TREATING CANCER STEM CELLS USING TARGETED CARGO PROTEINS
The disclosure provides targeted cargo proteins that are useful for targeting cancer stem cells, and methods of their use in treating cancer.
1 . A method of treating a cancer stem cell in a subject, comprising:
administering to the subject a targeted cargo protein, wherein the targeted cargo protein comprises:
(a) one or more cargo moieties; and
(b) one or more targeting moieties that bind to a target displayed by a cancer stem cell, wherein the targeting moiety is derived from a natural ligand to the target, thereby treating the cancer stem cell in the subject.
2 . The method of claim 1 , wherein the cargo moiety comprises a toxin.
3 . The method of claim 2 , wherein the toxin comprises a bacterial toxin, animal toxin, or plant toxin.
4 . The method of claim 2 , wherein the toxin comprises a pore-forming toxin.
5 . The method of claim 4 , wherein the pore-forming toxin comprises aerolysin or proaerolysin.
6 . The method of claim 3 , wherein the plant toxin comprises bouganin or ricin.
7 . The method of claim 3 , wherein the bacterial toxin comprises Pseudomonas exotoxin, cholera toxin, or diphtheria toxin.
8 . The method of claim 1 , wherein the cargo moiety comprises a pro-apoptosis member of the BCL-2 family selected from BAX, BAD, BAT, BAK, BIK, BOK, BID BIM, BMF and BOK.
9 . A method of treating a cancer stem cell in a subject, comprising:
administering to the subject a targeted cargo protein, wherein the targeted cargo protein comprises:
(a) one or more cargo moieties selected from aerolysin, proaerolysin, bouganin, ricin, Pseudomonas exotoxin, cholera toxin, diphtheria toxin, and BAD; and
(b) one or more targeting moieties that bind to a target displayed by a cancer stem cell, thereby treating the cancer stem cell in the subject.
10 . The method according to claim 9 , wherein the one or more targeting moieties is selected from an antibody, ligand or ligand variant.
11 . The method of claim 1 , wherein the target displayed by the cancer stem cell comprises a receptor selected from the group consisting of: IL-4, IL-3, IL-2, EGF, and GMCSF or an antigen comprising EpCAM, mesothelin, or CD22.
12 . The method of claim 9 , wherein the targeting moiety comprises a humanized antibody.
13 . The method of claim 1 , wherein the targeted cargo protein comprises a human cargo moiety selected from the group consisting of RNase A and perforin.
14 . The method of claim 1 , wherein the targeted cargo protein comprises a fusion protein.
15 . The method of claim 1 , wherein the targeted cargo protein is present in a pharmaceutically acceptable carrier.
16 . The method of claim 1 , wherein the subject has a recurrent cancer or a newly diagnosed cancer.
17 . The method of claim 1 , wherein the subject is refractory.
18 . The method of claim 1 , further comprising:
determining whether the subject is refractory to radiation or chemotherapy; wherein if the subject is refractory it indicates that they will benefit from administration of the targeted cargo protein.
19 . The method of claim 1 , further comprising administering chemotherapy or radiation therapy to the subject after administering the targeted cargo protein, or surgically removing at least part of a tumor after administering the targeted cargo protein.
20 . The method of claim 1 , further comprising administering chemotherapy or radiation therapy to the subject before administering the targeted cargo protein, or surgically removing at least part of a tumor before administering the targeted cargo protein.
21 . The method of claim 1 , further comprising administering chemotherapy or radiation therapy to the subject during treatment with the targeted cargo protein, or administering the targeted cargo protein during surgical removal of least part of a tumor in the subject.
22 . The method of claim 1 , further comprising:
administering to the subject an agonist that sensitizes the cancer stem cells prior to administering the targeted cargo protein.
23 . The method of claim 1 , wherein the targeted cargo protein is administered intratumorally.
24 . The method of claim 1 , wherein the targeted cargo protein comprises Pseudomonas exotoxin linked to circularly permuted IL-4, IL-2 linked to aerolysin, IL-2 linked to proaerolysin, IL4 linked to BAD, GMCSF linked to BAD, EGF linked to proaerolysin, anti-EpCAM antibody linked to Pseudomonas exotoxin, anti-EpCAM antibody linked to bouganin, anti-mesothelin antibody linked to PE, anti-CD22 antibody linked to PE, anti-CD22 antibody linked to RNase A, and anti-PSMA antibody linked to thapsigargin.
25 . The method of claim 1 , further comprising removing hematopoietic stem cells from the subject prior to administering the targeted cargo protein.
26 . The method of claim 25 , further comprising re-introducing to the subject the removed hematopoietic stem cells.
27 . The method of claim 1 , wherein the method further treats a bulk tumor in the subject.
28 . The method of claim 1 , wherein the targeted cargo protein further comprises a polymer, for example to increase stability, increase circulating half life or reduce immunogenicity of the targeted cargo protein.