
• Walder Harold

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K41/0066

  Psoralene-activated UV-A photochemotherapy (PUVA-therapy), e.g. for treatment of psoriasis or eczema, extracorporeal photopheresis with psoralens or fucocoumarins · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/436 Primary

  the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin · CPC title

• A61K31/37

  Coumarins, e.g. psoralen · CPC title