ZIA SC 004002 (ZIA) | |||
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Title | IL-2:IL-15 cytokine receptor: implications for cancer therapy and vaccine | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Waldmann, Thomas | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $1,007,184 | Project Dates | 00/00/0000 - 00/00/0000 |
Fiscal Year | 2016 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Autoimmune Diseases (10.0%) Cancer (100.0%) |
Brain (8.0%) Central Nervous System - Not Including Brain (4.0%) Hodgkins disease (20.0%) Leukemia (45.0%) Lung (1.0%) Melanoma (10.0%) Nervous System (15.0%) Non Hodgkins Lymphoma (10.0%) |
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Research Type | |||
Endogenous Factors in the Origin and Cause of Cancer Systemic Therapies - Clinical Applications |
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Abstract | |||
A major focus of the Waldmann/Staudt Laboratory is to define molecular abnormalities of HTLV-1 associated ATL. Previously we demonstrated that HTLV-1 encoded Tax transactivates two autocrine (IL-2/IL-2R, IL-15/IL-15R alpha) and one paracrine (IL-9) pathway. To extend these observations we performed molecular interference ""Achilles' heel"" screening of ATL cell lines employing a library of retroviral vectors for inducible expression of short-hairpin RNAs (shRNAs) to identify genes essential for leukemic cell survival. Using this loss-of-function screen, 6 of 7 distinct cytokine-dependent ATL cell lines were shown to be critically dependent on JAK1 and JAK3 for proliferation and survival. The critical nature of the gamma cytokine, JAK1/JAK3 pathway for ATL was supported by our observation that the ex vivo 6-day culture of PBMCs from patients with smoldering and chronic ATL could be inhibited by the administration of antibodies to the IL-2 receptor, as well as by pan-JAK inhibitor, tofacitinib and the JAK1/2 inhibitor, ruxolitinib. To translate these observations, the Waldmann and Conlon Group has initiated a phase II clinical trial involving the JAK1/2 inhibitor, ruxolitinib in patients with ATL. To extend these studies with Craig Thomas we searched for novel multicomponent (combination) drug therapies for ATL by applying high-throughput matrix screening for cellular signaling on ATL cell lines to define combination therapies that identify agents with synergy. Optimal synergy was demonstrated between the JAK1/2 inhibitor, ruxolitinib added in association with the Bcl-xL inhibitor, navitoclax. In molecular analyses our laboratory with Masao Nakagawa, a postdoctoral fellow, using RNA-seq identified nonsense mutations of CCR4 in 26% of the malignant cells of patients with ATL leukemic cells. In translation CCR4 is the target of a collaborative clinical trial involving patients with ATL using the anti-CCR4 monoclonal antibody, mogamulizumab. Furthermore, the Waldmann Laboratory has generated an anti-CCR4 CAR for use in clinical trials of patients with ATL to take advantage of the 90% CCR4 expression on ATL leukemic cells. In further analysis of ATL we focused on the viral transcription factor HBZ that is universally expressed by ATL cells. HBZ has been implicated in ATL but it remains unclear how HBZ exploits host pathways to maintain the malignant cellular proliferation. Again using RNA interference screening for ATL cells we discovered that their cellular proliferation was strongly dependent on the expression of a BATF3/IRF4, immune cell specific transcription factor complex. Genome-wide analysis for BRD4 binding and H3K27ac sites clarified that an ATL specific super-enhancer (SE) element was associated with BATF expression. The function of ATL specific SEs including the BATF3 locus were in part maintained through induction of BRD4 binding by HBZ together with IRF4/BATF3 expression itself establishing a regulatory circuit in ATL cells. Disruption of ATL specific SE function by using the BRD4 inhibitor, JQ-1 markedly decreased BATF3 expression in ATL cell lines and strongly suppressed ATL cellular proliferation in vitro and in vivo. Taken together this study exemplified how the viral transcription factor HBZ can regulate an oncogenic pathway through disease specific epigenetic modification and support the exploration of BRD4 inhibitors in clinical trials as a therapeutic option for this malignant disease with an 8-month median survival duration with current therapeutic interventions. In summary, the Waldmann Laboratory has made major contributions concerning the translation of molecular insights concerning ATL into new novel therapeutic strategies for this malignancy. |