cabozantinib and Disease-Models--Animal

Neurofibromatosis type 1 (NF1) plexiform neurofibromas (PNs) are progressive, multicellular neoplasms that cause morbidity and may transform to sarcoma. Treatment of Nf1

Topics: Adolescent; Adult; Anilides; Animals; Disease Models, Animal; Female; Genes, Neurofibromatosis 1; Humans; Male; Mice; Mice, Mutant Strains; Neurofibroma, Plexiform; Neurofibromatosis 1; Pain Measurement; Prospective Studies; Protein Kinase Inhibitors; Pyridines; Quality of Life; Receptor Protein-Tyrosine Kinases; Translational Research, Biomedical; Young Adult

Alzheimer's disease (AD) is a neurodegenerative disease characterized by Aβ deposition, tauopathy, neuroinflammation, and impaired cognition. The recent identification of associations between protein kinases and AD pathology has spurred interest in tyrosine kinase inhibitors (TKIs) as potential strategic therapeutic agents for AD. In the present study, we investigated whether the TKIs ibrutinib, PD180970, and cabozantinib, which have different on-targets, selectively regulate AD pathology in 3.5- to 4-month-old 5xFAD mice (a model of the early phase of AD). Ibrutinib (10 mg/kg, i.p.) effectively reduced amyloid-β (Aβ) plaque number, tau hyperphosphorylation and neuroinflammation in 5xFAD mice. Surprisingly, PD180970 (10 mg/kg, i.p.) did not alter Aβ plaque number or neuroinflammatory responses and exacerbated tau hyperphosphorylation in 5xFAD mice. Cabozantinib (10 mg/kg, i.p.) had no effect on amyloidopathy but partially relieved tau hyperphosphorylation and astrogliosis. Taken together, our results suggest that not all TKIs have therapeutic effects on AD pathology in a mouse model of AD. Consequently, optimization of drug dosage, injection periods and administration routes should be considered when repurposing TKIs as novel AD therapeutics.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Disease Models, Animal; Mice; Mice, Transgenic; Neurodegenerative Diseases; Neuroinflammatory Diseases; tau Proteins; Tyrosine Kinase Inhibitors

Two novel bioisosteres of cabozantinib,

Topics: Anilides; Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Liver Neoplasms; Mice; Molecular Structure; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyridines; Xenograft Model Antitumor Assays

Hepatocellular carcinoma (HCC) is the sixth most common primary cancer with an unsatisfactory long-term survival. Gain of function mutations of PIK3CA occur in a subset of human HCC. Alpelisib, a selective PIK3CA inhibitor, has been approved by the FDA to treat PIK3CA mutant breast cancers. In this manuscript, we evaluated the therapeutic efficacy of alpelisib, either alone or in combination, for the treatment of HCC. We tested alpelisib in mouse HCC induced by hydrodynamic injection of c-Met/PIK3CA(H1047R) (c-Met/H1047R), c-Met/PIK3CA(E545K) (c-Met/E545K), and c-Met/sgPten gene combinations. Alpelisib slowed down the growth of c-Met/H1047R and c-Met/E545K HCC but was ineffective in c-Met/sgPten HCC. Mechanistically, alpelisib inhibited p-ERK and p-AKT in c-Met/H1047R and c-Met/E545K HCC progression but did not affect the mTOR pathway or genes involved in cell proliferation. In human HCC cell lines transfected with PIK3CA(H1047R), alpelisib synergized with the mTOR inhibitor MLN0128 or the CDK4/6 inhibitor palbociclib to suppress HCC cell growth. In c-Met/H1047R mice, alpelisib/MLN0128 or alpelisib/palbociclib combination therapy caused tumor regression. Our study demonstrates that alpelisib is effective for treating PIK3CA-mutated HCC by inhibiting MAPK and AKT cascades. Furthermore, combining alpelisib with mTOR or CDK4/6 inhibitors has a synergistic efficacy against PIK3CA-mutated HCC, providing novel opportunities for precision medicine against HCC.

Topics: Anilides; Animals; Benzoxazoles; Carcinogenesis; Carcinoma, Hepatocellular; Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases; Disease Models, Animal; Female; Humans; Liver Neoplasms; MAP Kinase Signaling System; Mice; Molecular Targeted Therapy; Mutation; Piperazines; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-met; PTEN Phosphohydrolase; Pyridines; Pyrimidines; Thiazoles; Treatment Outcome; Tumor Burden

The lung, as the primary organ for gas exchange in mammals, is the main target organ for many pathogens and allergens, which may cause acute lung injury. A certain proportion of acute lung injury may progress into irreversible pulmonary fibrosis. Both acute lung injury and pulmonary fibrosis have high mortality rates and few effective treatments. Cabozantinib is a multi-target small molecule tyrosine kinase inhibitor and has been approved for the treatment of multiple malignant solid tumors. In this study, we explored the role of cabozantinib in acute lung injury and pulmonary fibrosis in vivo and in vitro. In the lipopolysaccharide and bleomycin induced mouse lung injury models, cabozantinib significantly improved the pathological state and reduced the infiltration of inflammatory cells in the lung tissues. In the bleomycin induced pulmonary fibrosis model, cabozantinib significantly reduced the area of pulmonary fibrosis and improved lung function in mice. The results of in vitro studies showed that cabozantinib could inhibit the inflammatory response and apoptosis of alveolar epithelial cells by inhibiting the activation of TLR4/NF-κB and NLRP3 inflammasome pathways. At the same time, cabozantinib could inhibit the activation of lung fibroblasts through suppressing the TGF-β1/Smad pathway, and promote the apoptosis of fibroblasts. In summary, cabozantinib could alleviate lung injury through regulating the TLR4 /NF-κB/NLRP3 inflammasome pathway, and alleviate pulmonary fibrosis by inhibiting the TGF-β1/Smad3 signaling pathway.

Topics: Anilides; Animals; Bleomycin; Disease Models, Animal; Disease Progression; Humans; Inflammation; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred C57BL; Protein Kinase Inhibitors; Pulmonary Fibrosis; Pyridines; Toll-Like Receptor 4

Intratumoral immunosuppression mediated by myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) represents a potential mechanism of immune checkpoint inhibitor (ICI) resistance in solid tumors. By promoting TAM and MDSC infiltration, IL1β may drive adaptive and innate immune resistance in renal cell carcinoma (RCC) and in other tumor types.. Using the RENCA model of RCC, we evaluated clinically relevant combinations of anti-IL1β plus either anti-PD-1 or the multitargeted tyrosine kinase inhibitor (TKI), cabozantinib. We performed comprehensive immune profiling of established RENCA tumors via multiparameter flow cytometry, tumor cytokine profiling, and single-cell RNA sequencing (RNA-seq). Similar analyses were extended to the MC38 tumor model.. Analyses via multiparameter flow cytometry, tumor cytokine profiling, and single-cell RNA-seq showed that anti-IL1β reduces infiltration of polymorphonuclear MDSCs and TAMs. Combination treatment with anti-IL1β plus anti-PD-1 or cabozantinib showed increased antitumor activity that was associated with decreases in immunosuppressive MDSCs and increases in M1-like TAMs.. Single-cell RNA-seq analyses show that IL1β blockade and ICI or TKI remodel the myeloid compartment through nonredundant, relatively T-cell-independent mechanisms. IL1β is an upstream mediator of adaptive myeloid resistance and represents a potential target for kidney cancer immunotherapy.

Topics: Anilides; Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Cell Line, Tumor; Cytokines; Disease Models, Animal; Female; Gene Expression Regulation, Neoplastic; Humans; Immune Checkpoint Inhibitors; Interleukin-1beta; Kidney Neoplasms; Mice; Mice, Inbred BALB C; Myeloid-Derived Suppressor Cells; Pyridines; RNA-Seq; Single-Cell Analysis; Treatment Outcome; Tumor Burden; Tumor-Associated Macrophages

Topics: Anilides; Animals; Disease Models, Animal; Humans; Male; Mice; Nanoparticles; Neutrophils; Prostatic Neoplasms; Pyridines; Receptor Protein-Tyrosine Kinases

Cabozantinib is a tyrosine kinase inhibitor (TKI) approved for the treatment of medullary thyroid cancer, renal cell carcinoma and hepatocellular carcinoma, and is currently in clinical trials for the treatment of prostate cancer and others. It exerts its therapeutic effect mainly through inhibition of the tyrosine kinases MET (hepatocyte growth factor receptor) and VEGFR2 (vascular endothelial growth factor receptor 2), in addition to several other kinases involved in cancer. PET imaging with TKIs such as [. [. Tissue distribution studies in non-tumor bearing mice revealed slow blood clearance, absence of brain uptake and a high myocardial uptake. In the tumor bearing mice, tumor uptake was low (0.58 ± 0.20% ID/g at 30 min post tracer injection), which was confirmed by μPET imaging. No differences in tissue distribution and kinetics were observed in both biodistributions and μPET studies after pretreatment with the MET inhibitor PF04217903. At 30 min post tracer injection, 60 ± 3% of the recovered radioactivity in plasma in non-tumor bearing mice was present as intact tracer. [

Topics: Anilides; Animals; Disease Models, Animal; Fluorine Radioisotopes; Male; Mice; Positron-Emission Tomography; Pyridines; Tissue Distribution

Medullary thyroid carcinoma (MTC) is a tumor deriving from the thyroid C cells. Vandetanib (VAN) and cabozantinib (CAB) are two tyrosine kinase inhibitors targeting REarranged during Transfection (RET) and other kinase receptors and are approved for the treatment of advanced MTC. We aim to compare the in vitro and in vivo anti-tumor activity of VAN and CAB in MTC. The effects of VAN and CAB on viability, cell cycle, and apoptosis of TT and MZ-CRC-1 cells are evaluated in vitro using an MTT assay, DNA flow cytometry with propidium iodide, and Annexin V-FITC/propidium iodide staining, respectively. In vivo, the anti-angiogenic potential of VAN and CAB is evaluated in

Topics: Angiogenesis Inhibitors; Anilides; Animals; Apoptosis; Carcinoma, Neuroendocrine; Cell Cycle; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Embryo, Nonmammalian; Humans; Neovascularization, Pathologic; Neovascularization, Physiologic; Piperidines; Pyridines; Quinazolines; Thyroid Neoplasms; Zebrafish

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Antiangiogenic therapy used in treatment of metastatic colorectal cancer (mCRC) inevitably succumbs to treatment resistance. Upregulation of MET may play an essential role to acquired anti-VEGF resistance. We previously reported that cabozantinib (XL184), an inhibitor of receptor tyrosine kinases (RTK) including MET, AXL, and VEGFR2, had potent antitumor effects in mCRC patient-derived tumor explant models. In this study, we examined the mechanisms of cabozantinib sensitivity, using regorafenib as a control. The tumor growth inhibition index (TGII) was used to compare treatment effects of cabozantinib 30 mg/kg daily versus regorafenib 10 mg/kg daily for a maximum of 28 days in 10 PDX mouse models.

Topics: Anilides; Animals; Antineoplastic Agents; Apoptosis; Autophagy; Biomarkers, Tumor; Cell Line, Tumor; Colorectal Neoplasms; Disease Models, Animal; Female; Humans; Magnetic Resonance Imaging; Mice; Neovascularization, Pathologic; Phosphatidylinositol 3-Kinases; Positron-Emission Tomography; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyridines; Signal Transduction; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

A significant fraction of patients with advanced prostate cancer treated with androgen deprivation therapy experience relapse with relentless progression to lethal metastatic castration-resistant prostate cancer (mCRPC). Immune checkpoint blockade using antibodies against cytotoxic-T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1/programmed cell death 1 ligand 1 (PD1/PD-L1) generates durable therapeutic responses in a significant subset of patients across a variety of cancer types. However, mCRPC showed overwhelming de novo resistance to immune checkpoint blockade, motivating a search for targeted therapies that overcome this resistance. Myeloid-derived suppressor cells (MDSCs) are known to play important roles in tumour immune evasion. The abundance of circulating MDSCs correlates with prostate-specific antigen levels and metastasis in patients with prostate cancer. Mouse models of prostate cancer show that MDSCs (CD11b

Topics: Anilides; Animals; CD8-Positive T-Lymphocytes; Chimera; Cytokines; Disease Models, Animal; Drug Synergism; Female; Humans; Imidazoles; Immunotherapy; Lymphocytes, Tumor-Infiltrating; Male; Mice; Molecular Targeted Therapy; Myeloid-Derived Suppressor Cells; Phosphoinositide-3 Kinase Inhibitors; Prostatic Neoplasms, Castration-Resistant; Pyridines; Quinolines; Signal Transduction; Tumor Microenvironment

Topics: Anilides; Animals; Carcinoma, Neuroendocrine; Cell Cycle; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Membrane Potential, Mitochondrial; Mice; Mitochondria; Mitochondrial Dynamics; Piperidines; Protein Kinase Inhibitors; Pyridines; Quinazolines; Thyroid Neoplasms; Xenograft Model Antitumor Assays

The use of clinical MRI scanners to conduct pre-clinical research facilitates comparisons with clinical studies. Here the utility and sensitivity of anatomical and functional MRI data/biomarkers acquired from transgenic mouse models of neuroblastoma using a dedicated radiofrequency (RF) coil on a clinical 3T scanner was evaluated.. Multiparametric MRI of transgenic mice bearing abdominal neuroblastomas was performed at 3T, and data cross-referenced to that acquired from the same mice on a pre-clinical 7T MRI system. T. Excellent T. Simultaneous multiparametric MRI of multiple tumour-bearing animals using this coil arrangement at 3T can provide high efficiency/throughput for both phenotypic characterisation and evaluation of novel therapeutics, and facilitate the introduction of functional MRI biomarkers into aligned imaging-embedded clinical trials.

Topics: Anaplastic Lymphoma Kinase; Anilides; Animals; Antineoplastic Agents; Contrast Media; Cyclophosphamide; Disease Models, Animal; Female; Magnetic Resonance Imaging; Magnets; Male; Mice; Mice, Transgenic; Mutation; N-Myc Proto-Oncogene Protein; Neuroblastoma; Phantoms, Imaging; Phenotype; Pyridines; Receptor Protein-Tyrosine Kinases; Signal-To-Noise Ratio; Stomach Neoplasms; Tumor Burden

MET plays an important role in the development and progression of papillary renal cell carcinoma (pRCC). Evaluation of efficacy of MET inhibitors against pRCC has been hampered by limited preclinical models depicting MET abnormalities. We established a new patient-derived xenograft (PDX) model of pRCC carrying an activating mutation of MET and tested the ability of cabozantinib, an inhibitor of receptor tyrosine kinases including MET, to inhibit tumor growth and metastasis. Precision-cut, thin tissue slices from a pRCC specimen obtained by nephrectomy were implanted under the renal capsule of RAG2

Topics: Anilides; Animals; Carcinoma, Renal Cell; Disease Models, Animal; Humans; Kidney Neoplasms; Mice; Mutation; Neoplasm Metastasis; Pyridines; Receptor Protein-Tyrosine Kinases; Xenograft Model Antitumor Assays

We performed parallel investigations in cabozantinib-treated patients in a phase II trial and simultaneously in patient-derived xenograft (PDX) models to better understand the roles of MET and VEGFR2 as targets for prostate cancer therapy.. In the clinical trial, radiographic imaging and serum markers were examined, as well as molecular markers in tumors from bone biopsies. In mice harboring PDX intrafemurally or subcutaneously, cabozantinib effects on tumor growth, MET, PDX in which MET was silenced, VEGFR2, bone turnover, angiogenesis, and resistance were examined.. In responsive patients and PDX, islets of viable pMET-positive tumor cells persisted, which rapidly regrew after drug withdrawal. Knockdown of MET in PDX did not affect tumor growth in mice nor did it affect cabozantinib-induced growth inhibition but did lead to induction of FGFR1. Inhibition of VEGFR2 and MET in endothelial cells reduced the vasculature, leading to necrosis. However, each islet of viable cells surrounded a VEGFR2-negative vessel. Reduction of bone turnover was observed in both cohorts.. Our studies demonstrate that MET in tumor cells is not a persistent therapeutic target for metastatic castrate-resistant prostate cancer (CRPC), but inhibition of VEGFR2 and MET in endothelial cells and direct effects on osteoblasts are responsible for cabozantinib-induced tumor inhibition. However, vascular heterogeneity represents one source of primary therapy resistance, whereas induction of FGFR1 in tumor cells suggests a potential mechanism of acquired resistance. Thus, integrated cross-species investigations demonstrate the power of combining preclinical models with clinical trials to understand mechanisms of activity and resistance of investigational agents.

Topics: Anilides; Animals; Antineoplastic Agents; Apoptosis; Bone Neoplasms; Cell Line, Tumor; Clinical Trials, Phase II as Topic; Disease Models, Animal; Drug Resistance, Neoplasm; Gene Knockdown Techniques; Humans; Male; Mice; Multicenter Studies as Topic; Neoplasm Staging; Phosphorylation; Positron-Emission Tomography; Prostatic Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyridines; Receptor, Fibroblast Growth Factor, Type 1; Signal Transduction; Treatment Outcome; Tumor Burden; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays

A recent phase III trial of the MET kinase inhibitor cabozantinib in men with castration-resistant prostate cancer (CRPC) failed to meet its primary survival end point; however, most men with CRPC have intact androgen receptor (AR) signaling. As previous work supports negative regulation of MET by AR signaling, we hypothesized that intact AR signaling may have limited the efficacy of cabozantinib in some of these patients. To assess the role of AR signaling on MET inhibition, we first performed an in silico analysis of human CRPC tissue samples stratified by AR signaling status ((+) or (-)), which identified MET expression as markedly increased in AR(-) samples. In vitro, AR signaling inhibition in AR(+) CRPC models increased MET expression and resulted in susceptibility to ligand (HGF) activation. Likewise, MET inhibition was only effective in blocking cancer phenotypes in cells with MET overexpression. Using multiple AR(+) CRPC in vitro and in vivo models, we showed that combined cabozantinib and enzalutamide (AR antagonist) treatment was more efficacious than either inhibitor alone. These data provide a compelling rationale to combine AR and MET inhibition in CRPC and may explain the negative results of the phase III cabozantinib study in CRPC. Similarly, the expression of MET in AR(-) disease, whether due to AR inhibition or loss of AR signaling, suggests potential utility for MET inhibition in select patients with AR therapy resistance and in AR(-) prostate cancer.

Topics: Androgen Receptor Antagonists; Anilides; Animals; Antineoplastic Agents; Benzamides; Cell Line, Tumor; Cell Survival; Cluster Analysis; Disease Models, Animal; Gene Expression Profiling; Gene Knockdown Techniques; Humans; Male; Mice; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyridines; Receptors, Androgen; Signal Transduction; Xenograft Model Antitumor Assays

Hepatocellular carcinoma is among the leading causes of cancer-related deaths worldwide, and the development of new treatment regimens is urgently needed to improve therapeutic approach. In our study, we found that the combination of a Met inhibitor, cabozantinib, and a novel FAK inhibitor, CT-707, exerted synergistic antitumor effects against hepatocellular carcinoma in vitro and in vivo Interestingly, further studies showed that therapeutic concentrations of cabozantinib increased the phosphorylation of FAK, which might attenuate the antitumor activity of cabozantinib. The simultaneous exposure to CT-707 effectively inhibited the activation of FAK that was induced by cabozantinib, which contributes to the synergistic effect of the combination. Furthermore, cabozantinib increased the mRNA and protein levels of integrin α5, which is a canonical upstream of FAK, and the introduction of cilengitide to block integrin function could abrogate FAK activation by cabozantinib, indicating that cabozantinib upregulated the phosphorylation of FAK in an integrin-dependent manner. Similar synergy was also observed on PHA-665752, another selective MET inhibitor, indicating that this observation might be a common characteristic of MET-targeting strategies. Our findings not only favor the development of the novel FAK inhibitor CT-707 as a therapeutic agent against hepatocellular carcinoma but also provide a new strategy of combining MET and FAK inhibitors to potentiate the anticancer activities of these two types of agents for treating hepatocellular carcinoma patients. Mol Cancer Ther; 15(12); 2916-25. ©2016 AACR.

Topics: Anilides; Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Drug Synergism; Enzyme Activation; Focal Adhesion Kinase 1; Humans; Liver Neoplasms; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-met; Pyridines; Signal Transduction; Tumor Burden; Xenograft Model Antitumor Assays

In the majority of gastrointestinal stromal tumors (GIST), oncogenic signaling is driven by KIT mutations. Advanced GIST is treated with tyrosine kinase inhibitors (TKI) such as imatinib. Acquired resistance to TKI is mainly caused by secondary KIT mutations, but can also be attributed to a switch of KIT dependency to another receptor tyrosine kinase (RTK). We tested the efficacy of cabozantinib, a novel TKI targeting KIT, MET, AXL, and vascular endothelial growth factor receptors (VEGFR), in patient-derived xenograft (PDX) models of GIST, carrying different KIT mutations. NMRI nu/nu mice (n = 52) were bilaterally transplanted with human GIST: UZLX-GIST4 (KIT exon 11 mutation, imatinib sensitive), UZLX-GIST2 (KIT exon 9, imatinib dose-dependent resistance), or UZLX-GIST9 (KIT exon 11 and 17 mutations, imatinib resistant). Mice were grouped as control (untreated), imatinib (50 mg/kg/bid), and cabozantinib (30 mg/kg/qd) and treated orally for 15 days. Cabozantinib resulted in significant tumor regression in UZLX-GIST4 and -GIST2 and delayed tumor growth in -GIST9. In all three models, cabozantinib inhibited the proliferative activity, which was completely absent in UZLX-GIST4 and significantly reduced in -GIST2 and -GIST9. Increased apoptotic activity was observed only in UZLX-GIST4. Cabozantinib inhibited the KIT signaling pathway in UZLX-GIST4 and -GIST2. In addition, compared with both control and imatinib, cabozantinib significantly reduced microvessel density in all models. In conclusion, cabozantinib showed antitumor activity in GIST PDX models through inhibition of tumor growth, proliferation, and angiogenesis, in both imatinib-sensitive and imatinib-resistant models. Mol Cancer Ther; 15(12); 2845-52. ©2016 AACR.

Topics: Anilides; Animals; Antineoplastic Agents; Apoptosis; Biopsy; Cell Line, Tumor; Disease Models, Animal; Female; Gastrointestinal Stromal Tumors; Humans; Imatinib Mesylate; Mice; Mutation; Necrosis; Neoplasm Grading; Neovascularization, Pathologic; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-kit; Pyridines; Signal Transduction; Tumor Burden; Xenograft Model Antitumor Assays

Abiraterone improves the overall survival of men with metastatic castration-resistant prostate cancer. However, de novo or adaptive resistance to abiraterone limits its activity. Rational combinations of drugs with different mechanisms of action that overcome resistance mechanisms may improve the efficacy of therapy. To that end, we studied the molecular and phenotypic effects of the combination of cabozantinib plus abiraterone.. Three prostate cancer cell lines were used to interrogate the in vitro molecular and antiproliferative effects of the single agents and combination of cabozantinib and abiraterone. The in vivo impact of the combination was assessed using the LAPC4-CR xenograft mouse model.. In vitro proliferation studies demonstrated single-agent doses between 2 μmol/L and 10 μmol/L for abiraterone and cabozantinib inhibit prostate cancer cell proliferation in a dose-dependent manner, and the anticancer activity of abiraterone is enhanced when combined with cabozantinib. In vivo LAPC4-CR xenograft mouse studies also showed that cabozantinib can improve the antitumor activity of abiraterone. Cabozantinib, a multiple receptor tyrosine kinase inhibitor, enhances the ability of abiraterone to inhibit AR activity in a cell line-dependent manner. In addition, our cell line studies demonstrate abiraterone-stimulated insulin-like growth factor I receptor (IGFIR) phosphorylation with downstream activation of MEK1/2 and ERK1/2, and that this potential adaptive resistance mechanism was inhibited by cabozantinib.. Cabozantinib can enhance the efficacy of abiraterone by blocking multiple compensatory survival mechanisms, including IGFIR activation, and supports the assessment of the combination in a clinical trial.

Topics: Androstenes; Anilides; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Drug Antagonism; Drug Resistance, Neoplasm; Humans; Male; Mice; Phosphorylation; Prostatic Neoplasms; Pyridines; Receptor Protein-Tyrosine Kinases; Receptor, IGF Type 1; Receptors, Androgen; Signal Transduction; Tumor Burden; Xenograft Model Antitumor Assays

Cabozantinib, an orally available multityrosine kinase inhibitor with activity against mesenchymal epithelial transition factor (MET) and VEGF receptor 2 (VEGFR2), induces resolution of bone scan lesions in men with castration-resistant prostate cancer bone metastases. The purpose of this study was to determine whether cabozantinib elicited a direct antitumor effect, an indirect effect through modulating bone, or both.. Using human prostate cancer xenograft studies in mice, we determined the impact of cabozantinib on tumor growth in soft tissue and bone. In vitro studies with cabozantinib were performed using (i) prostate cancer cell lines to evaluate its impact on cell growth, invasive ability, and MET and (ii) osteoblast cell lines to evaluate its impact on viability and differentiation and VEGFR2.. Cabozantinib inhibited progression of multiple prostate cancer cell lines (Ace-1, C4-2B, and LuCaP 35) in bone metastatic and soft tissue murine models of prostate cancer, except for PC-3 prostate cancer cells in which it inhibited only subcutaneous growth. Cabozantinib directly inhibited prostate cancer cell viability and induced apoptosis in vitro and in vivo and inhibited cell invasion in vitro. Cabozantinib had a dose-dependent biphasic effect on osteoblast activity and inhibitory effect on osteoclast production in vitro that was reflected in vivo. It blocked MET and VEGFR2 phosphorylation in prostate cancer cells and osteoblast-like cells, respectively.. These data indicate that cabozantinib has direct antitumor activity, and that its ability to modulate osteoblast activity may contribute to its antitumor efficacy.

Topics: Anilides; Animals; Antineoplastic Agents; Bone Neoplasms; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Humans; Immunoblotting; Immunohistochemistry; Male; Mice; Mice, SCID; Osteoblasts; Prostatic Neoplasms; Pyridines; Xenograft Model Antitumor Assays