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Ref Type Journal Article
PMID (31018997)
Authors Joshi S, Singh AR, Liu KX, Pham TV, Zulcic M, Skola D, Chun HB, Glass CK, Morales GA, Garlich JR, Durden DL
Title SF2523: Dual PI3K/BRD4 Inhibitor Blocks Tumor Immunosuppression and Promotes Adaptive Immune Responses in Cancer.
Journal Molecular cancer therapeutics
Vol 18
Issue 6
Date 2019 Jun
URL
Abstract Text Macrophages (MΘs) are key immune infiltrates in solid tumors and serve as major drivers behind tumor growth, immune suppression, and inhibition of adaptive immune responses in the tumor microenvironment (TME). Bromodomain and extraterminal (BET) protein, BRD4, which binds to acetylated lysine on histone tails, has recently been reported to promote gene transcription of proinflammatory cytokines but has rarely been explored for its role in IL4-driven MΘ transcriptional programming and MΘ-mediated immunosuppression in the TME. Herein, we report that BET bromodomain inhibitor, JQ1, blocks association of BRD4 with promoters of arginase and other IL4-driven MΘ genes, which promote immunosuppression in TME. Pharmacologic inhibition of BRD4 using JQ1 and/or PI3K using dual PI3K/BRD4 inhibitor SF2523 (previously reported by our group as a potent inhibitor to block tumor growth and metastasis in various cancer models) suppresses tumor growth in syngeneic and spontaneous murine cancer models; reduces infiltration of myeloid-derived suppressor cells; blocks polarization of immunosuppressive MΘs; restores CD8+ T-cell activity; and stimulates antitumor immune responses. Finally, our results suggest that BRD4 regulates the immunosuppressive myeloid TME, and BET inhibitors and dual PI3K/BRD4 inhibitors are therapeutic strategies for cancers driven by the MΘ-dependent immunosuppressive TME.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
SF2523 SF2523 5 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
JQ1 BET Inhibitor (Pan) 27 JQ1 is a BET bromodomain inhibitor with greatest specificity towards BRD4, resulting in decreased Myc expression, increased cell death, reduced macrophage immunosuppression, and inhibition of tumor growth (PMID: 24231268, PMID: 31018997, PMID: 30906568).
SF1126 BRD4 Inhibitor 7 PI3K Inhibitor (Pan) 37 SF1126 is a prodrug of LY294002, a pan PI3K inhibitor with additional activity against BRD4, which potentially results in reduced tumor immunosuppression and inhibits tumor growth (PMID: 23355037, PMID: 27496136, PMID: 31018997).
SF2523 BRD4 Inhibitor 7 PI3K Inhibitor (Pan) 37 SF2523 is a small molecule inhibitor that targets both BRD4 and PI3K, which results in anti-tumor immune response and inhibits tumor growth (PMID: 31018997).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown breast cancer not applicable SF2523 Preclinical Actionable In a preclinical study, SF2523 decreased tumor immunosuppression, and inhibited tumor growth and progression in a mouse breast cancer model (PMID: 31018997). 31018997
Unknown unknown lung carcinoma not applicable JQ1 Preclinical Actionable In a preclinical study, JQ1 decreased tumor immunosuppression, increased T-lymphocyte infiltration and reduced tumor growth and increased survival in syngeneic mouse lung carcinoma models (PMID: 31018997). 31018997
Unknown unknown pancreatic cancer not applicable SF2523 Preclinical Actionable In a preclinical study, SF2523 decreased tumor immunosuppression and inhibited tumor growth in orthotopic mouse pancreatic cancer models (PMID: 31018997). 31018997
Unknown unknown lung carcinoma not applicable SF1126 Preclinical Actionable In a preclinical study, SF1126 decreased tumor immunosuppression and reduced tumor growth in syngeneic mouse lung carcinoma models (PMID: 31018997). 31018997
Unknown unknown lung carcinoma not applicable SF2523 Preclinical Actionable In a preclinical study, SF2523 decreased tumor immunosuppression, increased T-lymphocyte infiltration, and reduced tumor growth in syngeneic mouse lung carcinoma models (PMID: 31018997). 31018997
Unknown unknown melanoma not applicable SF2523 Preclinical Actionable In a preclinical study, SF2523 reduced tumor growth and decreased lung metastasis in syngeneic mouse melanoma models (PMID: 31018997). 31018997
Unknown unknown colon adenocarcinoma not applicable JQ1 Preclinical Actionable In a preclinical study, JQ1 increased T-lymphocyte infiltration and reduced tumor growth in syngeneic mouse colon adenocarcinoma models (PMID: 31018997). 31018997
Unknown unknown melanoma not applicable JQ1 Preclinical Actionable In a preclinical study, JQ1 reduced tumor growth in syngeneic mouse melanoma models (PMID: 31018997). 31018997
Unknown unknown colon adenocarcinoma not applicable SF2523 Preclinical Actionable In a preclinical study, SF2523 increased T-lymphocyte infiltration and reduced tumor growth in syngeneic mouse colon adenocarcinoma models (PMID: 31018997). 31018997