Compositions and methods for treating cancer and diseases and conditions responsive to cell growth inhibition

Patent metadata

Field	Value
Publication number	US-2016015709-A1
Application number	US-201414325288-A
Country	US
Kind code	A1
Filing date	Jul 7, 2014
Priority date	Apr 5, 2012
Publication date	Jan 21, 2016
Grant date	—

Abstract

In alternative embodiments, the invention provides compositions and methods for overcoming or diminishing or preventing Growth Factor Inhibitor resistance in a cell, or, a method for increasing the growth-inhibiting effectiveness of a Growth Factor inhibitor on a cell, or, a method for re-sensitizing a cell to a Growth Factor Inhibitor, comprising for example, administration of a combination of a TBK1 inhibitor and an RTK inhibitor. In alternative embodiments, the cell is a tumor cell, a cancer cell or a dysfunctional cell. In alternative embodiments, the invention provides compositions and methods for determining: whether an individual or a patient would benefit from or respond to administration of a Growth Factor Inhibitor, or, which individuals or patients would benefit from a combinatorial approach comprising administration of a combination of: at least one growth factor and at least one compound, composition or formulation used to practice a method of the invention, such as an NFKB inhibitor, such as a lenalidomide or a REVLIMID™, or IKK inhibitor; or an inhibitor of Galectin-3.

First claim

1 . A method for:
overcoming or diminishing or preventing a Growth Factor Inhibitor (GFI) resistance in a cell, or increasing the growth-inhibiting effectiveness of a Growth Factor inhibitor on a cell, or sensitizing, increasing sensitivity to or re-sensitizing a cell to a Growth Factor Inhibitor (GFI), or sensitizing, increasing sensitivity to or re-sensitizing a dysfunctional cell, a tumor or cancer to a drug, sensitizing, increasing sensitivity to or re-sensitizing a tumor that is resistant to a cancer or anti-tumor drug, or reversing a tumor cell, a cancer cell, a cancer stem cell or a dysfunctional cell initiation or self-renewal capacity, wherein optionally the cell is a tumor cell, a cancer cell, a cancer stem cell, or a dysfunctional cell,
the method comprising:
(a) (1) providing at least one compound, composition or formulation comprising:
(i) an inhibitor or depleter of integrin α v β 3 (anb3), or an inhibitor of integrin α v β 3 (anb3) protein activity, or an inhibitor of the formation or activity of an integrin anb3/RalB signaling complex, or an inhibitor of the formation or signaling activity of an integrin α v β 3 (anb3)/RalB/NFkB signaling axis;
(ii) an inhibitor or depleter of a RalB protein or an inhibitor of a RalB protein activation, or an inhibitor or depleter of the recruitment of KRAS/RalB to the plasma membrane or the association of KRAS to RalB;
(iii) an inhibitor or depleter of a Src or a Tank Binding Kinase (TBK1) protein or an inhibitor of Src or TBK1 protein activation,
wherein optionally the inhibitor of the Src or the TBK1 protein activity is: an amlexanox (or 2-amino-7-isopropyl-5-oxo-5H-chromeno[2,3-b]pyridine-3-carboxylic acid), or an APHTHASOL™; or a γ(1)34.5 protein of herpes simplex viruses (HSV); or, BX795; or an azabenzimidazole or an analog or derivative thereof; or a 6-amino-pyrazolopyrimidine or an analog or derivative thereof; or, a compound having one of the following formulas, or an analog or derivative thereof:

Molecule
IKKε
TBK1
IKKβ
IKKα

0.77
0.44
>10
>10

>10
0.50
>10
>10

>10
0.64
8.76
>10

>10
0.67
>10
>10

>10
0.87
>10
>10

and optionally the inhibitor of the Src or the TBK1 protein activity is an allosteric inhibitor of Src or TBK1 protein activity;
(iv) an inhibitor or depleter of a NFKB or a Interferon regulatory factor 3 (IRF3) protein or an inhibitor of RalB protein activation,
wherein optionally the inhibitor of the NFKB or the IRF3 protein activity is an allosteric inhibitor of an NFKB or an Interferon regulatory factor 3 (IRF3) protein activity;
(v) an inhibitor or depleter of NFKB or IKK, or an inhibitor of NFKB or IKK protein activation,
wherein optionally the NFKB inhibitor comprises a lenalidomide or a REVLIMID™ (Celgene Corp., Summit, N.J.) and optionally the IKK inhibitor comprises a PS1145 (Millennium Pharmaceuticals, Cambridge, Mass.);
(vi) a lenalidomide or a REVLIMID™ and PS1145;
(vii) a lenalidomide or a REVLIMID™; a PS1145; and, a Receptor Tyrosine Kinase (RTK) inhibitor, and optionally the RTK inhibitor comprises SU14813 (Pfizer, San Diego, Calif.);
(viii) an inhibitor of Galectin-3; or
(ix) any combination of (i) to (viii), or

(2) one or any combination of the compound, composition or formulation, or compounds, compositions or formulations, of (1), and at least one growth factor inhibitor; and
(b) administering a sufficient amount of the at least one compound, composition or formulation to the cell, or the combination of compounds, to:
overcome or diminish or prevent a Growth Factor Inhibitor (GFI) resistance in a cell, or
increase the growth-inhibiting effectiveness of a Growth Factor inhibitor on a cell, or
sensitize, increase sensitivity or re-sensitize a cell to a Growth Factor Inhibitor (GFI), or
sensitize, increase sensitivity or re-sensitize a dysfunctional cell, a tumor or cancer to a drug, wherein optionally the drug is a Receptor Tyrosine Kinase (RTK) inhibitor, or an erlotinib, a lapatinib or a lenalidomide,
sensitize, increase sensitivity or re-sensitize a tumor that is resistant to a cancer or anti-tumor drug, or
reverse a tumor cell, a cancer cell, a cancer stem cell or a dysfunctional cell initiation or self-renewal capacity.

2 . The method of claim 1 , wherein:
(a) the at least one compound, composition or formulation, or combination of compounds, is formulated as a pharmaceutical composition; (b) the method of (a), wherein the compound, composition or formulation or pharmaceutical composition is administered in vitro, ex vivo or in vivo, or is administered to an individual in need thereof; or (c) the method of (a) or (b), wherein the at least one compound, composition or formulation is a pharmaceutical composition is formulated for administration intravenously (IV), parenterally, nasally, topically, orally, or by liposome or targeted or vessel-targeted nanoparticle delivery.

Assignees

• Univ California

Inventors

• Cheresh David
• Seguin Laetitia
• Anand Sudarshan

Classifications

• B65D75/36

  one sheet or blank being recessed and the other formed of relatively stiff flat sheet material, e.g. blister packages {, the recess or recesses being preformed (B65D73/0057, B65D73/0092 take precedence)} · CPC title

• A61K31/715

  Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61K38/05

  Dipeptides · CPC title