Macrophage Syk–PI3Kγ Inhibits Antitumor Immunity: SRX3207, a Novel Dual Syk–PI3K Inhibitory Chemotype Relieves Tumor Immunosuppression

Joshi, Shweta; Liu, Kevin X.; Zulcic, Muamera; Singh, Alok R.; Skola, Dylan; Glass, Christopher K.; Sanders, P. Dominick; Sharabi, Andrew B.; Pham, Timothy V.; Tamayo, Pablo; Shiang, Daniel; Dinh, Huy Q.; Hedrick, Catherine C.; Morales, Guillermo; Garlich, Joseph R.; Durden, Donald L.

doi:10.1158/1535-7163.mct-19-0947

Cited by 29 publications

(45 citation statements)

References 42 publications

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“…While iNOS is typically induced by M1 macrophages, studies have found that M2-like TAMs express iNOS at lower levels than M1 macrophages and these low levels of NO produced by TAMs inhibits tumor cell apoptosis and serves a cytoprotective function ( 126 – 128 ). Recent studies have shown that PTEN/PI3K/AKT signaling axis and Syk-Rac2 signaling axis promotes the stabilization of HIF1/2α in TAMs and polarization of macrophages into immunosuppressive phenotype in solid tumors ( 129 – 132 ). The inhibition of these signaling axes induces degradation of HIF1/2α in a proteasome-dependent manner and suppresses tumor growth and metastasis in solid tumors.…”

Section: Tams In Neuroblastomamentioning

confidence: 99%

“…One strategy to repolarize macrophages in vivo is the inhibition of Syk-Rac2 signaling axis. Our group has identified a novel signaling pathway by which α 4 β 1 integrin and CSF receptor activates Syk-PI3Kγ-Rac2 axes to polarize macrophages into immunosuppressive phenotype ( 130 – 132 ). Rac2 is a hematopoietic GTPase and our studies have shown that macrophage deletion of Rac2 blocks tumor growth in syngeneic NB9464 model of neuroblastoma ( 130 ).…”

Section: Tam Targeted Immunotherapy In Neuroblastomamentioning

confidence: 99%

“…Rac2 is a hematopoietic GTPase and our studies have shown that macrophage deletion of Rac2 blocks tumor growth in syngeneic NB9464 model of neuroblastoma ( 130 ). Moreover, genetic deletion or pharmacological inhibition of macrophage Syk kinase induces proinflammatory transcriptional programming in macrophages which resulted in activated T cell responses in lung adenocarcinoma and B16 melanoma model ( 132 ). These studies also identified that Syk kinase regulates stabilization of HIF1/2α to promote immunosuppression in TME while inhibition of Syk kinase promotes activation of NF-κB, leading to immunostimulation and tumor regression.…”

Section: Tam Targeted Immunotherapy In Neuroblastomamentioning

confidence: 99%

“…PI3Kγ is another molecular target that is highly expressed in macrophages and promotes anti-inflammatory polarization of macrophages in solid tumors ( 131 , 135 ). Our recent study demonstrated that combinatorial inhibition of Syk-PI3Kγ axis by a dual Syk-PI3Kγ inhibitor SRX3207 has shown great efficacy in solid tumors ( 132 ). Other strategies to repolarize macrophages include targeting histone deacetylase (HDAC) proteins or epigenetic reader proteins, including bromodomain-containing proteins (BRD).…”

Section: Tam Targeted Immunotherapy In Neuroblastomamentioning

confidence: 99%

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“Re-educating” Tumor Associated Macrophages as a Novel Immunotherapy Strategy for Neuroblastoma

Liu

Joshi

2020

Front. Immunol.

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Neuroblastoma is the most common extracranial pediatric tumor and often presents with metastatic disease, and patients with high-risk neuroblastoma have survival rates of ~50%. Neuroblastoma tumorigenesis is associated with the infiltration of various types of immune cells, including myeloid derived suppressor cells, tumor associated macrophages (TAMs), and regulatory T cells, which foster tumor growth and harbor immunosuppressive functions. In particular, TAMs predict poor clinical outcomes in neuroblastoma, and among these immune cells, TAMs with an M2 phenotype comprise an immune cell population that promotes tumor metastasis, contributes to immunosuppression, and leads to failure of radiation or checkpoint inhibitor therapy. This review article summarizes the role of macrophages in tumor angiogenesis, metastasis, and immunosuppression in neuroblastoma and discusses the recent advances in “macrophage-targeting strategies” in neuroblastoma with a focus on three aspects: (1) inhibition of macrophage recruitment, (2) targeting macrophage survival, and (3) reprogramming of macrophages into an immunostimulatory phenotype.

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Section: Tams In Neuroblastomamentioning

confidence: 99%

Section: Tam Targeted Immunotherapy In Neuroblastomamentioning

confidence: 99%

Section: Tam Targeted Immunotherapy In Neuroblastomamentioning

confidence: 99%

Section: Tam Targeted Immunotherapy In Neuroblastomamentioning

confidence: 99%

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“Re-educating” Tumor Associated Macrophages as a Novel Immunotherapy Strategy for Neuroblastoma

Liu

Joshi

2020

Front. Immunol.

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“…It was reported that down-regulation of LYN inhibited the proliferation, migration and invasion of melanoma cell lines via suppressing PI3K/AKT signaling pathway [43]. Combined treatment of SYK inhibitor and PI3K inhibitor induced anti-tumor immune responses via promoting pro-inflammatory macrophage phenotype and activating CD8 + T cells [44]. LCK was also reported to activate T cell via facilitating costimulatory molecule CD28-mediated signal transduction and LAT phosphorylation [45].…”

Section: Kinase Targets Of Hub Genesmentioning

confidence: 99%

Identification of genes with therapeutic and prognostic values in lung adenocarcinoma microenvironment

Jiang¹,

Gao²,

Zhang³

et al. 2020

Preprint

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Background As the most diagnosed malignancy, lung cancer is also the primary cause of cancer death in the entire world. The therapy of lung adenocarcinoma (LUAD), which is the most prevalent subtype of lung cancer, draw researchers’ increasing attentions. This research aimed to investigate the tumor microenvironment (TME)-related hub genes which might be novel targets for treatment. Materials and methods LUAD-associated data packages, including RNA-Seq information and clinical data of 522 patients, were obtained from The Cancer Genome Atlas (TCGA). For better evaluation of stromal and immune cell components, immune scores, stromal scores and estimate scores were obtained with ESTIMATE algorithm based on gene expression levels in tumors. The R package heatmap and clustering analysis were used to explore interested genes. Differentially expressed genes (DEGs) were identified by Venn diagram. Protein-protein interaction (PPI) network was applied to explore intrinsic connections of DEGs. Kaplan-Meier (K-M) survival curves, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were applied to investigate the prognostic values and intricate biological functions of DEGs. The relationships between 4 survival-related hub genes and 6 types of immune cells were examined using TIMER database. The LinkedOmics database was applied to look for kinase targets of hub genes. Results The immune/stromal/estimate scores were significantly correlated with clinical features, including the grades and sizes of LUAD, distant metastasis and outcomes. A total of 702 DEGs, 589 up-regulated and 113 down-regulated, were identified. GO and KEGG analysis showed that the DEGs had significant correlations with tumor immunology. PPI network suggested that the top 8 nodes were FPR2, C3AR1, MCHR1, CCR5, FPR1, CCL19, CCR2 and CXCL10. K-M survival curves indicated that FPR2, C3AR1, MCHR1 and CCR5, as hub genes, were significantly correlated with the overall survival (OS) of LUAD patients. The expression levels of C3AR1 and CCR5 were positively correlated with immune cell infiltration. LYN, LCK and SYK were the targeted kinases of these hub genes. Conclusion FPR2, C3AR1, MCHR1 and CCR5 were TME-related genes and potential biomarkers for the therapy and prognosis of LUAD.

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A phase Ib study evaluating the recommended phase II dose, safety, tolerability, and efficacy of mivavotinib in combination with nivolumab in advanced solid tumors

Juric,

Barve,

Vaishampayan

et al. 2024

Cancer Medicine

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Mivavotinib (TAK‐659/CB‐659), a dual SYK/FLT3 inhibitor, reduced immunosuppressive immune cell populations and suppressed tumor growth in combination with anti‐PD‐1 therapy in cancer models. This dose‐escalation/expansion study investigated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of mivavotinib plus nivolumab in patients with advanced solid tumors. Patients received oral mivavotinib 60–100 mg once‐daily plus intravenous nivolumab 3 mg/kg on days 1 and 15 in 28‐day cycles until disease progression or unacceptable toxicity. The dose‐escalation phase evaluated the recommended phase II dose (RP2D; primary endpoint). The expansion phase evaluated overall response rate (primary end point) at the RP2D in patients with triple‐negative breast cancer (TNBC). During dose‐escalation (n = 24), two dose‐limiting toxicities (grade 4 lipase increased and grade 3 pyrexia) occurred in patients who received mivavotinib 80 mg and 100 mg, respectively. The determined RP2D was once‐daily mivavotinib 80 mg plus nivolumab 3 mg/kg. The expansion phase was terminated at ~50% enrollment (n = 17) after failing to meet an ad hoc efficacy futility threshold. Among all 41 patients, common treatment‐emergent adverse events (TEAEs) included dyspnea (48.8%), aspartate aminotransferase increased, and pyrexia (46.3% each). Common grade ≥3 TEAEs were hypophosphatemia and anemia (26.8% each). Mivavotinib plasma exposure was generally dose‐proportional (60–100 mg). One patient had a partial response. Mivavotinib 80 mg plus nivolumab 3 mg/kg was well tolerated with no new safety signals beyond those of single‐agent mivavotinib or nivolumab. Low response rates highlight the challenges of treating unresponsive tumor types, such as TNBC, with this combination and immunotherapies in general.Trial registration IDNCT02834247.

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Macrophage Syk–PI3Kγ Inhibits Antitumor Immunity: SRX3207, a Novel Dual Syk–PI3K Inhibitory Chemotype Relieves Tumor Immunosuppression

Cited by 29 publications

References 42 publications

“Re-educating” Tumor Associated Macrophages as a Novel Immunotherapy Strategy for Neuroblastoma

“Re-educating” Tumor Associated Macrophages as a Novel Immunotherapy Strategy for Neuroblastoma

Identification of genes with therapeutic and prognostic values in lung adenocarcinoma microenvironment

A phase Ib study evaluating the recommended phase II dose, safety, tolerability, and efficacy of mivavotinib in combination with nivolumab in advanced solid tumors

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