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      Manipulating DNA damage-response signaling for the treatment of immune-mediated diseases

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          Significance

          Therapeutic immune suppression is essential for treating a variety of immune conditions, including autoimmune diseases, immunoregulatory disorders, and in transplantation. Reliance on broadly acting drugs carries substantial risks, and even pathway-specific agents are problematic, because most immune pathways have essential functions. The ideal form of immune suppression would be antigen-specific, suppressing an undesired immune response but sparing all others. We describe a unique strategy for therapeutic immune suppression, relying on targeted manipulation of DNA damage-response signaling, that exploits unique aspects of lymphocyte biology. This approach allows for highly selective suppression of recently activated T cells, displays clear therapeutic benefits, and has less off-target toxicity than conventional DNA-damaging drugs.

          Abstract

          Antigen-activated lymphocytes undergo extraordinarily rapid cell division in the course of immune responses. We hypothesized that this unique aspect of lymphocyte biology leads to unusual genomic stress in recently antigen-activated lymphocytes and that targeted manipulation of DNA damage-response (DDR) signaling pathways would allow for selective therapeutic targeting of pathological T cells in disease contexts. Consistent with these hypotheses, we found that activated mouse and human T cells display a pronounced DDR in vitro and in vivo. Upon screening a variety of small-molecule compounds, we found that potentiation of p53 (via inhibition of MDM2) or impairment of cell cycle checkpoints (via inhibition of CHK1/2 or WEE1) led to the selective elimination of activated, pathological T cells in vivo. The combination of these strategies [which we termed “p53 potentiation with checkpoint abrogation” (PPCA)] displayed therapeutic benefits in preclinical disease models of hemophagocytic lymphohistiocytosis and multiple sclerosis, which are driven by foreign antigens or self-antigens, respectively. PPCA therapy targeted pathological T cells but did not compromise naive, regulatory, or quiescent memory T-cell pools, and had a modest nonimmune toxicity profile. Thus, PPCA is a therapeutic modality for selective, antigen-specific immune modulation with significant translational potential for diverse immune-mediated diseases.

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          Most cited references38

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          Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide.

          Regulatory T cells (T(REGs)) control the key aspects of tolerance and play a role in the lack of antitumor immune responses. Cyclophosphamide (CY) is a chemotherapeutic agent with a dose-dependent, bimodal effect on the immune system. Although a previous study demonstrated that CY reduces the number of T(REGs), the mechanism involved in this process has yet to be defined. In this report, it is established that low-dose CY not only decreases cell number but leads to decreased functionality of T(REGs). CY treatment enhances apoptosis and decreases homeostatic proliferation of these cells. Expression of GITR and FoxP3, which are involved in the suppressive activity of T(REGs), is down-regulated after CY administration, though the level of expression varies depending on the time studied. This is the first report demonstrating that CY, in addition to decreasing cell number, inhibits the suppressive capability of T(REGs). The relevance of the loss of suppressor functionality and the changes in gene expression are further discussed.
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            Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents.

            Wee1 is a tyrosine kinase that phosphorylates and inactivates CDC2 and is involved in G(2) checkpoint signaling. Because p53 is a key regulator in the G(1) checkpoint, p53-deficient tumors rely only on the G(2) checkpoint after DNA damage. Hence, such tumors are selectively sensitized to DNA-damaging agents by Wee1 inhibition. Here, we report the discovery of a potent and selective small-molecule inhibitor of Wee1 kinase, MK-1775. This compound inhibits phosphorylation of CDC2 at Tyr15 (CDC2Y15), a direct substrate of Wee1 kinase in cells. MK-1775 abrogates G(2) DNA damage checkpoint, leading to apoptosis in combination with DNA-damaging chemotherapeutic agents such as gemcitabine, carboplatin, and cisplatin selectively in p53-deficient cells. In vivo, MK-1775 potentiates tumor growth inhibition by these agents, and cotreatment does not significantly increase toxicity. The enhancement of antitumor effect by MK-1775 was well correlated with inhibition of CDC2Y15 phosphorylation in tumor tissue and skin hair follicles. Our data indicate that Wee1 inhibition provides a new approach for treatment of multiple human malignancies.
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              AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies.

              Insights from cell cycle research have led to the hypothesis that tumors may be selectively sensitized to DNA-damaging agents resulting in improved antitumor activity and a wider therapeutic margin. The theory relies on the observation that the majority of tumors are deficient in the G1-DNA damage checkpoint pathway resulting in reliance on S and G2 checkpoints for DNA repair and cell survival. The S and G2 checkpoints are regulated by checkpoint kinase 1, a serine/threonine kinase that is activated in response to DNA damage; thus, inhibition of checkpoint kinase 1 signaling impairs DNA repair and increases tumor cell death. Normal tissues, however, have a functioning G1 checkpoint signaling pathway allowing for DNA repair and cell survival. Here, we describe the preclinical profile of AZD7762, a potent ATP-competitive checkpoint kinase inhibitor in clinical trials. AZD7762 has been profiled extensively in vitro and in vivo in combination with DNA-damaging agents and has been shown to potentiate response in several different settings where inhibition of checkpoint kinase results in the abrogation of DNA damage-induced cell cycle arrest. Dose-dependent potentiation of antitumor activity, when AZD7762 is administered in combination with DNA-damaging agents, has been observed in multiple xenograft models with several DNA-damaging agents, further supporting the potential of checkpoint kinase inhibitors to enhance the efficacy of both conventional chemotherapy and radiotherapy and increase patient response rates in a variety of settings.
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                Author and article information

                Journal
                Proc Natl Acad Sci U S A
                Proc. Natl. Acad. Sci. U.S.A
                pnas
                pnas
                PNAS
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                0027-8424
                1091-6490
                13 June 2017
                22 May 2017
                : 114
                : 24
                : E4782-E4791
                Affiliations
                [1] aDivision of Immunobiology, Department of Pediatrics, Cincinnati Children’s Medical Center and University of Cincinnati College of Medicine , Cincinnati, OH 45229;
                [2] bDivision of Allergy and Immunology, Department of Pediatrics, Cincinnati Children’s Medical Center and University of Cincinnati College of Medicine , Cincinnati, OH 45229;
                [3] cDivision of Experimental Hematology and Cancer Biology, Department of Pediatrics, Cincinnati Children’s Medical Center and University of Cincinnati College of Medicine , Cincinnati, OH 45229;
                [4] dDepartment of Hematology and Oncology, Medical University of South Carolina , Charleston, SC 29425;
                [5] eSection of Hematology/Oncology, Department of Pediatrics, Baylor College of Medicine , Houston, TX 77030;
                [6] fDepartment of Hematology and Oncology, Phoenix Children’s Hospital , Phoenix, AZ 85016;
                [7] gDepartment of Hematology, Children’s National Medical Center , Washington, DC 20010;
                [8] hDepartment of Pediatrics, University of California, San Francisco School of Medicine , San Francisco, CA 94143;
                [9] iDepartment of Hematology and Oncology, Nemours Children's Specialty Care , Jacksonville, FL 32258;
                [10] jDivision of Endocrinology, Diabetes Research Center, Department of Pediatrics, Cincinnati Children’s Medical Center and University of Cincinnati College of Medicine , Cincinnati, OH 45229;
                [11] kDivision of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children’s Medical Center and University of Cincinnati College of Medicine , Cincinnati, OH 45229
                Author notes
                2To whom correspondence may be addressed. Email: michael.jordan@ 123456cchmc.org or jonathan.katz@ 123456cchmc.org .

                Edited by Christopher C. Goodnow, The Garvan Institute of Medical Research, Darlinghurst, NSW, Australia, and approved April 27, 2017 (received for review March 13, 2017)

                Author contributions: J.P.M., S.H.M., V.C., N.L., C.E.T., K.R.C., S.P.H., P.R.A., D.A.H., J.D.K., and M.B.J. designed research; J.P.M., S.H.M., V.C., N.L., C.E.T., E.E.E., K.R.C., and M.B.J. performed research; J.K., C.E.A., M.M.H., J.N.G., S.L., M.L.H., M.J., and M.B.J. contributed new reagents/analytic tools; J.P.M., S.H.M., V.C., N.L., C.E.T., E.E.E., K.R.C., S.P.H., D.A.H., J.D.K., and M.B.J. analyzed data; and J.P.M., S.H.M., V.C., K.R.C., D.A.H., J.D.K., and M.B.J. wrote the paper.

                1J.P.M. and S.H.M. contributed equally to this work.

                Author information
                http://orcid.org/0000-0001-5072-6844
                Article
                PMC5474825 PMC5474825 5474825 201703683
                10.1073/pnas.1703683114
                5474825
                28533414
                73bac86a-c72d-4b46-b3e9-e2f508886b86
                History
                Page count
                Pages: 10
                Funding
                Funded by: HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 100000062
                Award ID: RO1DK081175
                Funded by: HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 100000062
                Award ID: RO1DK081175
                Funded by: HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) 100000060
                Award ID: RO1AI109810
                Funded by: HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) 100000060
                Award ID: RO1AI109810
                Funded by: HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) 100000060
                Award ID: RO1AI057753
                Categories
                PNAS Plus
                Biological Sciences
                Immunology and Inflammation
                PNAS Plus

                autoimmunity,immune regulation,DNA damage response,therapeutics

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