linifanib (ABT-869) / AbbVie - LARVOL DELTA

Systematic elucidation and pharmacologic targeting on non-oncogene dependencies in imatinib-resistant gastrointestinal stromal tumor. (PubMed, bioRxiv) - "The top prediction, linifanib, induced marked tumor growth inhibition in both PDXs across a wide dose range, while selinexor was also effective compared to imatinib. We leveraged our network-based platforms, OncoTreat and OncoTarget , to characterize Master Regulators of imatinib-resistance in GIST and identify candidate MR-targeting drugs, an unmet clinical need. Top predicted drugs were successfully validated in cognate PDXs, thus providing a path for translation."

Journal • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Oncology • Sarcoma

Identification and expression analysis of long noncoding RNAs in response to infection with VHSV in rainbow trout. (PubMed, Comp Biochem Physiol Part D Genomics Proteomics) - "We identified pairs of DElncRNA-DEmRNA interactions, such as "TP63-MSTRG.62, IL10-MSTRG.9783, IL10-MSTRG.9784, TK1-MSTRG.22826, and GLI1-MSTRG.17881" as cis interactions, while DOCK10-MSTRG.30015, MSTRG.36357-LOC101268921, and MSTRG.34190-ENPP2 exhibited trans interactions...We also introduced quantitative trait loci (QTLs) associated with these lncRNAs, underscoring their potential regulatory roles in viral stress responses. Overall, our findings provide novel insights into the molecular mechanisms underlying viral infections and lncRNA-mediated host immune responses."

IO biomarker • Journal • Hematological Disorders • Infectious Disease • ENPP2 • GLI1 • IL10 • TP63

Apoptotic effect of linifanib on human ovarian cancer OVCAR3 cell line. (PubMed, Res Pharm Sci) - "Notably, treatment with linifanib led to the inhibition of phosphorylated Akt at Ser473, accompanied by the activation of FOXO3. Taken together, these findings indicate that linifanib suppresses the proliferation of human ovarian cancer OVCAR3 cells, highlighting its potential as a therapeutic candidate for ovarian cancer treatment."

Journal • Preclinical • Oncology • Ovarian Cancer • Solid Tumor

Identification of RIPK1 as a novel target for angiogenesis regulation based on ABT-869 conjugated photoaffinity probes. (PubMed, Bioorg Chem) - "Meanwhile, RIPK1 was identified as a potential angiogenic target of ABT-869 and its activity was further verified. The results of this study are expected to provide a new target for angiogenesis regulation and lay a foundation for the development of novel angiogenesis regulation drugs."

Journal • Oncology • KDR • RIPK1

Exploration of molecular targets and drug repurposing approaches for therapeutic advancement in primary central nervous system lymphoma (Sarcoma-RC 2025) - "Conclusions Atorvastatin, Propranolol, Linifanib, and Ponatinib are potential candidates for drug repurposing. Legal entity responsible for the study The authors. Funding Has not received any funding."

CNS Lymphoma • CNS Tumor • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Primary Central Nervous System Lymphoma • CCL19 • CD22 • CD5 • FLT3 • IGLL5

Linifanib alone and in combination with metronomic chemotherapy is active on cutaneous T-cell lymphoma cells by targeting the AKT/mTOR signaling pathway. (PubMed, Invest New Drugs) - "Our aim was to evaluate the in vitro antitumor activity of the multi-kinase inhibitor linifanib, either alone or in combination with metronomic vinorelbine (mVNR) or etoposide (mETO), on CTCL cells. Linifanib significantly increased the VNR and ETO intracellular concentrations in HH cells, evaluated by UPLC-HRMS technology, and strongly reduced the ABCB1 and ABCG2 gene expression in HH. In conclusion, we reported a striking antitumor activity of daily, long-term linifanib and a clear synergistic effect when administered in combination with mCHEMO on CTCL cells, as a promising base for future clinical approaches in T-cell lymphomas."

Journal • Cutaneous T-cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • ABCB1 • ABCG2

Phase I-IV Drug Trials on Hepatocellular Carcinoma in Asian Populations: A Systematic Review of Ten Years of Studies. (PubMed, Int J Mol Sci) - "Eighteen studies compared the efficacy of sorafenib with that of other drugs, including lenvatinib, cabozantinib, tepotinib, tigatuzumab, linifanib, erlotinib, resminostat, brivanib, tislelizumab, selumetinib, and refametinib. This study provides comprehensive insights into effective treatment interventions for HCC in Asian populations. The overall assessment indicates that sorafenib, used alone or in combination with atezolizumab and bevacizumab, has been the first treatment choice in the past decade to achieve better outcomes in patients with HCC in Asian populations."

Journal • Review • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • Transplantation

Surface-engineered mesenchymal stem cell for refractory asthma therapy: Reversing airway remodeling. (PubMed, J Control Release) - "Herein, we constructed surface-engineered mesenchymal stem cells (MSCs/PVLA) via the bioconjugation of MSCs and reactive oxygen species-responsive polymeric micelles loaded with vactosertib (VST) and linifanib (LFN) for treating refractory asthma through reversing airway remodeling. Meanwhile, MSCs reduced inflammatory cell infiltration and cytokine secretion to regulate the pathological microenvironment. Our results suggested that MSCs/PVLA could serve as a promising candidate to prevent disease exacerbations and treat refractory asthma."

Journal • Asthma • Fibrosis • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases

Development and Validation of a New Eco-Friendly HPLC-PDA Bioanalytical Method for Studying Pharmacokinetics of Seliciclib. (PubMed, Medicina (Kaunas)) - "Materials and The chromatographic resolution of SEL and linifanib as an internal standard (IS) was achieved on Zorbax Eclipse Plus C18 HPLC column (150 mm length × 4.6 mm internal diameter, 5 µm particle size), with a mobile phase composed of acetonitrile-ammonium acetate, pH 5 (50:50, v/v) at a flow rate of 1.0 mL min-1. The proposed method stands as a valuable tool for studying SELs for pharmacokinetics in humans. It aids in achieving the targeted therapeutic advantages and safety of treatment with SEL by optimizing the SEL dosage and dosing schedule."

Journal • PK/PD data • CNS Disorders • Infectious Disease • Nephrology • Oncology

Development and Validation of a Comprehensive Prognostic and Depression Risk Index for Gastric Adenocarcinoma. (PubMed, Int J Mol Sci) - "With the Genomics of Drug Sensitivity in Cancer database, we found that the gastric adenocarcinoma patients with high risk-score may be sensitive to Pazopanib, XMD8.85, Midostaurin, HG.6.64.1, Elesclomol, Linifanib, AP.24534, Roscovitine, Cytarabine, and Axitinib. The gene signature consisting of the NDUFA4L2, ANKRD45, and AQP3 genes is a promising biomarker to distinguish the prognosis, the molecular and immune characteristics, the depressive risk, and the therapy candidates for gastric adenocarcinoma patients."

Biomarker • Journal • CNS Disorders • Depression • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Major Depressive Disorder • Mood Disorders • Oncology • Psychiatry • Solid Tumor • NDUFA4L2

Novel prognostic signature for hepatocellular carcinoma using a comprehensive machine learning framework to predict prognosis and guide treatment. (PubMed, Front Immunol) - "Linifanib was a potential drug for high-risk populations...A nomogram provided a clinical practice reference. We constructed an HPRGS for HCC, which can accurately predict OS and guide the treatment decisions for patients with HCC."

Biomarker • IO biomarker • Journal • Machine learning • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • ECT2 • SOCS2

Rational Design of Targeted Gold Nanoclusters with High Affinity to Integrin αvβ3 for Combination Cancer Therapy. (PubMed, Bioconjug Chem) - "The AuNCs were functionalized with anticancer drugs (5-fluorouracil or signaling pathways inhibitors, such as capivasertib, linifanib, tanespimycin, and taselisib) and integrin-targeting peptides (RGD4C or QS13), and we identified the optimal mixed ligand layer to enhance their binding affinity to the cancer cell receptor. Our simulations also revealed that Mn2+ cations are crucial for stabilizing the αvβ3-AuNC complex. These findings demonstrate the potential of carefully designing the surface composition of TNDDSs to optimize their target affinity and specificity."

Journal • Oncology

Quantification and analyses of seven tyrosine kinase inhibitors targeting hepatocellular carcinoma in human plasma by QuEChERS and UPLC-MS/MS. (PubMed, J Chromatogr B Analyt Technol Biomed Life Sci) - "Herein, seven TKIs, namely sorafenib tosylate, axitinib, erlotinib, cediranib, brivanib, linifanib, and golvatinib, were successfully analyzed in human plasma by following a quick, easy, cheap, effective, rugged, and safe (QuEChERS) pretreatment method combined with ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS)...In this study, dovitinib was used as the internal standard...The intraday and interday accuracy values ranged from -6.12 % to 7.31 %, with a precision (RSD) of ≤ 10.57 %. The method was rapid, accurate, specific, simple, reproducible, and suitable for the quantitative determination of the seven TKIs in human plasma."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

A Multistep In Silico Approach Identifies Potential Glioblastoma Drug Candidates via Inclusive Molecular Targeting of Glioblastoma Stem Cells. (PubMed, Mol Neurobiol) - "The growth inhibitory effect of these final shortlisted compounds was examined on a panel of GBM cell lines and compared with temozolomide through the drug sensitivity EC50 values and AUC from the PRISM Repurposing Secondary Screen, and the IC50 values were obtained from GDSC portal...Our results show GSK-2126458/omipalisib, linifanib, drospirenone, eltrombopag, nilotinib, and PD198306 as candidate drugs which can be further evaluated for their anti-tumor potential against GBM. Through this work, we identified repurposed candidate therapeutics against GBM utilizing a GSC inclusive targeting approach, which demonstrated high in vitro efficacy and can prospectively evade drug resistance. These drugs have the potential to be developed as individual or combination therapy to improve GBM outcomes."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • PSMA2 • PSMC2 • RPA3

A ten long noncoding RNA-based prognostic risk model construction and mechanism study in the basal-like immune-suppressed subtype of triple-negative breast cancer. (PubMed, Transl Cancer Res) - "In addition, drug sensitivity analysis identified 3 compounds, including BMS-754807, cytochalasin b, and linifanib, that could have a potential therapeutic effect on patients with the BLIS subtype. The risk prognosis model showed good prognostic value for the BLIS subtype patients, and the ten lncRNAs may be potential therapeutic targets."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AR • DIO3OS • FZD10 • SPARCL1

Novel Targets in HCC (APPLE 2023) - "This includes tyrosine kinase inhibitors (e.g., sorafenib, Lenvatinib, regorafenib, cabozantinib), and immune checkpoint inhibitor-based combination therapies (e.g., atezolizumab plus bevacizumab, tremelimumab plus durvalumab). Most effective therapies targe angiogenesis, but notable, other potent antiangiogenics have shown limited efficacy or significant toxicity in HCC (e.g., linifanib, sunitinib)...The potential benefit of targeting oncogene addiction events in HCC (e.g., FGF19 overexpression) has been tested in early phase clinical trials. In summary, new targets are being explored, but several issues remain to be addressed, such as the impact of intratumoral heterogeneity and clonal evolution in the future of target development for HCC."

IO biomarker • CNS Disorders • Fibrosis • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immune Modulation • Immunology • Oncology • Psychiatry • Solid Tumor • FGF19

Optimal First-Line Therapy for HCC (APPLE 2023) - "The agents which failed to prove their activity in HCC were sunitinib, linifanib, brivanib, nintedanib in the first-line treatment and axitinib, ramucirumab, brivanib, erlotinib, everolimus, tivantinib, ADI-PEG20 in the second-line treatment after sorafenib failure. Recently, lenvatinib, another angiogenesis inhibitor, showed non-inferior overall survival in the 1st-line treatment compared with sorafenib in the REFLECT trial...For the patients who failed sorafenib treatment, regorafenib and cabozantinib, mainly angiogenesis inhibitors overcame placebo control in RESORCE and CELESTIAL trials. In addition, nivolumab showed meaningful results for HCC in phase II checkmate 040 trial...However, the current effects of systemic treatments for HCC are far from satisfaction as ever. By looking at the trials currently conducted for HCC, we are discussing ways to improve the prognosis of HCC patients."

Clinical • IO biomarker • Gastrointestinal Cancer • Hepatocellular Cancer • Immune Modulation • Oncology • Solid Tumor • BRAF • KDR • PDGFRB

Identification of potential RapJ hits as sporulation pathway inducer candidates in Bacillus coagulans via structure-based virtual screening and molecular dynamics simulation studies. (PubMed, J Mol Model) - "Based on the binding compartment, through molecular docking, MD simulation, hydrogen bonds, and binding-free energy calculations, a series of novel hits against RapJ named tandutinib, infigratinib, sitravatinib, linifanib, epertinib, surufatinib, and acarbose were identified. Consequently, acarbose is probably the most suitable hit for RapJ enzyme. Notably, experimental validation is crucial to confirm the effectiveness of the selected ligands."

Journal

Inactive mutated VEGFR2 promotes melanoma growth via heterodimerization with wild-type receptor (EACR 2023) - "Also, the expression of VEGFR2R1032Q increases melanoma cell resistance to the VEGFR2-targeted TKi linifanib and vatalanib.Remarkably the R1032Q substitution of VEGFR2 occurs in a hot-spot residue of the kinase domain which is recurrently mutated in many other receptor tyrosine kinases (RTKs), including EGFR, KIT, FLT3, FLT4 and PDGFRA, among others. Therefore, our results anticipate the effects and druggability of all other uncharacterized mutations corresponding to the substitution R1032Q of VEGFR2.ConclusionOur data reveal a possible ligand-independent inter-receptor kinase activation of VEGFR2/VEGFR2R1032Q heterodimers which drives tumor progression. This novel mechanism of activation of VEGFR2, which may be shared by other RTKs, could be exploited to develop new therapeutic approaches to treat tumors harboring the VEGFR2R1032Q mutation and possibly all other corresponding ones."

Melanoma • Oncology • Solid Tumor • FLT3 • FLT4 • KDR • PDGFRA

PHDs-seq: a large-scale phenotypic screening method for drug discovery through parallel multi-readout quantification. (PubMed, Cell Regen) - "Notably, the potent ATP-competitive VEGFR/PDGFR inhibitor compound, ABT869, was found to promote the transition from fibroblasts to adipocytes. This study highlights the power and accuracy of the PHDs-seq platform for high-throughput drug screening in stem cell research, and supports its use in basic explorations of the molecular mechanisms underlying disease development."

Journal • Fibrosis

Efficacy and safety of frontline systemic therapy for advanced hepatocellular carcinoma (aHCC): A network meta-analysis of landmark phase III trials. (ASCO-GI 2023) - "These tested respectively: sorafenib (S) vs placebo (SHARP and Asia Pacific), sunitinib (Sun) vs S, brivanib (Bri) vs S, linifanib (Lin) vs S, lenvatinib (L) vs S, nivolumab (Nivo) vs S, atezolizumab+bevacizumab (A+B) vs S, sintilimab+IBI-305 vs S, durvalumab+tremelimumab (D+T) vs S, atezolizumab+cabozantinib (A+C) vs S, donafenib vs S, camrelizumab plus rivoceranib (C+R) vs S, pembrolizumab plus lenvatinib (P+L) vs L, and tislelizumab (TS) vs S as first line treatments for aHCC... Combination of ICI + anti-VEGF antibodies leads to the greatest OS benefit compared to sorafenib, whereas ICI + kinase inhibitor regimens are associated with greater PFS benefit at the cost of higher toxicity rates."

Metastases • P3 data • Retrospective data • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

First-line systemic treatment strategies for unresectable hepatocellular carcinoma: A cost-effectiveness analysis. (PubMed, PLoS One) - "For oral multikinase inhibitors, the order of possible treatment options is sunitinib > lenvatinib > sorafenib plus erlotinib > linifanib > brivanib > donafenib. For ICIs, the order of possible treatment options is sintilimab plus IBI305 > atezolizumab plus bevacizumab."

Cost effectiveness • HEOR • Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Immune Modulation • Oncology • Solid Tumor

[VIRTUAL] Evaluation of firstline systemic treatments for unresectable hepatocellular carcinoma (uHCC): A network metaanalysis (ESMO Asia 2020) - "In total, 1398 records were screened and 27 were eligible for analysis, and the treatments included were atezolizumab+bevacizumab, brivanib, FOLFOX4, donafenib, dovitinib, lenvatinib, linifanib, nintedanib, nivolumab, sorafenib, sunitinib, vandetanib, 11 sorafenib combination therapies and three other combination therapies. This NMA suggested that greater ORR and TTP benefits with first-line use of Lenvatinib than others. Although Atezolizumab+Bevacizumab showed more benefit in PFS, more discontinuation because of AE should also take into consideration."

Retrospective data • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Oncology • Solid Tumor

[VIRTUAL] Evaluation of first:line systemic treatments for unresectable hepatocellular carcinoma (uHCC): A network meta:analysis (ESMO Asia 2020) - "Results In total, 1398 records were screened and 27 were eligible for analysis, and the treatments included were atezolizumab+bevacizumab, brivanib, FOLFOX4, donafenib, dovitinib, lenvatinib, linifanib, nintedanib, nivolumab, sorafenib, sunitinib, vandetanib, 11 sorafenib combination therapies and three other combination therapies. Legal entity responsible for the study: The authors. Funding: Has not received any funding."

Retrospective data • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Oncology • Solid Tumor

[VIRTUAL] Evaluation of firstline systemic treatments for unresectable hepatocellular carcinoma (uHCC): A network metaanalysis (ESMO Asia 2020) - "In total, 1398 records were screened and 27 were eligible for analysis, and the treatments included were atezolizumab+bevacizumab, brivanib, FOLFOX4, donafenib, dovitinib, lenvatinib, linifanib, nintedanib, nivolumab, sorafenib, sunitinib, vandetanib, 11 sorafenib combination therapies and three other combination therapies. This NMA suggested that greater ORR and TTP benefits with first-line use of Lenvatinib than others. Although Atezolizumab+Bevacizumab showed more benefit in PFS, more discontinuation because of AE should also take into consideration."

Retrospective data • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Oncology • Solid Tumor