Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	18	6	2019 Jun	1036-1044	Mol Cancer Ther

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
JQ1	JQ1	9	0
SF2523	SF2523	0	0

Drug Name	Synonyms	Drug Classes	Drug Description
JQ1	JQ-1	BET Inhibitor (Pan) 32	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, PMID: 32800944).
SF1126		BRD4 Inhibitor 10 PI3K Inhibitor (Pan) 40	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 10 PI3K Inhibitor (Pan) 40	SF2523 is a small molecule inhibitor that targets both BRD4 and PI3K, which results in anti-tumor immune response and inhibits tumor growth (PMID: 30824188, 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