METHODS FOR IMPROVING MEDICAL THERAPIES
Methods are provided herein for enhancing the effectiveness of medical therapies by administering agents that suppress a biological damage response that is inducible by the medical therapy administered to a subject. In certain embodiments, a method is provided for administering an anti-senescent cell agent that suppresses a biological response comprising cellular senescence that is induced by the medical therapy.
1 . A method for enhancing the effectiveness of a medical therapy in a subject comprising administering to the subject an agent that suppresses a biological damage response inducible by the medical therapy, wherein the agent is administered prior to, subsequent to, or concurrent with administration of the medical therapy.
2 . The method of claim 1 wherein the agent is administered to the subject at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 10 days, at least 30, at least 60, or at least 90 days subsequent to administration of the medical therapy.
3 . The method of either claim 1 or claim 2 wherein the agent that suppresses the biological damage response selectively destroys or facilitates selective destruction of one or more senescent cells.
4 . The method of claim 1 wherein the agent is administered to the subject prior to administration of the medical therapy.
5 . The method of claim 4 wherein the agent is administered to the subject at least 1 day, at least 2-6 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4-5 weeks, at least 6-8 weeks, or at least 10-12 weeks prior to administration of the medical therapy.
6 . The method of claim 1 wherein the agent is administered concurrently with at least a portion of the administered medical therapy.
7 . The method of any one of claims 1 - 6 wherein the agent that suppresses the biological damage response inhibits expression or secretion of one or more senescence cell-associated molecules produced by a senescent cell.
8 . The method of any one of claims 1 - 7 wherein the agent is a small molecule, polypeptide, peptide, antibody, antigen-binding fragment, peptibody, recombinant viral vector, or a nucleic acid.
9 . The method of any one of claims 1 - 8 wherein the medical therapy increases the proportion of senescent cells in a subject.
10 . The method of any one of claims 1 - 9 wherein the medical therapy comprises radiation, a chemotherapy, an anti-viral therapy, or a hormone.
11 . The method of any one of claims 1 - 10 wherein the subject has a cancer, is in cancer remission, is at risk of developing a recurrence of a cancer, or is at risk of developing a cancer, and wherein the medical therapy comprises an anti-cancer therapy.
12 . The method of claim 11 , wherein the cancer comprises a solid tumor or a liquid tumor.
13 . The method of either claim 11 or claim 12 , wherein the cancer is metastatic cancer.
14 . The method of claim 10 wherein the anti-viral therapy is an HIV/AIDS management therapy.
15 . The method of claim 14 wherein the HIV/AIDS management therapy comprises a highly active antiretroviral therapy (HAART).
16 . The method of any one of claims 1 - 13 wherein the subject has a cancer and has received or will receive a stem cell transplant, and wherein the medical therapy is high dose chemotherapy or high dose radiotherapy or a combination thereof.
17 . The method of claim 16 wherein the stem cell transplant is selected from (a) an autologous stem cell transplant, and (b) an allogenic stem cell transplant.
18 . The method of any one of claims 1 - 10 wherein the subject has a cardiovascular disease or is at risk of developing a cardiovascular disease, and wherein the medical therapy is angiotensin.
19 . The method of any one of claims 1 - 10 wherein the subject has diabetes, and wherein the medical therapy is insulin.
20 . A method for enhancing the effectiveness of a medical therapy in a subject comprising:
(a) administering to the subject the medical therapy, which medical therapy induces senescence in one or more cells of the subject; and then
(b) administering to the subject an anti-senescent cell agent, which agent selectively destroys or facilitates the selective destruction of the one or more senescent cells.
21 . The method of claim 20 , wherein the agent is administered to the subject at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, or at least 10 days, at least 30 days, at least 60 days, or at least 90 days subsequent to administration of the medical therapy.
22 . The method of either claim 20 or 21 , wherein the agent is a small molecule, polypeptide, peptide, antibody, antigen-binding fragment, peptibody, recombinant viral vector, or a nucleic acid.
23 . The method of any one of claims 20 - 22 wherein the medical therapy increases the proportion of senescent cells in a subject.
24 . The method of any one of claims 20 - 23 wherein the medical therapy comprises radiation, a chemotherapy, an anti-viral therapy, or a hormone.
25 . The method of any one of claims 20 - 24 wherein the subject has a cancer, is in cancer remission, is at risk of developing a recurrence of a cancer, or is at risk of developing a cancer, and wherein the medical therapy comprises an anti-cancer therapy.
26 . The method of claim 25 , wherein the cancer comprises a solid tumor or a liquid tumor.
27 . The method of either claim 25 or claim 26 , wherein the cancer is metastatic cancer.
28 . The method of claim 24 wherein the anti-viral therapy is an HIV/AIDS management therapy.
29 . The method of claim 28 wherein the HIV/AIDS management therapy comprises a highly active antiretroviral therapy (HAART).
30 . The method of any one of claims 20 - 27 , wherein the subject has a cancer and has received or will receive a stem cell transplant, and wherein the medical therapy comprises high dose chemotherapy or high dose radiotherapy or a combination thereof.
31 . The method of claim 30 wherein the stem cell transplant is selected from (a) an autologous stem cell transplant, and (b) an allogenic stem cell transplant.
32 . The method of any one of claims 20 - 24 wherein the subject has a cardiovascular disease or is at risk of developing a cardiovascular disease, and wherein the medical therapy is angiotensin.
33 . The method of any one of claims 20 - 24 wherein the subject has diabetes, and wherein the medical therapy is insulin.
34 . Use of an agent that suppresses a biological damage response inducible by a medical therapy for enhancing the effectiveness of the medical therapy, wherein the agent is suitable for administration prior to, subsequent to, or concurrent with administration of the medical therapy.
35 . The use of claim 34 wherein the agent is suitable for administration at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 10 days, at least 30, at least 60, or at least 90 days subsequent to administration of the medical therapy.
36 . The use of either claim 34 or claim 35 wherein the agent that suppresses the biological damage response selectively destroys or facilitates selective destruction of one or more senescent cells.
37 . The use of claim 34 wherein the agent is administered prior to administration of the medical therapy.
38 . The use of claim 37 wherein the agent is administered at least 1 day, at least 2-6 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4-5 weeks, at least 6-8 weeks, or at least 10-12 weeks prior to administration of the medical therapy.
39 . The use of claim 34 wherein the agent is administered concurrently with at least a portion of the administered medical therapy.
40 . The use of claim 34 wherein the agent that suppresses the biological damage response inhibits expression or secretion of one or more senescence cell-associated molecules produced by a senescent cell.
41 . The use of any one of claim 34 wherein the agent is a small molecule, polypeptide, peptide, antibody, antigen-binding fragment, peptibody, recombinant viral vector, or a nucleic acid.
42 . The use of claim 34 wherein the medical therapy increases the proportion of senescent cells in a subject.
43 . The use of claim 34 wherein the medical therapy comprises radiation, a chemotherapy, an anti-viral therapy, or a hormone.
44 . The use of claim 34 wherein the medical therapy is an anti-cancer therapy.
45 . The use of claim 44 , wherein the cancer comprises a solid tumor or a liquid tumor.
46 . The use of either claim 44 or claim 45 , wherein the cancer is metastatic cancer.
47 . The use of claim 43 wherein the anti-viral therapy is an HIV/AIDS management therapy.
48 . The use of claim 47 wherein the HIV/AIDS management therapy comprises a highly active antiretroviral therapy (HAART).
49 . The use of claim 34 wherein the medical therapy is high dose chemotherapy or high dose radiotherapy or a combination thereof, which is administered prior to or subsequent to administration of a stem cell transplant.
50 . The use of claim 49 wherein the stem cell transplant is selected from (a) an autologous stem cell transplant, and (b) an allogenic stem cell transplant.
51 . The use of claim 34 for treating or preventing a cardiovascular disease wherein the medical therapy is angiotensin.
52 . The use of claim 1 for treating or preventing diabetes, wherein the medical therapy is insulin.
53 . A use of an anti-senescent cell agent for enhancing the effectiveness of a medical therapy wherein the medical therapy induces senescence in one or more cells, and wherein the agent selectively destroys or facilitates the selective destruction of the one or more senescent cells.
54 . The use of claim 53 , wherein the agent is suitable for administration at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, or at least 10 days, at least 30 days, at least 60 days, or at least 90 days subsequent to administration of the medical therapy.
55 . The use of claim 53 , wherein the agent is a small molecule, polypeptide, peptide, antibody, antigen-binding fragment, peptibody, recombinant viral vector, or a nucleic acid.
56 . The use of claim 53 wherein the medical therapy increases the proportion of senescent cells.
57 . The use of claim 53 wherein the medical therapy comprises radiation, a chemotherapy, an anti-viral therapy, or a hormone.
58 . The use of claim 53 wherein the medical therapy comprises an anti-cancer therapy for treating or preventing a cancer.
59 . The use of claim 58 , wherein the cancer comprises a solid tumor or a liquid tumor.
60 . The use of claim 58 , wherein the cancer is metastatic cancer.
61 . The use of claim 57 wherein the anti-viral therapy is an HIV/AIDS management therapy.
62 . The use of claim 61 wherein the HIV/AIDS management therapy comprises a highly active antiretroviral therapy (HAART).
63 . The use of claim 53 for treatment or prevention of a cardiovascular disease, wherein the medical therapy is angiotensin.
64 . The use of claim 53 for treating or preventing diabetes, wherein the medical therapy is insulin.
65 . A method of identifying a compound that selectively inhibits the senescence associated secretory phenotype (SASP), said method comprising:
(a) contacting senescent cells with a candidate agent and contacting quiescent cells with the candidate agent;
(b) determining the level of one or more senescence associate molecules produced by the senescent cells and by the quiescent cells;
(c) determining viability of the senescent cells and quiescent cells; and
(d) comparing the level of the one or more senescence associate molecules produced by the senescent cells with the level of the one or more senescence associate molecules produced by the quiescent cells,
wherein reduction in the level of one or more senescence associated molecules produced by the senescent cells compared with reduction in the level of the one or more senescence associated molecules produced by the quiescent cells, and wherein viability of the senescence cells and the quiescent cells is not reduced in the presence of the candidate agent identifies a compound that selectively inhibits the senescence associated secretory phenotype.
66 . The method according of claim 65 , wherein said one or more components characteristic of the SASP comprises one or more components selected from the group consisting of IL-6, IL-8, GM-CSF, MCP3, IGF1, PDGF-BB, EGF, BMP4, and MCP-2.
67 . The method of claim 65 or 66 , wherein said method is performed in a high throughput screening (HTS) format.