tasquinimod (ABR-215050)

P2, N=33, Not yet recruiting, M.D. Anderson Cancer Center | Initiation date: Mar 2024 --> Sep 2024

P2, N=33, Not yet recruiting, M.D. Anderson Cancer Center

P1, N=34, Recruiting, University of Pennsylvania

Finally, we found that S100A9-targeting approaches could significantly increase venetoclax sensitivity in AML cells, which was associated with a downregulation of BCL-2 and c-MYC in the combination group compared to single agent therapy. This study identifies S100A9 as a novel molecular target to treat AML and supports the therapeutic evaluation of tasquinimod in venetoclax-based regimens for AML patients.

Additionally, our findings showed that co-treatment with TM (5 to 30 µM) and ruxolitinib (250 to 1000 nM), BET inhibitor OTX015 (50 to 250 nM) or pelabresib (CPI-0610) (100 to 500 nM), or BCL2/Bcl-xL inhibitor navitoclax induced synergistic lethality in advanced MPN-BP cells exhibiting delta synergy scores of >1.0 (by the ZIP method). In a separate experiment on the same PDX model, treatment with TM (30 mg/kg/day) also induced significantly greater survival advantage than treatment with ruxolitinib (30 mg/kg/day) or OTX015 (30 mg/kg/day) by oral gavage. These findings clearly demonstrate preclinical efficacy of TM in advanced MPN-BP cellular models and create the rationale to further interrogate the efficacy of TM alone and in combinations with current, front-line therapies for advanced MPN with excess blasts.

In conclusion, this study provides the first evidence for an in vivo effect of TASQ in a murine model of MDS, suggesting improved erythropoiesis and positive effects on the bone phenotype. These results warrant further investigations of TASQ in human trials, particularly in MDS patients in whom anemia and bone loss often coexist.

Ongoing studies using the S100A8/A9 inhibitor Tasquinimod are examining the dependency of Dnmt3a-mutant hematopoiesis on alarmin production ex vivo and in vivo. Given that S100A8/A9 are heavily involved in the pathogenesis of acute inflammation and myeloproliferative neoplasms, induction of senescence through the alarmin axis is a mechanistic link between aging, clonal hematopoiesis and haematologic malignancy.

These findings now allow an intensified translational focus in the current funding period: the phase Ib/II TasquForce MPN clinical trial assesses, in pts with MF, the efficacy and tolerability of the small molecule inhibitor tasquinimod, which targets the alarmin heterodimer S100A8/A9 and was shown by members of our consortium to antagonize the MPN phenotype including MF in a murine model...Moreover, we are generating and evaluating spatio-temporal transcriptional landscapes and epigenetic information of BM fibrosis to identify novel therapeutic targets and optimize and prognosticate the success of allogeneic stem cell transplantation (P1, P2, P3, P4, SP). Together, these projects will allow us to design better means of early diagnosis and prevention of MPN progression in pts with early-stage MPN and better treatment options for pts with later-stage MPN, particularly overt MF.

The S100A9 inhibitor Tasquinimod (TASQ, Active Biotech) has shown promising results in treating various solid tumors by demonstrating both antitumor and immunomodulatory properties in preclinical and clinical studies... This study suggests that distinct CD271 +/- MDS MSC subpopulations drive the inflammatory and immunosuppressive phenotype and can be targeted by TASQ to potentially attenuate the disease.

This increased therapeuticindex nominates ESATA-20 as a lead candidate forclinical development as an orally active third generation quinoline-3-carboxamide analog thatretains its on-target ability to disrupt HDAC4/HIF-1α/MEF-2-dependent adaptive survival signaling in the compromisedtumor microenvironment found in mCRPC.

Finally, we also confirm the specificity of our results using specific inhibitors either for S100-A9 (Tasquinimod and Paquinimod) or EMMPRIN (blocking antibody, -clon/UM-8D6-)...This work describes for the first time a new survival/proliferation axis initiated by S100-A9/EMMPRIN interaction, which appears to be active in CLL patients during disease progression. Overall, our results raise new questions about the role of inflammation during CLL evolution and propose new targets to be explored within the heterogeneous biological and clinical scenario of CLL.

Paquinimod (PaQ) and Tasquinimod (TasQ) were administered at a dosage of 25 mg/Kg in drinking water ad libitum for 4 weeks... Genetic and pharmacological targeting of S100-A9 impairs CLL cell growth in vivo, probably through a MAPK pathway-dependent mechanism. This data demonstrates for the first time the significance of targeting S100-A9 as a novel therapeutic approach in CLL.

Tasquinimod upregulated the Nur77/Bcl-2 pathway to induce apoptosis in SKOV3/DDP cells and enhanced the anti-tumor effect of DDP in SKOV3/DDP xenografts. Therefore, tasquinimod can be expected to find clinical applications in enhancing DDP resistance.

We demonstrate that alarmins need to be secreted and that transcriptional overexpression by lentiviral overexpression and genetic hematopoietic knock-in of S100A8/S100A9 do not lead to myeloproliferation or to an MPN phenotype as S100A8/S100A9 levels do not increase. The S100A8/S100A9 heterodimer levels determined by ELISA correlate with the MPN severity in murine models but also in large cohorts of patient samples. As a nextstep, we will answer whether alarmins can act not only as a biomarker for progression but also for tasquinimod response in a clinical trial (tasqForce MPN), which will be started by the end of the year (PIs: P. te Boekhorst, M. Crysandt, Scientific PI: R. Schneider).

In vivo, knockdown of HDAC4 or treatment with small molecule inhibitor Tasquinimod targeting HDAC4 could significantly inhibit the proliferation and metastasis of NPC by upregulating LHPP. In conclusion, our finding demonstrated that HDAC4/LHPP signal axis promotes the proliferation and metastasis of NPC through upregulating TYK2-STAT1 phosphorylation activation. This research will provide novel evidence and intervention targets for NPC metastasis.

We are conducting a phase 1 trial (NCT04405167) of tasq as a single agent and in combination with ixazomib (ixa), lenalidomide (len), and dexamethasone (dex) (IRd) in pts with RRMM. We enrolled pts with RRMM refractory to, intolerant of, or with contraindication to len, pomalidomide (pom), bortezomib, carfilzomib (cfz), and a CD38 monoclonal antibody... Tasquinimod, an S100A9 inhibitor, is well tolerated in pts with RRMM as a single-agent and in combination with IRd, with a single-agent MTD of 1 mg daily after a 1-week dose escalation. Tasq has anti-myeloma activity in combination with IRd, as evidenced by a partial response in a patient previously refractory to Imid/PI combination therapy. Enrollment continues to tasq with IRd at dose level 2.

Taken together, we develop an IMS system and identify an immune tolerant C3 subtype that exhibits the poorest prognosis. A multiomics-guided combination strategy by PD-1 blockade and tasquinimod improves responses to immunotherapy by depleting S100A9 macrophages in vivo.

Specifically, we discovered a novel role of S100A8/S100A9, the most abundant proteins produced by neutrophils and monocytes, in regulation of myeloma progression via promotion of the megakaryocyte expansion and angiogenesis. Tasquinimod, an inhibitor of S100A9, has potent antimyeloma effects as a single agent and in combination with lenalidomide and with proteasome inhibitors.

Our study provides novel insights in the dual therapeutic effects of the immunomodulator tasquinimod and fosters its evaluation in combination therapy trials for MM patients.

The novel small molecular drug Tasquinimod (TASQ, Active Biotech) is a S100A9 inhibitor and has demonstrated antitumor and immunomodulatory properties in a broad range of solid tumors; however, little is known about its effects in myeloid malignancies...In conclusion, CD271+ MSCs play a crucial role in the inflammatory MDS BMME. The inhibition by TASQ efficiently blocks adipogenic differentiation and secretion of pro-inflammatory cytokines, thereby modulating the MSC energetic profile and enhancing their potential to support hematopoiesis in vitro.

Our results showed that blocking the S100A9-TLR4 interaction using tasquinimod could inactivate the NF-κB pathway and inhibit the growth of CTCL tumor cells, and trigger cell apoptosis. Collectively, our study revealed a landscape of immunosuppressive TME mediated by interactions between malignant T cells and myeloid cells, and provided novel targets and potential treatment strategies for advanced CTCL patients.

In co-cultures with HSPCs, we observed a decreased number of cobblestone area forming cells (CAF-C) as well as reduced numbers of colonies (CFU) in a subsequent clonogenic assay, indicating a disturbed hematopoietic support by S100A9 treated MSCs, which could be restored by TASQ pre-treatment. Conclusion We provide evidence that TASQ mitigates the pathological inflammasome activation in the myelodysplastic BM niche in vitro by inhibition of the S100A9-mediated TLR4 signalling as well as its effects on NF-kB-p65 transcription and PD-L1 expression, resulting in improved hematopoietic support by MSCs, which suggests a beneficial effect in cytopenic MDS patients.

We demonstrate that Tasquinimod-loading of this dopamine-modified pH sensitive hydrogel is more effective than Tasquinimod alone for inhibiting the proliferation of KRAS mutant lung cancer cells. Combination of conventional drugs with hydrogels may thus provide a new treatment modality for lung cancer.

Conclusion In summary, we provide evidence that the pathological inflammasome activation in the myelodysplastic bone marrow can be rescued by TASQ at least in part by inhibition of the S100A9 mediated TLR4 downstream signalling including NF-kB-p65 transcription and PD-L1 expression. These effects result in an improved hematopoietic support by MSCs, suggesting a potential efficacy to improve cytopenia in low-risk MDS patients.

Moreover, it stimulates osteogenesis in vivo . Taken together, all these data provide evidence for the therapeutic benefits of TasQ as an anti-MM therapy for patients.

We also showed that the HDAC4 inhibitor tasquinimod suppresses tumor growth in NPC. Thus, HDAC4 may be a potential diagnostic marker and therapeutic target in patients with NPC.

In pre-clinical models of MM, TASQ has significant anti-tumor effects as a single agent and in combination with bortezomib, a proteasome inhibitor (PI) and lenalidomide, an immunomodulator (IMiD) (Lin C, et al...Part B combines TASQ with standard-dose IRd: 28-day cycles of ixazomib 4 mg on days 1, 8, and 15, lenalidomide 25 mg on days 1-21, and dexamethasone 40 mg on days 1, 8, 15, and 22...Key secondary endpoints include toxicity (treatment-emergent grade 3/4 adverse events using the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 5), preliminary antimyeloma activity (using the response criteria of the International Myeloma Working Group), changes in the BM microenvironment, and systemic TASQ exposure during therapy with single-agent TASQ and during therapy with TASQ in combination with IRd. These results will determine whether TASQ, alone or combined with standard anti-MM therapy, represents a promising novel treatment strategy in MM.