PF-04217903 / Pfizer - LARVOL DELTA

Identification of immunomodulatory compounds by high-throughput proteomics: insights from quantification of 1000 proteins in a 20,000 sample screen (SITC 2025) - "We identified 68 cytotoxic compounds; of note, while most of these reduced cytokine expression, doxorubicin induced cytokine expression even at non-toxic doses, consistent with its reported pro-inflammatory properties. Other notable exceptions included the GSK-3 inhibitor LY2090314, and the BET inhibitor (+)-JQ1, which were toxic at higher doses, but induced the expression of distinct chemokines at lower doses...For example, the Met inhibitor PF-04217903 potently induced CXCL9-10 and IL-12 expression by hepatocytes, with no signs of toxicity. Considering that PF-04217903 was well tolerated in the clinic but was not pursued for strategic reasons, our results suggest potential for development in combination with checkpoint inhibitors for Met-driven tumors.Conclusions Our results demonstrate the value of high-throughput proteomics to identify new immunomodulatory compounds and simultaneously characterize their safety profile."

Immunomodulating • IO biomarker • Oncology • CASP3 • CXCL9 • EIF2A • EIF2S1 • GAPDH • IL12A • IL6 • MAPK3 • TNFA

Heterogeneous c-Met Activation in Osteosarcoma Dictates Synergistic Vulnerability to Combined c-Met Inhibition and Methotrexate Therapy. (PubMed, Anticancer Res) - "PHA665752 combined with MTX synergistically inhibits OS cell growth via dual suppression of c-Met signaling (PI3K/AKT, MAPK/ERK). and MTX-mediated cytotoxicity, highlighting the potential of co-targeting overlapping pathways to enhance OS treatment efficacy."

Heterogeneity • Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • NOS1

Construction of a Liver Cancer Prognostic Model Based on Interferon-Gamma-Related Genes for Revealing the Immune Landscape. (PubMed, J Environ Pathol Toxicol Oncol) - "Drugs that had high correlations with the feature genes included SPANXB1: PF-04217903, SGX-523, MMP1: PF-04217903, DUSP13: Imatinib, TFF1: KHK-Indazole, and Fulvestrant. It was found that L-group patients were more suitable for immunotherapy. This study provided valuable information on the prognosis of liver cancer."

IO biomarker • Journal • Gastrointestinal Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • DUSP1 • IFNG • MMP1 • TFF1

Inhibition of AXL along with c-Met potentially halts resistance development in renal cell carcinoma (KCRS 2024) - "We found that prolonged treatment with c-Met inhibitors Cabo, Crizotinib, and PF4217903, induced c-Met and AXL overexpression in RCC cells...Finally, silencing AXL (using siRNA) or inhibiting AXL (using TP0903) in CaboR cells, induced significant apoptosis. Conclusions Together, our data suggest that CaboR cells have a distinct epigenomic and transcriptomic profile, and that targeting AXL along with c-Met inhibition can be beneficial in preventing acquired therapeutic resistance in RCC."

Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • ETV1 • GAS6 • HOXA9 • MET

c-Met/AXL crosstalk in mediating therapeutic resistance in renal cell carcinoma (AACR 2024) - "We have also found that prolonged treatment of c-Met inhibitor Cabo, (including Crizotinib and PF-4217903) induced c-Met and AXL overexpression in RCC cells...Furthermore, either silencing of AXL (using siRNA) or inhibiting AXL (using TP0903) induced significant apoptosis in these Cabo-resistant cells. Together, our data suggest that inhibition of AXL along with c-Met can be beneficial in preventing acquired therapeutic resistance in RCC."

Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • AXL • KDR • KRAS • MET

Synthesis and preclinical evaluation of a selective MET kinase positron emission tomography tracer. (PubMed, J Labelled Comp Radiopharm) - "The selective MET inhibitor PF04217903 (1) formed the basis for a bioisosteric replacement, leading to the deoxyfluorinated analog [ F]2. [ F]2 could be synthesized with a "hydrous fluoroethylation" protocol in 6.3 ± 2.6% radiochemical yield and a molar activity of >50 GBq/μmol. In vitro autoradiography indicated that [ F]2 selectively binds to MET in PC3 tumor tissue, and in vivo biodistribution in mice showed predominantly a hepatobiliary excretion along with a low retention of radiotracer in other organs."

Journal • Preclinical • Oncology

Upregulation of Biomarker Limd1 Was Correlated with Immune Infiltration in Doxorubicin-Related Cardiotoxicity. (PubMed, Mediators Inflamm) - "In total, 120 DEGs were discovered in a mouse model of doxorubicin-induced cardiotoxicity, and PF-04217903, propranolol, azithromycin, etc. were found to be potential drugs against this pathological condition. Finally, Limd1 expression was significantly positively correlated with "dendritic cells activation' and negatively correlated with "monocytes" and "macrophages M1'. In summary, our results suggested that limd1 is a valuable biomarker and a potential inflammation regulator in doxorubicin-induced cardiotoxicity."

Biomarker • Journal • Cardiovascular • Oncology

Combination of an oncokinase inhibitor merestinib with anti-PD-L1 results in enhanced immune mediated antitumor activity in CT26 murine tumor model (AACR 2017) - P1a/1b; "Additionally, the anti-tumor effect of Mer was tested in vivo on established CT26 and B16F10 tumors compared to MET specific TKIs (savolitinib, PF4217903) alone or in combination with PD-L1 antibody (Ab) blockade. The enhanced immune activation of the combination therapy, leading to synergistic anti-tumor efficacy, demonstrates that merestinib has the potential to augment immunotherapy while targeting the tumor directly. This preclinical data provides the rationale for the clinical investigation of merestinib in combination with checkpoint therapies targeting the PD-L1/PD1 axis (NCT02791334)."

Checkpoint inhibition • Combination therapy • Biosimilar • Colorectal Cancer • Gastrointestinal Cancer • Immunology • Melanoma • Oncology

Characterization of the anti-angiogenic properties of merestinib (LY2801653), an oncokinase inhibitor (AACR 2017) - P1a/1b; "...In contrast, the MET-specific kinase inhibitor, PF04217903, only weakly inhibited cord formation and endothelial sprouting...In addition, while MET antibody emibetuzumab (human anti-MET antibody) plus ramucirumab (human anti-VEGFR2 antibody) decreased vascular density by 64%, merestinib plus ramucirumab decreased it by 92%...These data suggest that the anti-angiogenic activity of merestinib includes activities of other kinases targeted by merestinib. These data provide rationale and support for the clinical evaluation of combination of merestinib with ramucirumab (NCT02745769)."

Biosimilar • Gastric Cancer • Gastrointestinal Cancer • Oncology

Blocking the HGF-MET Pathway Induces Resolution of Neutrophilic Inflammation by Promoting Neutrophil Apoptosis and Efferocytosis. (PubMed, Pharmacol Res) - "In human neutrophils, the combined use of LPS and HGF increased MET phosphorylation and provided a prosurvival signal, whereas blocking MET with PF-04217903 induced caspase-dependent neutrophil apoptosis. Taken together, these data demonstrate that blocking HGF/MET signalling may be a potential therapeutic strategy for inducing the resolution of neutrophilic inflammatory responses."

Journal • Gout • Immunology • Inflammation • Inflammatory Arthritis • Respiratory Diseases • Rheumatology • ANXA1 • CXCL1 • IL1B

Kinomic profile in patient-derived glioma cells during hypoxia reveals c-MET-PI3K dependency for adaptation. (PubMed, Theranostics) - "Repurposed c-MET inhibitors PF04217903 and tivantinib exhibited hypoxic-dependent drug synergism with temozolomide, resulting in reduced tumor load and growth of GPC xenografts. Detailed analysis of bulk and single-cell glioblastoma transcriptomes associates the cellular subpopulation over-expressing c-MET with inflamed, hypoxic, metastatic, and stem-like phenotypes. Thus, our "bench to bedside (the use of patient-derived GPCs and xenografts for basic research) and back (validation with independent glioblastoma transcriptome databases)" analysis unravels the novel therapeutic indications of c-MET and PI3K/Akt inhibitors for the treatment of glioblastoma, and potentially other cancers, in the hypoxic tumor microenvironment."

Clinical • Journal • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • MET

Preclinical evaluation of [F]cabozantinib as a PET imaging agent in a prostate cancer mouse model. (PubMed, Nucl Med Biol) - "[F]cabozantinib exhibits non-favorable properties as a PET imaging probe, demonstrated by slow excretion kinetics along with low tumor uptake and high non-specific binding in tumor and heart tissue. The results reflect cabozantinibs multi-kinase activity, making PET imaging of tumor specific kinase expression with [F]cabozantinib challenging."

Journal • Preclinical • Gastrointestinal Cancer • Genito-urinary Cancer • Hepatocellular Cancer • Hepatology • Oncology • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • Thyroid Gland Medullary Carcinoma • HGF

Transforming Growth Factor- β1 Signaling in Vascular Endothelial Cells Inhibits Hematopoietic Stem Cell Regeneration (ASH 2016) - "HGF treatment of HUVEC activated endothelial Akt signaling and led to a >10-fold increase in HSC regeneration that could be blocked by the c-Met inhibitor PF04217903. HGF treatment also dramatically increased long-term multi-lineage hematopoiesis from HUVEC regenerated HSC. Our findings reveal a novel suppressive role for TGF-β1 in the vascular niche and demonstrate that EC-derived growth factors such as HGF have the potential to attenuate this suppression and significantly enhance HSC regeneration."

Preclinical • Biosimilar • Hematological Malignancies • Oncology • Venous Thromboembolism

Hgf/Met activation mediates resistance to BRAF inhibition in murine anaplastic thyroid cancers. (PubMed, J Clin Invest) - "A trial of vemurafenib in nonmelanoma BRAFV600E-mutant cancers showed significant, although short-lived, responses in ATCs, indicating that these virulent tumors remain addicted to BRAF despite their high mutation burden...The relapsed tumors had elevated MAPK transcriptional output, and retained responses to the MEK/RAF inhibitor CH5126766 in vivo and in vitro...Growth, signaling and viability of Met-amplified tumor cells were suppressed in vitro and in vivo by the Met kinase inhibitors PF-04217903 and crizotinib, whereas primary ATCs and Met-diploid relapses were resistant. Hence, recurrences are the rule after BRAF suppression in murine ATCs, most commonly due to activation of HGF/MET signaling, which generates exquisite dependency to MET kinase inhibitors."

Journal • Preclinical • Tumor Mutational Burden

Peptide-Functionalized Nanoinhibitor Restrains Brain Tumor Growth by Abrogating MET Signaling. (PubMed, Nano Lett) - "The medium survival in mouse models was extended by 59%, which is similar to the effects of PF-04217903, a small molecule MET inhibitor currently in clinical trials...To the best of our knowledge, this is the first report of therapeutic inhibition of glioma growth by blocking MET signaling by a novel nanoinhibitor. Compared to the antibodies and chemical inhibitors that are in clinical trials, blockage of MET signaling by the nanoinhibitor provides a new approach for the treatment of glioma with advantages of high efficiency, affordability, and, most importantly, potentially reduced drug resistance."

Journal

Targeting c-MET and MAPK pathway in metastatic castration-resistant prostate cancer (AACR 2019) - "...Thus, treatment selection could be based on the molecular Background: of the disease rather than on tumor histology in the near future.However clinical validation of most alterations is lacking and only preclinical models are available.We describe a prostate cancer patient refractory to standard therapies that was found to harbor both a c-Met activating mutation and a BRAF fusion that greatly responded to the MEK inhibitor (MEKi) trametinib.EXPERIMENTAL PROCEDURESThe Next Generation Sequencing (NGS) platforms (Oncomine Assay and Archer Variant Plex) were used to characterize molecularly FFPE tissue from the primary tumor of a 73 years old man with metastatic castration-resistant prostate cancer (mCRPC) refractory to Docetaxel, Enzalutamide and Radium 223.Immunostaining was performed to evaluate the status of protumoral pathways activated by the identified genomic alterations.RESULTSOncomine assay detected a pathogenic c-MET mutation that affected the splicing of exon..."