METHODS AND COMPOSITIONS FOR INHIBITING FIBROBLAST ACTIVATION
Disclosed are methods of treating a subject in need thereof comprising applying an alternating electric field, to a target site of the subject in need thereof; and administering a cancer associated fibroblast (CAF) inhibitor to the subject in need thereof. Disclosed are methods of reducing or preventing CAF activation comprising applying alternating electric fields, to a population of cells comprising one or more fibroblasts; and contacting a CAF activation inhibitor to the population of cells. Disclosed are methods of reducing CAF signaling comprising applying alternating electric fields, to a population of cells comprising one or more fibroblasts; and contacting a cancer associated fibroblast (CAF) signaling inhibitor to the population of cells.
1 . A method of treating a subject in need thereof comprising:
a) applying an alternating electric field, to a target site of the subject in need thereof; and
b) administering a cancer associated fibroblast (CAF) inhibitor to the subject in need thereof.
2 . The method of claim 1 , wherein the CAF inhibitor is a CAF activation inhibitor or a CAF signaling inhibitor.
3 . The method of claim 2 , wherein the CAF activation inhibitor is a fibroblast activation protein (FAP) inhibitor, a selective PDGFRb inhibitor, a Hsp90 inhibitor, a LRRC15 inhibitor, a selective Hedgehog inhibitor, a selective Hyaluronic acid secretion inhibitor, or an IL-1R inhibitor.
4 . The method of claim 3 , wherein the FAP inhibitor is Talabostat, FAP-2286, or TAM558.
5 . The method of claim 3 , wherein the selective PDFGRb inhibitor is sPDGFRbIg, Crenolanib, Orantinib,CP-673451, SU16f, Tyrphostin AG 1296, Tyrphostin AG1433 or Seralutinib.
6 . The method of claim 3 , wherein the Hsp90 inhibitor is XL888, Geldanamycin, Gedunin, Tanespimycin, Luminespib, BIIV 021, CCT 018159, or 17-AAG.
7 . The method of claim 3 , wherein the LRRC15 inhibitor is ABBV-085 antibody.
8 . The method of claim 2 , wherein the CAF signaling inhibitor is a Lysyl oxidase (LOX) inhibitor, a Lysyl oxidase like (LOXL) inhibitor, CXCR4 inhibitor or CXCR12 inhibitor.
9 . A method of reducing or preventing cancer associated fibroblast (CAF) activation comprising:
a) applying an alternating electric field, to a population of cells comprising one or more fibroblasts; and
b) contacting a CAF activation inhibitor to the population of cells.
10 . A method of reducing cancer associated fibroblast (CAF) signaling comprising:
a) applying alternating electric fields, to a population of cells comprising one or more fibroblasts; and
c) contacting a CAF signaling inhibitor to the population of cells.
11 . The method of claim 1 , wherein the target site comprises one or more cancer cells.
12 . The method of claim 1 , wherein the alternating electric field is applied before, after, or simultaneously with administering the CAF inhibitor.
13 . The method of claim 1 , wherein the CAF inhibitor is administered intratumorally, intracranially, intraventricularly, intrathecally, epidurally, intradurally, intravascularly, intravenously, intraarterially, intramuscularly, subcutaneously, intraperitoneally, orally, intranasally, topically, via intratumor injection, or via inhalation.
14 . The method of claim 2 , wherein the CAF activation inhibitor inhibits or decreases fibroblast activation protein (FAP), alpha smooth muscle actin (aSMA), or platelet derived growth factor receptor beta (PDGFRb) expression, and/or
prevents PDGFRb from interacting with or binding to PDGF, and/or
prevents Hsp90 from ATPase activity that upregulates fibroblast activation.
15 . The method of claim 1 , wherein the CAF inhibitor prevents Lox or Loxl from covalently cross-linking collagen and elastin in extracellular matrix (ECM).
16 . The method of claim 1 , wherein the alternating electric field has a frequency between 50 kHz and 1 MHz.
17 . The method of claim 1 , wherein the alternating electric field has a frequency about 150 or 250 kHz.
18 . The method of claim 1 , wherein the alternating electric field has a field strength of between 0.5 and 10 V/cm RMS.
19 . The method of claim 1 , wherein the alternating electric field has a field strength of about 0.9 V/cm RMS.