Our results revealed that Rux-PCL-NPs, which increased the efficacy of ruxolitinib, regulated apoptosis and the JAK2/STAT5 pathway.

P3, N=218, Completed, Children's Oncology Group | Active, not recruiting --> Completed

This study constructed a cellular senescence-related signature that could be used to predict HCC patients' responses to and prognosis after TACE treatment, aiding in the development of personalized treatment plans.

Lestaurtinib also displayed synergy when combined with cisplatin and olaparib, including in a model of PARPi resistance. In contrast, the most well-known JAK/STAT inhibitor, ruxolitinib, lacked antineoplastic activity against all ovarian cancer cell lines and PDX models tested...Taken together, these findings indicate that lestaurtinib, and other treatments that converge on JAK/STAT signaling, are worthy of further pre-clinical and clinical exploration for the treatment of highly aggressive and advanced forms of ovarian cancer. Lestaurtinib is a novel inhibitor of ovarian cancer, including chemotherapy- and PARPi-resistant models, that acts through robust inhibition of the JAK/STAT pathway and synergizes with standard-of-care agents at clinically relevant concentrations.

The prediction of IC50 based on bioinformatics method indicated DLBCL patients in the high-risk group were more sensitive to doxorubicin, IPA-3, lenalidomide, gemcitabine, and CEP.701, while patients in the low-risk group were sensitive to cisplatin and dasatinib. In accordance with the prediction, cytotoxicity assay in DLBCL cell lines suggested the higher sensitivity to doxorubicin and gemcitabine in the high-risk group and the higher sensitivity to dasatinib in the low-risk group in DLBCL. The ARG-based signature may provide a promising direction for prognosis prediction and treatment optimization for DLBCL patients.

Therefore, pimozide could be a promising agent to support TKI therapies in ponatinib resistance. This research would help to clarify the role of cytokines in ponatinib resistance and advance the development of new therapeutics to utilize the STAT5 inhibitor pimozide in combination with TKIs.

This work demonstrated that cytosolic ssDNA accumulation promotes breast cancer immunogenicity and may be a novel therapeutic strategy to improve the efficacy of ICB with minimal toxicities.

Additionally, western blot analysis of compound 5h revealed inhibition of STAT3 and STAT5 phosphorylation at Tyr705 and Tyr694, respectively, with only a slight decrease in the total expression of STAT3 and STAT5 proteins. And lastly, molecular docking research provided additional insight on the 5h binding mechanism in the STAT3 and STAT5 SH2 domains.

Of two CDX and six clinical samples of OS and Ewing's sarcoma, DST identified proteasome inhibitors (bortezomib, carfilzomib) and CEP-701 as potentially effective drugs in common. This unique method of in vitro drug testing using 3D-cell cultures is feasible in surgically resected tissues of metastatic malignant bone tumors.

P3, N=218, Active, not recruiting, Children's Oncology Group | Trial completion date: Jul 2023 --> Jun 2024

Lestaurtinib treatment reduces tumor growth and increases mice survival. Our data indicate that Lestaurtinib produces in MB cells poly-pharmacological effects extending beyond the inhibition of its validated targets, supporting the possibility of repositioning this drug for MB treatment.

Castrate-resistant prostate cancer (CRPC) is challenging to treat, despite improvements with next-generation anti-androgens such as enzalutamide, due to acquired resistance. While CCG-1423 had a more pronounced effect on the expression of cell cycle checkpoint proteins, CCG-257081 and lestaurtinib decreased proliferation also through induction of cellular senescence. In conclusion, we show that inhibition of an AR co-factors, namely SRF, provides a promising approach to overcoming resistance to AR inhibitors currently used in the clinic.

No abstract available

Pharmacogenetic prediction identified lestaurtinib as a potent drug for KIRC in the context of low IMMT expressions. This study highlights the potential of IMMT as a novel biomarker, prognostic predictor and pharmacogenetic predictor to inform the development of more personalized and effective cancer treatments. Additionally, it provides important insights into the role of IMMT in the mechanism underlying mitochondrial activity and angiogenesis development in KIRC, which suggests IMMT as a promising target for the development of new therapies.

Our results suggest that the mitochondrial-related risk model could be a reliable prognostic biomarker for personalized treatment of STAD patients.

Despite initial responses to first line platinum- and paclitaxel-based chemotherapies, >70% of ovarian cancers recur with increasingly resistant disease; and nearly all of these women die of their disease. Recently, the use of targeted therapies such as bevacizumab and PARP inhibitors have been shown to improve progression-free survival in a subset of patients...Through an unbiased drug screen, we have identified lestaurtinib as a potent inhibitor of many sensitive and resistant ovarian cancer cell lines and patient derived organoid models...Finally, combining lestuartinib with standard-of-care cisplatin or olaparib (a PARP inhibitor) is shown to be synergistic, indicating that pharmacological inhibition of JAK/STAT signaling has the potential to counteract drug resistance. Ongoing studies are aimed at further understanding the role of JAK/STAT signaling in ovarian cancer, elucidating the mechanistic processes by which STAT1/3 mediate progression of this disease, and identifying the most effective pharmacological strategies to study in possible future clinical trials.

BC cell lines resistant to paclitaxel (PTX) and cis-diamminedichloro-platinum (DDP) were prepared...miR-182 inhibited NLRP3. Overall, Stat5 bound to the promoter region of miR-182 to promote miR-182 expression and inhibit NLRP3 transcription, thereby suppressing pyroptosis and enhancing CR of BC cells.

Down-regulation of Myb mediates Stat5b-KD-induced inhibition of proliferation and induction of apoptosis in GSCs. This may represent a promising novel therapeutic strategy against glioblastoma.

AK-2292 effectively induces STAT5 depletion in normal mouse tissues and human chronic myeloid leukemia (CML) xenograft tissues and achieves tumor regression in two CML xenograft mouse models at well-tolerated dose schedules. AK-2292 is not only a powerful research tool with which to investigate the biology of STAT5 and the therapeutic potential of selective STAT5 protein depletion and inhibition but also a promising lead compound toward ultimate development of a STAT5-targeted therapy.

In A375 cells, reductive stress induced UPR activation and promoted TrkAIII expression and, in transient transfectants, promoted TrkAIII and Akt phosphorylation, enhancing resistance to reductive stress-induced death, which was prevented by lestaurtinib and entrectinib. In contrast, fully spliced TrkA was dysfunctional in A375 cells. The data identify fully spliced TrkA dysfunction as a novel mechanism for reducing melanoma suppression, support a causal relationship between reductive stress, UPR activation, alternative TrkAIII splicing and TrkAIII activation and characterise a targetable oncogenic pro-survival role for TrkAIII in CMM.

It is suggested that STAT1, STAT4, and STAT6 may be potential targets for the proper treatment of ovarian cancer. STAT5A and P-STAT5A, biomarkers identified in ovarian cancer, may offer new perspectives for predicting prognosis and assessing therapeutic effects.

Collectively, these findings highlight the effect of imatinib plus ISRIB in the eradication of leukemic cells resistant to TKIs and suggest potential clinical benefits for leukemia patients with TKI resistance related to RAS/RAF/MAPK or STAT5 signaling. We propose that personalized treatment based on the genetic selection of patients carrying mutations that cause overactivation of the targeted pathways and therefore make their sensitivity to such treatment probable should be considered as a possible future direction in leukemia treatment.

In response to anticancer drugs, patients in the TIS-high group exhibited enhanced susceptibility to several conventional chemotherapeutic agents (5-fluorouracil, docetaxel, doxorubicin, gemcitabine, and etoposide), as well as several inhibitors of pathways involved in cellular senescence (cell-cycle inhibitors, bromodomain and extraterminal domain family (BET) inhibitors, PI3K-AKT pathway inhibitors, and multikinase inhibitors). Additionally, four putative drugs (palbociclib, JAK3 inhibitor VI, floxuridine, and lestaurtinib) were identified as potential compounds for patients in the TIS-high group...Our study provides comprehensive clues demonstrating the role of novel TIS in predicting HCC prognosis, immunotherapeutic response, and candidate drugs. This work highlights the significance of tumorigenesis- and immune infiltration-related cellular senescence in cancer therapy.

Given that these mechanisms are also relevant in FLT3-ITD AML, we investigated the efficacy of CFZ in targeting FLT3-ITD mutant AML cells by itself and in combination with TKI.Method : FLT3-ITD mutant MV4-11 and MOLM13 cell lines and primary AML CD34+ cells were treated with CFZ as a single agent or in combination with FLT3 TKIs, Quizartinib (AC220) and Giltertinib followed by determination of cell cytotoxicity using CellTiter-Glo, apoptosis using Annexin V labeling, and differentiation using cell surface markers. We are currently investigating the effect of CFZ alone and with TKI in a large panel of FLT3-ITD AML samples and analyzing the role of STAT5 inhibition and increased oxidative stress in mediating the observed effects.Conclusion : Our studies indicate that the FDA-approved anti-leprosy agent CFZ demonstrates activity against FLT3-ITD+ AML stem and progenitor cells and significantly enhances FLT3 TKI targeting of these populations. These results support further investigation of CFZ as a potential therapeutic agent in FLT3-ITD+ AML.

Our data suggest NIK-mediated inhibitory JAK2 phosphorylation at serine 633 that might be amenable for future therapeutic interventions in patients.

In the dose-escalation phase of the study, RVU120 shows clinical activity in AML and HR-MDS with a tolerable safety profile. Relevant target inhibition is achieved at the current dose level and is expected to increase at higher doses. Currently available data warrant further testing of RVU120 in hematologic disorders, and dose escalation in the Phase Ib study continues.

FLT3 inhibitors are divided into first generation multi-kinase inhibitors (such as sorafenib, lestaurtinib, midostaurin) and next generation inhibitors (such as quizartinib, crenolanib, gilteritinib) or based on their specificity of FLT3 inhibition [type I inhibitors (midostaurin, gilteritinib) inhibit FLT3 ITD and TKD mutations whereas type II inhibitors (sorafenib, quizartinib) have only FLT3 ITD activity]. Type II FLT3 TKIs had worse cardiac safety profile in our cohort and an increased risk of cardiac toxicity, particularly in patients with prior reduced ejection fraction or A-fib. A careful cardiac history and management of predisposing conditions to serious cardiac events could help improve drug tolerance, morbidity, and mortality. Further studies are required to elucidate the precise mechanisms of increased incidence of cardiac arrythmias and ways to mitigate them.

Clear hallmarks of erythroid differentiation were further identified in several patients by specific changes in surface markers. These patients achieved meaningful clinical responses such as reduction of blasts and transfusion independence, respectively.

Patients with advanced neuroblastoma (NB) receive multimodal clinical therapy, including the potent anthracycline chemotherapy drug doxorubicin (Dox). The inhibitory effects of lestaurtinib, entrectinib, crizotinib, and LY294002 on the Dox-induced TrkAIII and Akt phosphorylation and resistance confirm roles for TrkAIII and IP3-K consistent with Dox-induced, TrkAIII-mediated pro-survival IP3K/Akt signaling. This mechanism has the potential to select resistant dormant TrkAIII-expressing NB cells, supporting the use of Trk inhibitors during Dox therapy in TrkAIII-expressing NBs.

In patient-derived xenograft (PDX) models of IDH1-mutated AML, combination treatment with ivosidenib and the STAT5 inhibitor pimozide was superior to each agent alone in inducing differentiation in leukemic cells without compromising normal hematopoiesis. These findings demonstrate that STAT5 is a critical mediator of resistance to IDH inhibitors and provide the rationale for combining STAT5 and IDH inhibitors in the treatment of IDH-mutated AML.

STAT5b inhibition neither altered the cell proliferation nor reduced the clonogenic proliferative potency of GBM cells, and did not sensitize them to the cytotoxic effect of ionizing radiation and temozolomide in vitro...In conclusion, STAT5b is frequently activated in GBM and correlates inversely with patient survival. It does not contribute to the growth and resistance of these tumors, and is thus rather a potential prognostic marker than a therapeutic target in these tumors.

We targeted the key downstream IL2R-intermediate JAK 3 using a clinically relevant highly specific JAK3-inhibitor (JAK3i; PF-06651600) that potently inhibited STAT5-phosphorylation in vitro...Low-dose JAK3i combined with cellular and peptide vaccine strategies further decreased tumor load compared to both monotherapies alone. Collectively, these results identify JAK3 as a novel and promising target for combination immunotherapy.

As a result, AToMI analysis revealed AKT and mitochondrial pyruvate dehydrogenase kinase PDK1 and PDK4 as kinase targets of staurosporine derivatives UCN-01, CEP-701, and K252a that synergized with PP2A activation across heterogeneous glioblastoma cells. Based on these proof-of-principle results, we propose that the application and further development of AToMI for clinically applicable multi-kinase inhibitors could provide significant benefits in overcoming the challenge of lack of knowledge of the target specificity of multi-kinase inhibitors.

The selected genes were associated with drug sensitivity/resistance to 10 commonly used NSCLC therapeutic regimens. Lestaurtinib was discovered as a potential repositioning drug for treating NSCLC.

The combination of crenolanib and sorafenib was tolerable with antileukemic activities and rare emergence of FLT3-TKD mutations, which warrants further investigation.

IL-2/STAT5-mediated expansion of CD26+Tregs contributes to a poor clinical outcome in SMZL and may represent a therapeutic opportunity in this disease.