elraglusib (9-ING-41)

Finally, in co-culture experiments with CD8 + T cells, 9-ING-41 improved immune recognition of the neuroblastoma cells, as evidenced by augmented T-cell activation marker levels and T-cell proliferation, which was further enhanced by PD-1 immune checkpoint inhibition. Our preclinical study provides experimental support to further explore the GSK-3β inhibitor 9-ING-41 as an immunomodulatory agent to increase tumor immune recognition in neuroblastoma.

GSK-3β functions as an oncogene in ATL and could be a potential therapeutic target.

P1, N=68, Recruiting, Actuate Therapeutics Inc. | Active, not recruiting --> Recruiting

Our preliminary analysis of gene mutations in liquid biopsy samples obtained from patients in the ongoing 1801 Part 3B phase 2 trial identified potential predictive biomarkers of clinical outcome in mPDAC patients treated with combination of elraglusib/GnP. Clinical trial information: NCT03678883.

P2, N=35, Active, not recruiting, Glenn J. Hanna | Recruiting --> Active, not recruiting

P2, N=70, Recruiting, Colin D. Weekes, M.D., PhD | Trial completion date: Jul 2024 --> Jul 2026 | Trial primary completion date: Dec 2023 --> Dec 2025

P2, N=17, Completed, Actuate Therapeutics Inc. | Active, not recruiting --> Completed

P2, N=350, Active, not recruiting, Actuate Therapeutics Inc. | Recruiting --> Active, not recruiting

P2, N=350, Recruiting, Actuate Therapeutics Inc.

P2, N=35, Recruiting, Glenn J. Hanna | Trial primary completion date: Jan 2024 --> Jun 2024

The IC 50 of elraglusib remains similar despite a significant reduction in levels of GSK3, again suggesting that GSK3 is not its cytotoxic target. Importantly, elraglusib retains therapeutic potential in lymphoma however GSK3 is not a surrogate marker for its efficacy and additional studies are required to elucidate the mechanisms through which it mediates its cytotoxic effects.

P2, N=32, Active, not recruiting, Anwaar Saeed | Trial primary completion date: Aug 2024 --> Dec 2024

P2, N=35, Recruiting, Glenn J. Hanna | Trial primary completion date: Sep 2023 --> Jan 2024

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.

P2, N=32, Active, not recruiting, Anwaar Saeed | Trial completion date: Mar 2025 --> Jun 2025 | Trial primary completion date: Mar 2024 --> Aug 2024

To confirm the importance of its action on GSK3β, we treated 3 lymphoma cell lines with selective, structurally distinct GSK3 inhibitors: CT99021, SB216763, LY2090314, tideglusib, and elraglusib. These data question GSK3 as the target of elraglusib in lymphoma, and hence the utility of GSK3 expression as a 'stand-alone', therapeutic biomarker in NHL. Video Abstract.

P1, N=68, Active, not recruiting, Actuate Therapeutics Inc. | Trial primary completion date: Apr 2023 --> Dec 2024

9-ING-41 is a maleimide-based small molecule that crosses the blood brain barrier and selectively inhibits GSK-3β...p53 stabilization is not mediated by MDM2 and may be downstream of the ATM pathway. Further studies are underway to demonstrate its efficacy in mouse models.

This ongoing study, to our knowledge, represents the first digital spatial analysis of tumor biopsies from patients treated with elraglusib. These novel circulating biomarkers of response to GSK-3 inhibition could provide significant clinical utility and the spatial proteomics data may give us insights into the immunomodulatory mechanisms of GSK-3 inhibition.

Additionally, both cancer cell lines as well as TALL-104 T-cells and NK-92 NK cells were treated with 0.5 μM 9-ING-41 for 24 hours and harvested for Luminex cytokine profiling. The treatment cohorts for these experiments include 9-ING-41 combined with either anti-PD-L1, anti-PD-1, or anti-CTLA-4 immune checkpoint inhibitors. Our results suggest a promising combination therapeutic strategy for patients with soft tissue and bone sarcomas and future work will strive to better elucidate the mechanisms of efficacy.

P1, N=68, Active, not recruiting, Actuate Therapeutics Inc. | Recruiting --> Active, not recruiting

"Tempus...announced a brand-new multi-omics collaboration with Actuate Therapeutics, Inc...to support its ongoing Phase 1/2 Study of elraglusib, formerly known as 9-ING-41 (NCT03678883). The Tempus’ xF+ liquid biopsy and Research Use Only (RUO) DNA methylation tests will be used to help discover and further validate biomarker profiles in patients who may benefit from treatment with elraglusib, a selective GSK-3β inhibitor."

P2, N=350, Recruiting, Actuate Therapeutics Inc. | Phase classification: P1/2 --> P2 | Trial completion date: Nov 2023 --> Nov 2025 | Trial primary completion date: Nov 2022 --> Nov 2024

GSK3 inhibition also blocked hyperresponsiveness to IL-6 receptor signaling in TRAF3-deficient BCL cells. Together, these results support the utility of 9-ING-41 as a treatment for BCL, and suggest that a decrease or loss of TRAF3 in BCLs could act as a biomarker for increased susceptibility to GSK3 inhibitor treatment.

These data highlight the potential of elraglusib as an immune-modulatory agent and demonstrate the benefit of a sequential approach with immune checkpoint inhibition followed by GSK-3β inhibition in melanoma and provide a rationale for clinical investigation of elraglusib combined with immune checkpoint inhibitory molecules, including those targeting PD-1, TIGIT and LAG-3. This has several potential implications for current immunotherapy regimes, including possibly reducing the intensity of anti-PD-1 mAb treatment needed for response in patients receiving elraglusib, especially given the benign adverse event profile of elraglusib observed to date. Based on these data, a clinical study of elraglusib, an anti-PD-1 mAb and chemotherapy is ongoing (NCT NCT05239182).

Ongoing experiments are investigating the hypothesis that 9-ING-41-induced T cell activation and immunomodulation contributes to its clinical activity. Further clinical investigation of 9-ING-41 for treatment of ATLL is warranted.

All received upfront radiation/temozolomide (18/18), plus salvage nitrosoureas (15/18), bevacizumab (8/18), TTFields (6/18), or immunotherapy (4/18). Median OS was 5.5 (95% CI: 2.8-11.4) months and PFS-6 was 16.7%. 9-ING-41 plus/minus lomustine is safe and warrants further study in glioma patients.

Murine serum cytokine profiling showed that responders had lower concentrations of tumorigenic cytokines (BAFF, CCL7, CCL12, VEGF, VEGFR2, CCL21) and higher concentrations of immunomodulatory cytokines (CCL4, TWEAK, GM-CSF, CCL22, IL-12p70) compared to non-responders. These results demonstrate that small-molecule inhibition of GSK-3 with 9-ING-41 may increase the anti-tumor effects of ICB and improve response in patients with MSS CRC via modulation of anti-tumor immunity and cytokine signaling.

9-ING-41 decreases ETMR and ATRT cell viability at clinically relevant concentrations and these doses increase the p53 pathway and induce apoptosis while reducing the expression of stemness associated genes.

P2, N=0, Withdrawn, Actuate Therapeutics Inc. | N=40 --> 0 | Trial completion date: Jun 2024 --> Jun 2034 | Initiation date: Sep 2021 --> Dec 2030 | Recruiting --> Withdrawn | Trial primary completion date: Jun 2023 --> Jun 2033

Mechanistically, 9-ING-41 induces significant apoptosis of STS cells via suppression of NF-κB-mediated X-linked inhibitor of apoptosis protein (XIAP) expression. These data support the inclusion of patients with STS in clinical studies of 9-ING-41 alone and in combination with chemotherapy.

Although molecular biomarkers of 9-ING-41 efficacy are yet to be identified, the addition of 9-ING-41 to the standard-of-care drugs 5-FU and oxaliplatin could significantly enhance growth inhibition in certain CRC cells...Notably, we find substantial similarity in the changes of the transcriptomic profile after inhibition of GSK-3β and suppression of STK33, another critically important kinase for K-Ras-dependent cells, which could be an interesting point for future research. Overall, the results of this study provide a rationale for the further investigation of GSK-3 inhibitors in combination with standard-of-care treatment of CRC.

All received initial radiation and temozolomide (18/18), prior salvage therapies included nitrosoureas (15/18), bevacizumab (8/18), TTFields (6/18), checkpoint inhibitor (4/18). Median PFS and OS were 1.9 (0.3-11.1) and 6.0 (1.6-16.6) months, respectively. CONCLUSIONS 9-ING-41 plus/minus lomustine is safe and warrants further study in glioma patients.

P2, N=40, Recruiting, Actuate Therapeutics Inc. | Not yet recruiting --> Recruiting

P1/2, N=350, Recruiting, Actuate Therapeutics Inc. | Trial completion date: Nov 2022 --> Nov 2023

P1, N=68, Recruiting, Actuate Therapeutics Inc. | N=48 --> 68 | Trial completion date: Dec 2021 --> Dec 2024 | Trial primary completion date: Apr 2021 --> Apr 2023

No abstract available

Small molecule inhibitors of glycogen synthase kinase-3 beta have demonstrated therapeutic potential in pre-clinical models and are currently being evaluated in early phase clinical trials involving pancreatic cancer patients with interim results showing favorable results. Moreover, recent studies support a rationale for the combination of glycogen synthase kinase-3 beta inhibitors with chemotherapy and immunotherapy, warranting the evaluation of novel combination regimens in the future.

P2, N=40, Not yet recruiting, Actuate Therapeutics Inc. | Initiation date: Jun 2021 --> Sep 2021

In vitro studies are ongoing to investigate the potential association of 9-ING-41 with the BCL2 inhibitor Venetoclax. Targeting GSK-3β may expand therapeutic options for CLL patients. Ongoing work continues to assess combinations with approved targeted agents in order to overcome drug-induced resistance.

In chemoresistant PDX models of glioblastoma (GBM), 9-ING-41 enhanced the antitumor effect of CCNU and CPT-11...All received first-line radiation and temozolomide (18/18), prior therapies for recurrences included nitrosoureas (15/18), bevacizumab (8/18), TTFields (6/18), immune checkpoint inhibitor (4/18)...Best overall response: 1 minimal response (-43%) after 2 cycles of 9-ING-41 and lomustine . These results show 9-ING-41 alone or in combination is safe and warrants further study in glioma patients.