gandotinib (LY 2784544) / Eli Lilly - LARVOL DELTA

TIMP-2 Modulates 5-Fu Resistance in Colorectal Cancer Through Regulating JAK-STAT Signalling Pathway. (PubMed, J Cell Mol Med) - "The main reason for the failure of chemotherapy therapies based on 5-Fluorouracil (5-Fu) is the development of resistance to 5-Fu in cancer patients, particularly those with colorectal cancer...Moreover, anti-TIMP-2 antibody or small molecule drug LY2784544 targeting the JAK-STAT signalling pathway can effectively reverse the resistance of CRC cells to 5-Fu. It is exactly TIMP-2 that mediates the resistance of CRC to 5-Fu through the JAK-STAT signalling pathway. Targeting drugs for TIMP-2 or the JAK-STAT signalling pathway are expected to be opportunities to reverse 5-Fu resistance in CRC."

Journal • Colorectal Cancer • Oncology • Solid Tumor • TIMP2

JAK2 Inhibitors Induce Apoptosis and Enhance the Efficacy of KIT-Targeting Tyrosine Kinase Inhibitors In Human KIT-Mutant Mast Cells (AAAAI-WAO 2025) - "Results Among various JAK1/2, JAK1 and JAK2 inhibitors, the two JAK2 inhibitors fedratinib and gandotinib were found to induce apoptosis and to decrease viability and proliferation in the human KIT D816V-mutant MC lines HMC-1.2 and ROSA KITD816V . In contrast, the JAK1/2 inhibitors ruxolitinib and baricitinib and the JAK1 inhibitors upadacitinib and abrocitinib failed to affect MC functions. Combinatorial treatment with JAK2 inhibitors and the two KITD816V-targeting TKI avapritinib and midostaurin was more effective than treatment with TKI alone...We also demonstrate that JAK2 inhibitors act synergistically with TKI in inducing apoptosis of MC. These findings suggest exploring JAK2 inhibitors as novel treatment option in mastocytosis."

Clinical

Fedratinib and gandotinib induce apoptosis and enhance the efficacy of tyrosine kinase inhibitors in human mast cells. (PubMed, Am J Cancer Res) - "In contrast, ruxolitinib, baricitinib, upadacitinib and abrocitinib failed to affect MC functions. Combinatorial treatment with fedratinib, gandotinib and the two TKI avapritinib and midostaurin was more effective than treatment with TKI alone...These results indicate that fedratinib and gandotinib, but not the other JAK inhibitors used in this study, can suppress viability and induce apoptosis in KIT D816V-mutant and KIT WT MC and increase effects of TKI. These findings suggest to explore fedratinib and gandotinib as novel treatment option in mastocytosis."

Journal

A Study of LY2784544 in Participants With Myeloproliferative Neoplasms (clinicaltrials.gov) - P2 | N=110 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Dec 2024 ➔ Dec 2025

Trial completion date • Hematological Disorders • Hematological Malignancies • Myeloproliferative Neoplasm • Oncology • JAK2

Identifying Novel Drug Vulnerabilities in Specified Molecular Subsets of Chronic Lymphocytic Leukemia (ASH 2024) - "Supporting the clinical and biological relevance of our results, venetoclax and ibrutinib were highly effective across CLL, nutlin-3 was ineffective in p53 mutant CLL. Novel drugs with the greatest pan-CLL effects include abexinostat, navitoclax, cerdulatinib, gandotinib and nutlin-3...We found many such associations including high sensitivity of IGHV-mutated CLL (M-CLL) to nutlin-3, IGHV-unmutated CLL (U-CLL) to Onalespib (MWU test, q<0.1), the intermediate epigenetic subtype (i-CLL) to Rapamycin (ANOVA, q<0.1). RNA subtype EC-m4 (TNF- and IFN- high M-CLLs) was specifically sensitive to nutlin-3 and onalespib; and EC-m2 (trisomy 12 enriched M-CLLs) demonstrated resistance to venetoclax and sensitivity to abexinostat (MWU test, p<0.05). Response to lenalidomide was associated with trisomy 12 (MWU, p=0.002)...In summary, we present an experimental strategy to rapidly prioritize novel treatments for CLL patients and a computational framework to inform precision..."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • BCL2 • CD5 • IGH • TP53

Enhancing Quality of Life in Myeloproliferative Neoplasms: Insights from Janus Kinase Inhibitors-a Comprehensive Review and Meta-Analysis (ASH 2024) - "Most patients had MF 70.6%, followed by PV 17.6% (3/17), while ruxolitinib was the most commonly used JAKi 41.2%, followed by Momelotinib 23.5%, Pacritinib 11.7%, Fedratinib 17.6%, and Gandotinib 6%. Anemia 31%, diarrhea 29.5%, thrombocytopenia 21.6%, and nausea 13.7% were the most commonly reported side effects, with a mortality rate of 10.7%.ConclusionsThis analysis shows symptomatic improvement as well as better QoL with JAKi in MPN patients. However, further randomized studies are needed to better delineate these findings and establish guidelines."

HEOR • Retrospective data • Review • Anemia • Anorexia • CNS Disorders • Fatigue • Hematological Disorders • Insomnia • Myeloproliferative Neoplasm • Oncology • Sleep Disorder • Thrombocytopenia

UNRAVELING JAK/STAT3 ACTIVATION PATTERNS IN DERMATOMYOSITIS: IMPLICATIONS FOR UNDERSTANDING THE IFN-I SIGNALING PATHWAYS (EULAR 2024) - "Separated peripheral blood mononuclear cells (PMBC) were evaluated for phosphorylated STAT3 levels by fluorescence-activated cell sorting (FACS) analysis, both in CD4 pos and CD14 pos cells, before and after incubation in separated cultures with half-maximal inhibitory concentration (IC50) of abrocitinib, gandotinib, peficitinib, or deucravacitinib (Biovision Inc. The JAK/STAT3 pathway is significantly activated in patients affected by DM. Specifically, DM patients presented a high activation of pSTAT3 that was modified mainly by direct inhibition of JAK-1 and especially TYK-2 in both lymphocytes and monocytes, thus modulating IFN-I effects. Our findings, to be confirmed in larger studies also evaluating phosphorylation of other STATs, pave the way for the clinical use of JAK-inhibitors in DM patients [3], in particular acting on JAK-1/TYK-2 such as the new brepocitinib."

Dermatomyositis • Immunology • Myositis • CD14 • JAK1 • JAK2 • JAK3 • STAT3 • TYK2

A Study of LY2784544 in Participants With Myeloproliferative Neoplasms (clinicaltrials.gov) - P2 | N=110 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Dec 2023 ➔ Dec 2024

Trial completion date • Hematological Disorders • Hematological Malignancies • Myeloproliferative Neoplasm • Oncology • JAK2

Novel janus-kinase (JAK) inhibitors in myelofibrosis. (PubMed, Expert Opin Investig Drugs) - "This review includes the current status of JAKi treatment for myelofibrosis, mainly focusing on investigational JAKis; jaktinib, lestaurtinib, itacitinib, gandotinib, BMS-911543, ilginatinib, TQ05105, and flonoltinib maleate...In patients with myelofibrosis, momelotinib was effective in treating anemia, whereas jaktinib was effective in both anemia and Total Symptom Score (TSS)...The increasing variety of JAKis will allow for more personalized treatment options for myelofibrosis in the future. The potential impact on disease progression, molecular responses, and the duration of this response will become important parameters for future evaluations of these drugs."

Journal • Review • Hematological Disorders • Myelofibrosis • Myeloproliferative Neoplasm • Oncology

Kv1.3 mediates ox-LDL-induced vascular smooth muscle cell proliferation through JAK2/STAT3 signaling pathway. (PubMed, Arch Biochem Biophys) - "Treatment with the JAK2 inhibitor LY2784544 also prevented the increase in VSMCs proliferation treated with ox-LDL. Our findings demonstrated that Kv1.3 promoted proliferation of VSMCs treated with ox-LDL, and that this effect might be mediated through activation of the JAK2/STAT3 signaling pathway."

Journal • Dyslipidemia • CCNB1 • CCND1

A Study of LY2784544 in Participants With Myeloproliferative Neoplasms (clinicaltrials.gov) - P2 | N=110 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Dec 2022 ➔ Dec 2023

Trial completion date • Hematological Disorders • Hematological Malignancies • Myeloproliferative Neoplasm • Oncology • JAK2

Integrating High-Throughput Dynamic BH3 Profiling and Molecular Phenotyping to Identify Therapeutic Vulnerabilities in CLL (ASH 2022) - "Despite recent advances in chronic lymphocytic leukemia (CLL) therapy, such as the use of targeted agents including, Bruton's tyrosine kinase (BTK) inhibitor ibrutinib and the potent BCL-2 antagonist venetoclax, this disease remains incurable for most patients, who are refractory or become resistant to the novel agents...Other drugs that demonstrated high priming included navitoclax (BCL-XL/BCL-2), nutlin-3 (MDM2), abexinostat (HDAC), gandotinib (JAK2), duvelisib (PI3K δ/γ), idelalisib (PI3Kδ) and cerdulatinib (SYK/JAK)...First, we found that IGHV-mutated CLLs (M-CLLs) became more primed to apoptosis than IGHV-unmutated CLLs (U-CLLs) across the panel of drugs (p<0.001, paired t-test) and significantly in response to fludarabine and umbralisib (FDR<0.1, t-test)...EC-i, associated with the intermediate methylation subtype of CLL, was the most resistant EC to ibrutinib but was very sensitive to navitoclax, more than to any other drug. Altogether, we present a..."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • BCL2L1 • CD19 • CD5 • IGH • IL10 • JAK2 • PIK3CD • SYK

Novel Drugs to Target JAK2 Rearrangements in Pediatric Acute Lymphoblastic Leukemia (ASH 2022) - "After 48h monotherapy treatment by CHZ868, we detected decreased cell viability (20-75% at IC50), which increased in the combination with dexamethasone...Importantly, combination of BIBF1120 and CHZ868 showed a synergistic effect (-45%, at IC50)...Indeed, active caspase 3 increased after ruxolitinib and chloroquine (autophagy inhibitor) combination (+20% vs ruxolitinib alone, p<0.01)...Instead, AT9283 (p<0.001 vs LCLs), Fedratinib (p<0.01 vs LCLs) and Gandotinib (p<0.05 vs LCLs) were found to be potent, specific, and non-toxic JAK2 inhibitors. Additionally, this extended screening led us to identify drugs, not belonging to JAK inhibitors, specific and non-toxic for rearranged JAK2 cohort, such as Birinapant (Smac mimetic), JQ1 (BRD4 inhibitor), Fludarabine (Chemotherapy) among the others. CHZ868 is a promising drug for the treatment of JAK2 fusions. Further studies will focus on effective and specific novel drugs found to be highly effective and specific on..."

Clinical • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Pediatrics • ATF7IP • BRD4 • CASP3 • CD19 • CRLF2 • MME • P2RY8 • PAX5 • PDPK1 • STAT3 • STAT5 • ZEB2

Artificial-intelligence-driven consensus gene signatures for improving bladder cancer clinical outcomes identified by multi-center integration analysis. (PubMed, Mol Oncol) - "Patients with low AIGS scores were sensitive to immunotherapy, whereas patients with high AIGS scores might benefit from seven potential therapeutics: BRD-K45681478, 1S,3R-RSL-3, RITA, U-0126, temsirolimus, MRS-1220, and LY2784544. Additionally, some mutations (TP53 and RB1), copy number variations (7p11.2), and a methylation-driven target were characterized by AIGS-related multi-omics alterations. Overall, AIGS provides an attractive platform to optimize decision-making and surveillance protocol for individual BLCA patients."

Clinical data • IO biomarker • Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • RB1 • TP53

Role of STAT3 in the initiation, progression, proliferation and metastasis of breast cancer and strategies to deliver JAK and STAT3 inhibitors. (PubMed, Life Sci) - "JAK and STAT3 are involved in various phases from initiation to metastasis, and targeting this pathway is a promising approach to inhibit the various stages of BC development and to prevent metastasis. A number of phytochemicals and synthetic and biological molecules have demonstrated potential inhibitory effects on JAK and STAT3, thereby paving the way for the development of better therapeutics against BC."

Journal • Review • Breast Cancer • Oncology • Solid Tumor

A Study of LY2784544 in Participants With Myeloproliferative Neoplasms (clinicaltrials.gov) - P2; N=110; Active, not recruiting; Sponsor: Eli Lilly and Company; Trial completion date: Dec 2021 ➔ Dec 2022

Clinical • Trial completion date • Hematological Disorders • Hematological Malignancies • Myeloproliferative Neoplasm • Oncology • JAK2

A Study of LY2784544 in Participants With Myeloproliferative Neoplasms (clinicaltrials.gov) - P2; N=110; Active, not recruiting; Sponsor: Eli Lilly and Company; Trial completion date: Dec 2020 ➔ Dec 2021

Trial completion date • Hematological Disorders • Hematological Malignancies • Myeloproliferative Neoplasm • Oncology • JAK2

A Study of LY2784544 in Participants With Myeloproliferative Neoplasms (clinicaltrials.gov) - P2; N=110; Active, not recruiting; Sponsor: Eli Lilly and Company; Trial completion date: Aug 2018 ➔ Dec 2019

Trial completion date • Biosimilar • Hematological Malignancies • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Polycythemia Vera

A Study in Myeloproliferative Disorders (clinicaltrials.gov) - P1; N=80; Active, not recruiting; Sponsor: Eli Lilly and Company; Trial completion date: Aug 2018 ➔ Dec 2019

Trial completion date • Acute Myelogenous Leukemia • Biosimilar • Fibrosis • Hematological Malignancies • Immunology • Myelodysplastic Syndrome • Myelofibrosis • Oncology • Polycythemia Vera • Venous Thromboembolism

JAK2 inhibition in JAK2-bearing leukemia cells enriches CD34 leukemic stem cells that are abolished by the telomerase inhibitor GRN163L. (PubMed, Biochem Biophys Res Commun) - "Several JAK2 inhibitors such as ruxolitinib and gandotinib (LY2784544) currently in clinical trials and, provide improvements in MPNs including myelofibrosis. JAK2 inhibitors thus cause enrichment of LSCs and are unlikely to cure MPN as a monotherapy. Simultaneously targeting JAK2V617F and KLF4 or telomerase may be a novel strategy for MPN therapy, which should be of significance both biologically and clinically."

Journal • Hematological Disorders • Hematological Malignancies • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • CD34 • JAK3 • KLF4

A Study of LY2784544 in Participants With Myeloproliferative Neoplasms (clinicaltrials.gov) - P2; N=110; Active, not recruiting; Sponsor: Eli Lilly and Company; Trial completion date: Dec 2019 ➔ Dec 2020

Clinical • Trial completion date • JAK2