GSK-3 inhibitor elraglusib enhances tumor-infiltrating immune cell activation in tumor biopsies and synergizes with anti-PD-L1 in a murine model of colorectal cancer

Huntington, Kelsey E.; Louie, Anna D.; Srinivasan, P.; Schorl, Christoph; Lu, Shaolei; Silverberg, David; Newhouse, Daniel; Wu, Zhijin; Zhou, Lanlan; Borden, Brittany A.; Giles, Frank; Dooner, Mark S.; Carneiro, Benedito A.; El‐Deiry, Wafik S.

doi:10.1101/2023.02.07.527499

Cited by 5 publications

(4 citation statements)

References 50 publications

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“…Although the complexity of PD-1 regulation patterns for T cells makes it difficult for PD-1 expression status alone to discriminate between exhausted and activated T cells within the tumor microenvironment (43), our present findings demonstrated that clinical-stage GSK-3b inhibitor, 9-ING-41, which has been reported to activate and transcriptionally attenuate expression of various immune checkpoint molecules of T cells in either preclinical or clinical environment (35,44,45), in combination with oAd armed with immune-stimulatory and ECM-degrading therapeutic genes could effectively diminish PD-1 + cell infiltration into the periphery of the bladder tumor and synergistically enhanced the infiltration and recruitment of CD8 + PD-1 − T cells in both tumor and spleen (Figures 7B, C). These findings suggested that the potential risk of T-cell exhaustion via activation of PD-1/PD-L1 signaling axis could be effectively mitigated by the rational combination of HY-oAd and 9-ING-41.…”

Section: Discussionmentioning

confidence: 68%

Tumor microenvironment-modulating oncolytic adenovirus combined with GSK-3β inhibitor enhances antitumor immune response against bladder cancer

Yoon,

Jiao,

Hong

et al. 2024

Front. Immunol.

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Bladder cancer is a common type of cancer around the world, and the majority of patients are diagnosed with non-muscle-invasive bladder cancer (NMIBC). Although low-risk NMIBC has a good prognosis, the disease recurrence rate and development of treatment-refractory disease remain high in intermediate- to high-risk NMIBC patients. To address these challenges for the treatment of NMIBC, a novel combination therapy composed of an oncolytic adenovirus (oAd) co-expressing interleukin (IL)-12, granulocyte-macrophage colony-stimulating factor (GM-CSF), and relaxin (RLX; HY-oAd) and a clinical-stage glycogen synthase kinase (GSK)-3β inhibitor (9-ING-41; elraglusib) was investigated in the present report. Our findings demonstrate that HY-oAd and 9-ING-41 combination therapy (HY-oAd+9-ING-41) exerted superior inhibition of tumor growth compared with respective monotherapy in a syngeneic NMIBC tumor model. HY-oAd+9-ING-41 induced high-level tumor extracellular matrix (ECM) degradation and a more potent antitumor immune response than the respective monotherapy. In detail, HY-oAd+9-ING-41 induced superior accumulation of intratumoral T cells, prevention of immune cell exhaustion, and induction of tumor-specific adaptive immune response compared to either monotherapy. Collectively, these results demonstrate that the combination of HY-oAd and 9-ING-41 may be a promising approach to elicit a potent antitumor immune response against bladder cancer.

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Section: Discussionmentioning

confidence: 68%

Tumor microenvironment-modulating oncolytic adenovirus combined with GSK-3β inhibitor enhances antitumor immune response against bladder cancer

Yoon,

Jiao,

Hong

et al. 2024

Front. Immunol.

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“…Interestingly, we observed a downregulation of PD-L1 expression in PanCK+ segments at the post-treatment biopsy as compared to the pre-treatment biopsies. This was unexpected as we, and others, have shown that GSK-3 inhibition upregulates tumor cell PD-L1 expression [ 8 , 55 ]. The observed decrease in PanCK+ PD-L1 expression may be a result of the late timepoint of the post-treatment biopsies, as the average time-on-study at the post-treatment timepoint was 270 days.…”

Section: Discussionmentioning

confidence: 97%

GSK-3 Inhibitor Elraglusib Enhances Tumor-Infiltrating Immune Cell Activation in Tumor Biopsies and Synergizes with Anti-PD-L1 in a Murine Model of Colorectal Cancer

Huntington

Louie

Srinivasan

et al. 2023

IJMS

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Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that has been implicated in numerous oncogenic processes. GSK-3 inhibitor elraglusib (9-ING-41) has shown promising preclinical and clinical antitumor activity across multiple tumor types. Despite promising early-phase clinical trial results, there have been limited efforts to characterize the potential immunomodulatory properties of elraglusib. We report that elraglusib promotes immune cell-mediated tumor cell killing of microsatellite stable colorectal cancer (CRC) cells. Mechanistically, elraglusib sensitized CRC cells to immune-mediated cytotoxicity and enhanced immune cell effector function. Using western blots, we found that elraglusib decreased CRC cell expression of NF-κB p65 and several survival proteins. Using microarrays, we discovered that elraglusib upregulated the expression of proapoptotic and antiproliferative genes and downregulated the expression of cell proliferation, cell cycle progression, metastasis, TGFβ signaling, and anti-apoptotic genes in CRC cells. Elraglusib reduced CRC cell production of immunosuppressive molecules such as VEGF, GDF-15, and sPD-L1. Elraglusib increased immune cell IFN-γ secretion, which upregulated CRC cell gasdermin B expression to potentially enhance pyroptosis. Elraglusib enhanced immune effector function resulting in augmented granzyme B, IFN-γ, TNF-α, and TRAIL production. Using a syngeneic, immunocompetent murine model of microsatellite stable CRC, we evaluated elraglusib as a single agent or combined with immune checkpoint blockade (anti-PD-1/L1) and observed improved survival in the elraglusib and anti-PD-L1 group. Murine responders had increased tumor-infiltrating T cells, augmented granzyme B expression, and fewer regulatory T cells. Murine responders had reduced immunosuppressive (VEGF, VEGFR2) and elevated immunostimulatory (GM-CSF, IL-12p70) cytokine plasma concentrations. To determine the clinical significance, we then utilized elraglusib-treated patient plasma samples and found that reduced VEGF and BAFF and elevated IL-1 beta, CCL22, and CCL4 concentrations correlated with improved survival. Using paired tumor biopsies, we found that tumor-infiltrating immune cells had a reduced expression of inhibitory immune checkpoints (VISTA, PD-1, PD-L2) and an elevated expression of T-cell activation markers (CTLA-4, OX40L) after elraglusib treatment. These results address a significant gap in knowledge concerning the immunomodulatory mechanisms of GSK-3 inhibitor elraglusib, provide a rationale for the clinical evaluation of elraglusib in combination with immune checkpoint blockade, and are expected to have an impact on additional tumor types, besides CRC.

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“…Elraglusib was developed as a targeted GSK3β inhibitor, and its anti-cancer effects have been variously attributed to GSK3 inhibition within cancer cells, resulting in abnormal regulation of NFkB, impaired DNA-damage responses or myc downregulation, and to immunomodulatory effects within NK and T-cells (7,13,24,25). We, and others, have reported that the drug inhibits both the α and β paralogs of GSK3, along with several other kinases in cellfree assays (10,17).…”

Section: Discussionmentioning

confidence: 99%

“…The in vitro CD3/CD28 co-stimulation model we utilised to stimulate T lymphocytes is designed to mimic T-cell responses to antigenpresenting cells in vivo, suggesting that elraglusib may have immunosuppressive effects in patients (37). However, it is important to note that elraglusib was recently shown to enhance immune cell activation, and synergise with anti-PD-L1 therapy in a mouse model of colorectal cancer (24). Whether these effects are due to direct effects on the immune system or enhanced immune engagement due to cytotoxic effects on colorectal cancer cells remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Elraglusib induces cytotoxicity via direct microtubule destabilisation independently of GSK3 inhibition

Coats,

Li,

Tanaka

et al. 2024

Preprint

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Elraglusib (9-ING-41) is an ATP-competitive inhibitor of glycogen synthase kinase-3 (GSK3) with pre-clinical studies demonstrating broad activity against many tumour types. Promising early-phase clinical trial data led to FDA orphan drug status, and a randomised phase 2 study in combination with cytotoxic chemotherapy in pancreatic cancer has recently completed its recruitment. Similarly, single-agent responses in adult T-cell leukaemia/lymphoma and melanoma, and combination treatment data in several other tumour types have been encouraging. The elraglusib mechanism of action is unknown, but it is unlikely to act through GSK3 inhibition because cytotoxicity is observed below the IC50for GSK3 and other small molecule GSK3 inhibitors do not produce cytotoxic effects, at least in lymphoma cells. We show here that elraglusib perturbs chromosomal alignment to cause a mitotic arrest in multiple tumour lines. This arrest is caused by microtubule depolymerisation, which prevents the attachment of kinetochores to microtubules. At clinically relevant doses, these mitotically arrested cells eventually undergo mitotic slippage leading to gross chromosome missegrations, DNA damage and apoptosis. These effects explain the cytotoxicity of elraglusib because temporarily pausing cell cycle progression with the CDK4/6 inhibitor palbociclib abolishes any drug-induced genotoxicity and apoptosis. In summary, elraglusib acts as a potent microtubule destabiliser across multiple cancer types resulting in mitotic arrest, DNA damage and apoptosis. These effects likely account for its broad pan-cancer activity, which does not rely upon GSK3 inhibition as they are not replicated by other GSK3 inhibitors.

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GSK-3 inhibitor elraglusib enhances tumor-infiltrating immune cell activation in tumor biopsies and synergizes with anti-PD-L1 in a murine model of colorectal cancer

Cited by 5 publications

References 50 publications

Tumor microenvironment-modulating oncolytic adenovirus combined with GSK-3β inhibitor enhances antitumor immune response against bladder cancer

Tumor microenvironment-modulating oncolytic adenovirus combined with GSK-3β inhibitor enhances antitumor immune response against bladder cancer

GSK-3 Inhibitor Elraglusib Enhances Tumor-Infiltrating Immune Cell Activation in Tumor Biopsies and Synergizes with Anti-PD-L1 in a Murine Model of Colorectal Cancer

Elraglusib induces cytotoxicity via direct microtubule destabilisation independently of GSK3 inhibition

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