cabozantinib and Neoplasms

Rearranged during transfection (RET) is a receptor tyrosine kinase essential for the normal development and maturation of a diverse range of tissues. Aberrant RET signaling in cancers, due to RET mutations, gene fusions, and overexpression, results in the activation of downstream pathways promoting survival, growth, and metastasis. Pharmacological manipulation of RET is effective in treating RET-driven cancers, and efforts toward developing RET-specific therapies have increased over the last 5 years. In 2020, RET-selective inhibitors pralsetinib and selpercatinib achieved clinical approval, which marked the first approvals for kinase inhibitors specifically developed to target the RET oncoprotein. This Perspective discusses current development and clinical applications for RET precision medicine by providing an overview of the incremental improvement of kinase inhibitors for use in RET-driven malignancies.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Drug Development; Humans; Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret

Cabozantinib is an oral small-molecule multitargeted tyrosine kinase inhibitor (TKI) that may confer an advantage over other TKIs that target a single receptor. It was approved by the U.S. Food and Drug Administration for the treatment of both advanced renal cell carcinoma and progressive metastatic medullary thyroid cancer, and it is being investigated for a wide array of other malignancies. Rationale for use, clinical trial data, and current recommendations for cabozantinib in renal cell cancer, thyroid cancer, prostate cancer, hepatocellular cancer, and lung cancer are detailed in this article. Common adverse events are reviewed, and management strategies for select adverse events are discussed. Implications for contemporary practitioners are also provided because use of this novel agent is likely to increase as more studies are completed.

Topics: Administration, Oral; Anilides; Animals; Antineoplastic Agents; Drug Approval; Humans; Neoplasms; Protein Kinase Inhibitors; Pyridines

The fatigue associated with five newly approved vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) (regorafenib, vandetanib, cabozantinib, lenvatinib, axitinib) is poorly understood. We conducted this systematic review to fully investigate the fatigue associated with these VEGFR-TKIs in cancer patients. Relevant studies of randomized controlled trials in cancer patients treated with the five VEGFR-TKIs were retrieved and a systematic evaluation was conducted. EMBASE, MEDLINE, and PubMed were searched for articles published until March 2017. Thirteen randomized controlled trials and 4395 patients were included. The current analysis suggested that the use of five newly approved VEGFR-TKIs increased the risk of all-grade fatigue (1.43; 95% CI 1.23-1.66; p < 0.00001) and high-grade (≥grade 3) fatigue (1.97; 95% CI1.44-2.70; p < 0.0001). On subgroup analysis, the risk ratio (RR) of all-grade fatigue varied significantly within drug type, but high-grade fatigue did not. The RR of all-grade and high-grade fatigue did not vary significantly according to cancer type, treatment line, and treatment duration. The risk of high-grade fatigue may vary with treatment duration, whereas all-grade fatigue may not. The available data suggest that the use of the five newly approved VEGFR-TKIs is associated with a significantly increased risk of fatigue in cancer patients. Physicians should be aware of this adverse effect and should monitor cancer patients receiving these drugs.

Topics: Anilides; Axitinib; Fatigue; Humans; Imidazoles; Indazoles; Neoplasms; Odds Ratio; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Quinolines; Receptors, Vascular Endothelial Growth Factor

The old-fashioned anticancer approaches, aiming at arresting cancer cell proliferation interfering with non-specific targets (e.g. DNA), have been replaced, in the last decades, by more specific target oriented ones. Nonetheless, single-target approaches have not always led to optimal outcomes because, for its complexity, cancer needs to be tackled at various levels by modulation of several targets. Although at present, combinations of individual singletarget drugs represent the most clinically practiced therapeutic approaches, the modulation of multiple proteins by a single drug, in accordance with the polypharmacological strategy, has become more and more appealing. In the perspective of a multi-target approach, the closely related evolutionary members of the tyrosine kinase family are ideal candidates. Indeed, tyrosine kinase activities are not only critical in tumor phenotype maintenance, but also modulate several functions in the tumor microenvironment. Consequently, several multikinase inhibitors were approved in the last decade, and many new molecules are currently in preclinical or clinical development. In the present review we report on the most widely FDA-approved multitargeted drugs, discussing about their mechanism of action and outlining the clinical trials that have brought them to approval.

Topics: Anilides; Crizotinib; Humans; Imatinib Mesylate; Imidazoles; Indoles; Neoplasms; Niacinamide; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridazines; Pyridines; Pyrroles; Quinazolines; Receptor Protein-Tyrosine Kinases; Sorafenib; Sunitinib

Cabozantinib (XL184) is an oral inhibitor of multiplereceptor tyrosine kinases including mesenchymal-epithelial transition factor (MET) and vascular endothelial growth factor receptor 2 (VEGFR2). Hypertension is one of its major side effects, but the incidence rate and overall risk has not been systematically studied. We thus conducted this meta-analysis to investigate the overall incidence and risk of developing hypertension in cancer patients treated with cabozantinib.. Pubmed, Embase and oncology conference proceedings were searched for relevant studies. Eligible studies were phase II and III prospective clinical trials of cabozantinib in cancer patients with data on hypertension available. A total of 1,514 patients (cabozantinib, 1083; control, 431) with a variety of solid tumors from 8 prospective clinical trials were included for the meta-analysis. The use of cabozantinib was associated with significantly increased risk of developing all grade (RR 5.48; 95%CI, 3.76-7.99; p < 0.001) and high grade (5.09; 95% CI: 2.71-9.54, p < 0.001) hypertension in comparison with controls. Additionally, the risk of high grade hypertension with cabozantinib was substantially higher than other four approved VEGFR-TKIs (sorafenib, sunitinib, vandetanib and pazopanib). Expert commentary: Cancer patients receiving cabozantinib have an increased risk of developing hypertension. Close monitoring and management of hypertension are recommended.

Topics: Anilides; Antineoplastic Agents; Clinical Trials as Topic; Humans; Hypertension; Incidence; Neoplasms; Protein Kinase Inhibitors; Pyridines; Risk

The process of angiogenesis involves the formation of new blood vessels from pre-existing vasculature by the over expression of certain factors leading to the growth and development of all solid tumor types. Hepatocyte growth factor receptor abbreviated as c-Met and vascular endothelial growth factor abbreviated as VEGF are some of the factors responsible for the induction in tumor growth and development. Recently a number of analogues associated with these receptors are under study. US FDA on November 29, 2012 approved a drug named cabozantinib formerly known as XL184 which is being marketed under the trade name of Cometriq for the treatment of Medullary Thyroid Cancer (MTC). Designing of the drug has been done in such a fashion that it can inhibit both VEGFR2 and c-Met simultaneously without over expressing any of the factors leading to the inhibition of angiogenesis. The drug is still under study for the evaluation of its efficacy in cases of many other solid tumor types including breast cancer, castration resistant prostate cancer (CRPC), renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), gastric or gastroesophageal junction cancer, melanoma, small cell lung cancer (SCLC), ovarian cancer and primary peritoneal or fallopian tube carcinoma. This review article consists of preclinical and clinical data of cabozantinib and its efficacy and safety towards various types of solid tumors.

Topics: Angiogenesis Inhibitors; Anilides; Animals; Humans; Neoplasms; Neovascularization, Pathologic; Protein-Tyrosine Kinases; Pyridines

Cabozantinib is a receptor tyrosine kinase inhibitor with activity against MET, VEGFR2, FLT3, c-KIT, and RET. Activity of cabozantinib toward a broad range of tumor models could be detected in several preclinical studies. Of note, cabozantinib decreases metastasis potential and tumor invasiveness when compared with placebo or agents that target VEGFR and have no activity against MET. Clinical phase I and II studies with cabozantinib have been conducted in various malignancies including medullary thyroid cancer (MTC), NSCLC, breast, ovarian, pancreatic, and prostate cancer. In MTC, gain of function mutations of RET are central for tumorigenesis. Hereditary forms of MTC (MEN II) are caused by germline mutations of RET, in sporadic MTC in up to 50% of cases RET mutations occur. Additionally, activating molecular changes in VEGFR and MET pathways have also been implicated in MTC progression. Clinical responses with cabozantinib in MTC could be observed in early clinical trials, and following confirmation of clinical benefit in a randomized phase III trial, cabozantinib gained FDA approval for first-line treatment of advanced MTC in 2012. In prostate cancer models, MET expression increases with androgen ablation and clinical progression of bone and lymph node metastasis. A phase II trial with cabozantinib also showed very promising response rates in patients with metastatic prostate cancer. Therefore, randomized phase III studies are currently ongoing to validate the efficacy of cabozantinib in heavily pretreated prostate cancer patients.

Topics: Anilides; Animals; Antineoplastic Agents; Humans; Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Proto-Oncogene Proteins c-ret; Pyridines; Vascular Endothelial Growth Factor Receptor-2

The c-Met/hepatocyte growth factor receptor and its family members are known to promote cancer cell migration and invasion. Signaling within and beyond this pathway contributes to the systemic spread of metastases through induction of the epithelial-mesenchymal transition, a process also implicated in mediating resistance to current anticancer therapies, including radiation. Induction of c-Met has also been observed after irradiation, suggesting that c-Met participates in radiation-induced disease progression through the epithelial-mesenchymal transition. Therefore, c-Met inhibition is an attractive target for potentially mitigating radiation resistance. This article summarizes key findings regarding crosstalk between radiotherapy and c-Met and discusses studies performed to date in which c-Met inhibition was used as a strategy to increase cellular radiosensitivity.

Topics: Anilides; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Cell Movement; DNA Damage; Epithelial-Mesenchymal Transition; Erlotinib Hydrochloride; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Invasiveness; Neoplasms; Neovascularization, Pathologic; Proto-Oncogene Proteins c-met; Pyridines; Pyrrolidinones; Quinazolines; Quinolines; Radiation Tolerance; Signal Transduction; Up-Regulation

XL-184 (cabozantinib) is a novel, small-molecule, multitargeted receptor tyrosine kinase inhibitor with particular activity against hepatocyte growth factor receptor (tyrosine-protein kinase Met), vascular endothelial growth factor receptor 2 (VEGFR-2) and proto-oncogene tyrosine-protein kinase receptor Ret. There is ample evidence of Met, VEGFR-2 and Ret signaling in several tumor types. Preclinical data suggest that XL-184 has activity in tumors derived from both epithelial and mesenchymal origins. Phase I and II clinical studies support significant antitumor activity, particularly in medullary thyroid cancer and cancers metastatic to the bone. This review will evaluate XL-184's preclinical pharmacology, pharmacokinetics, drug interactions and clinical activity in phase I through phase III studies.

Topics: Anilides; Animals; Antineoplastic Agents; Clinical Trials as Topic; Drug Interactions; Drugs, Investigational; Humans; Neoplasms; Proto-Oncogene Mas; Pyridines; Receptor Protein-Tyrosine Kinases

Cabozantinib is an inhibitor of tyrosine kinases, including MET, vascular endothelial growth factor receptor, AXL and RET. This multi-cohort phase II randomised discontinuation trial explored anticancer activity of cabozantinib in nine tumour types.. Cabozantinib was administered (100 mg, once daily) to patients with advanced, recurrent or metastatic cancers. Those with stable disease at week 12 were randomised 1:1 to cabozantinib or placebo. Primary end-points were objective response rate (ORR) at week 12 and progression-free survival (PFS) in the randomised phase.. A total of 526 patients were enrolled. The highest ORR was observed in ovarian cancer (OC) (21.7%); the largest PFS benefit was observed in castration-resistant prostate cancer (CRPC) (median 5.5 versus 1.4 months for placebo; hazard ratio 0.14, 95% confidence interval: 0.04, 0.52). Disease control rates were >40% for CRPC, OC, melanoma, metastatic breast cancer (MBC), hepatocellular carcinoma (HCC) and non-small cell lung cancer. Median duration of response ranged from 3.3 (MBC) to 11.2 months (OC). Encouraging efficacy results and symptomatic improvements prompted early suspension of the randomised stage and conversion to open-label non-randomised expansion cohorts. Dose reductions to manage adverse events (AEs) occurred in 48.7% of patients. The most frequent grade III-IV AEs were fatigue (12.4%), diarrhoea (10.5%), hypertension (10.5%) and palmar-plantar erythrodysesthesia syndrome (8.7%).. Clinical antitumour activity of cabozantinib was observed in a subset of tumour types: CRPC and OC were evaluated further in expansion cohorts. Phase III programs were initiated in CRPC and HCC. Interpretation of efficacy outcomes was limited by early termination of the randomised portion of the trial.. NCT00940225.

Topics: Anilides; Antineoplastic Agents; Belgium; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Early Termination of Clinical Trials; Female; Humans; Israel; Kaplan-Meier Estimate; Male; Neoplasms; Protein Kinase Inhibitors; Pyridines; Taiwan; Time Factors; Treatment Outcome; United States

The case report describes the presentation of incident heart failure with reduced ejection fraction, following Cabozantinib chemotherapy. In contrast to previous cases, despite maximal medical therapy for this gentleman it became irreversible and contributed to his death. Hence the case illustrates the potential cardiotoxicity of Cabozantinib and reinforces the need for co-ordinated multi-disciplinary team care for such patients. Within existing cardio-oncology infrastructure, it may mean that such patients require enhanced echocardiographic surveillance.

Topics: Anilides; Heart Failure; Humans; Neoplasms; Ventricular Dysfunction, Left

In patients with renal cell carcinoma (RCC) on cabozantinib, venous thromboembolism (VTE) management remains challenging due to limited safety data regarding direct oral anticoagulants (DOACs) use in conjunction with cabozantinib. We investigated the safety of cabozantinib with different anticoagulants in patients with RCC.. In this retrospective multicenter study (9 sites), patients with advanced RCC were allocated into 4 groups: (1) cabozantinib without anticoagulation, cabozantinib with concomitant use of (2) DOACs, (3) low molecular weight heparin (LMWH), or (4) warfarin. The primary safety endpoint was the proportion of major bleeding events (defined per International Society on Thrombosis and Hemostasis criteria). The primary efficacy endpoint was the proportion of new/recurrent VTE while anticoagulated.. Between 2016 and 2020, 298 patients with RCC received cabozantinib (no anticoagulant = 178, LMWH = 41, DOAC = 64, and warfarin = 15). Most patients had clear cell histology (78.5%) and IMDC intermediate/poor disease (78.2%). Cabozantinib was first, second, or ≥ third line in 21.8%, 31.9%, 43.3% of patients, respectively. Overall, there was no difference in major bleeding events between the no anticoagulant, LMWH, and DOAC groups (P = .088). Rate of new/recurrent VTE was similar among anticoagulant groups. Patients with a VTE had a statistically significantly worse survival than without a VTE (HR 1.48 [CI 95% 1.05-2.08, P = .02]).. This real-world cohort provides first data on bleeding and thrombosis complications in patients with RCC treated with cabozantinib with or without concurrent anticoagulation. DOACs appear safe for VTE treatment for patients with RCC on cabozantinib, but optimized anticoagulation management, including individualized risk-benefit discussion, remains important in clinical practice.

Topics: Administration, Oral; Anticoagulants; Carcinoma, Renal Cell; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Kidney Neoplasms; Neoplasms; Venous Thromboembolism; Warfarin

Topics: Humans; Immunity; Killer Cells, Natural; Neoplasms; Protein Kinase Inhibitors; Tyrosine Kinase Inhibitors

Some studies indicate that the angiogenesis process is related to vascular endothelial growth factor, which can interact with endothelial cell surface receptors (VEGF-R1, VEGF-R2, and VEGF-R3); this biochemical process and other factors result in the promotion and growth of new blood vessels under normal conditions. However, some studies indicate that this phenomenon could also occur in cancer cells. It is important to mention that some amino derivatives have been prepared as VEGF-R1 inhibitors; however, their interaction with VEGF-R1 is not clear, perhaps due to different experimental approaches or differences in their chemical structure.. The aim of this study was to evaluate the theoretical interaction of several amino-nitrile derivatives (Compounds 1 to 38) with VEGF-R1.. The theoretical interaction of amino-nitrile derivatives with VEGF-R1 was carried out using the 3hng protein as the theoretical model. In addition, cabozantinib, pazopanib, regorafenib, and sorafenib were used as controls in the DockingServer program.. The results showed different amino acid residues involved in the interaction of amino-nitrile derivatives with the 3hng protein surface compared with the controls. In addition, the inhibition constant (Ki) was lower for Compounds 10 and 34 than for cabozantinib. Other results show that Ki for Compounds 9, 10, 14, 27-29 and 34-36 was lower in comparison with pazopanib, regorafenib, and sorafenib.. All theoretical data suggest that amino-nitrile derivatives could produce changes in the growth of some cancer cell lines through VEGFR-1 inhibition. Therefore, these amino-nitrile derivatives could be a therapeutic alternative to treat some types of cancer.

Topics: Humans; Models, Theoretical; Neoplasms; Sorafenib; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

Topics: Adaptor Proteins, Signal Transducing; Anilides; Crizotinib; Golgi Matrix Proteins; Humans; Neoplasms; Protein-Tyrosine Kinases; Proto-Oncogene Proteins

Clinical trials using Cabozantinib have shown promising results in metastatic breast cancer. This efficacy mainly results from removing and/or polarization of tumor-promoting myeloid cells. Nevertheless, whether such myeloid-derived suppressor cells (MDSCs) depletion can be used to improve the efficacy of anti-HER2 antibodies in early breast cancer has not been defined yet.. BALB/c mice were inoculated with 4T1 and 4T1-HER2 murine tumor cell lines, and after 7 days, the mice were divided into different groups. Cabozantinib was orally administrated for 15 consecutive days, and anti-HER2 monoclonal antibody (mAb) 1 T0 was intraperitoneally injected twice a week. Tumor size was measured every other day.. Our findings indicated that Cabozantinib combined with anti-HER2 mAb dramatically reduced tumor growth and increased tumor rejection (p = 0.0001). Flow cytometry analysis showed MDSC population decreased in TME, lymph nodes, and spleens by roughly 20%, 0.8%, and 35%, respectively. Myeloid suppressive phenotype was altered through inhibition of the expression of immunosuppressive factor Arg-1. Cytokine profiling of different groups indicated that the level of INF-γ was approximately two times higher than that in the control group, and IL-17 increased compared to the control group. However, IL-4 level was significantly reduced in the groups treated with Cabozantinib. These could bring about a 10% increase in CD8. Collectively, our data provide pre-clinical evidence for using Cabozantinib to reshape the primary TME, which can enhance the effectiveness of anti-HER2 mAb immunotherapy in primary breast cancer.

Topics: Animals; Antibodies, Monoclonal; Immunologic Factors; Immunotherapy; Mice; Mice, Inbred BALB C; Myeloid-Derived Suppressor Cells; Neoplasms

Rare oncogenic NTRK gene fusions result in uncontrolled TRK signaling leading to various adult and pediatric solid tumors. Based on the architecture of our multi-targeted clinical candidate BPR1K871 (10), we designed and synthesized a series of quinazoline compounds as selective and orally bioavailable type II TRK inhibitors. Property-driven and lead optimization strategies informed by structure-activity relationship studies led to the identification of 39, which showed higher (about 15-fold) selectivity for TRKA over AURA and AURB, as well as potent cellular activity (IC

Topics: Administration, Oral; Animals; Aurora Kinase A; Aurora Kinase B; Binding Sites; Cell Line, Tumor; Drug Design; Half-Life; Humans; Mice; Mice, Nude; Molecular Docking Simulation; Neoplasms; Protein Kinase Inhibitors; Rats; Receptor, trkA; Structure-Activity Relationship; Transplantation, Heterologous

Topics: Adrenal Insufficiency; Angiogenesis Inhibitors; Anilides; Antineoplastic Combined Chemotherapy Protocols; Drug Synergism; Humans; Immune Checkpoint Inhibitors; Neoplasms; Nivolumab; Pyridines; Risk Assessment

A series of 21 novel N

Topics: Apoptosis; Cell Movement; Cell Proliferation; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; HT29 Cells; Humans; Neoplasms; Phosphorylation; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-met; Thiazolidines; Urea

Topics: Animals; Antineoplastic Agents; Aurora Kinase A; Aurora Kinase B; Azepines; Cell Line, Tumor; Humans; Mice; Mice, Nude; Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Vascular Endothelial Growth Factor Receptor-2

c-Met and VEGFR-2 have attracted interest as novel targets for treatment of various cancers. Aiming to develop potent dual c-Met and VEGFR-2 inhibitors, a series of pyrrolo[1,2-f][1,2,4]triazine derivatives were designed and synthesized. The majority of target compounds exhibited potent antiproliferative effect against c-Met addictive cancer cell lines with IC

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; Humans; Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrroles; Triazines; Vascular Endothelial Growth Factor Receptor-2

An integrated population pharmacokinetic (popPK) model was developed to describe the pharmacokinetics (PK) of tyrosine kinase inhibitor cabozantinib in healthy volunteers (HVs) and patients with various cancer types and to identify any differences in cabozantinib PK across these populations.. Plasma concentration data used to develop the popPK model were obtained from nine clinical trials (8072 concentrations from 1534 HVs or patients) of cabozantinib in HVs and patients with renal cell carcinoma (RCC), medullary thyroid carcinoma (MTC), glioblastoma multiforme, castration-resistant prostate cancer, or other advanced malignancies.. PK data across studies were adequately characterized by a two-compartment disposition model with dual first- and zero-order absorption processes and first-order elimination. Baseline demographic covariates (age, weight, gender, race, and cancer type) were generally predicted to have a small-to-moderate impact on apparent clearance (CL/F). However, MTC cancer type did show an approximately 93% higher CL/F relative to HVs following chronic dosing, resulting in approximately 40-50% lower predicted steady-state cabozantinib plasma concentrations.. This popPK analysis showed cabozantinib CL/F values to be higher for patients with MTC and may account for the higher dosage required in this patient population (140-mg) to achieve plasma exposures comparable to those in patients with RCC and other tumor types administered a 60-mg cabozantinib tablet dose. Possible factors that may underlie the higher cabozantinib clearance observed in MTC patients are discussed.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anilides; Antineoplastic Agents; Clinical Trials as Topic; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Models, Biological; Neoplasms; Protein Kinase Inhibitors; Pyridines; Young Adult

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Humans; Isoxazoles; Mice; Models, Molecular; Mutation; Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Pyrazoles

In this study, a series of novel pyridine and pyrimidine-containing derivatives were designed, synthesized and biologically evaluated for their c-Met inhibitory activities. In the biological evaluation, half of the target compounds exhibited moderate to potent c-Met inhibitory activities. Among which, it is noteworthy that compounds 13d not only showed most potent c-Met inhibitory potency but also displayed excellent anti-proliferative activity (IC

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; Humans; Molecular Docking Simulation; Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyridines; Pyrimidines

Cabozantinib (XL184) is a small molecule tyrosine kinase receptor inhibitor, which targets c-Met and VEGFR2. Cabozantinib has been approved by the Food and Drug Administration to treat advanced medullary thyroid cancer and renal cell carcinoma. In the present study, we evaluated the ability of cabozantinib to modulate the function of the ATP-binding cassette subfamily G member 2 (ABCG2) by sensitizing cells that are resistant to ABCG2 substrate antineoplastic drugs. We used a drug-selected resistant cell line H460/MX20 and three ABCG2 stable transfected cell lines ABCG2-482-R2, ABCG2-482-G2, and ABCG2-482-T7, which overexpress ABCG2. Cabozantinib, at non-toxic concentrations (3 or 5μM), sensitized the ABCG2-overexpressing cells to mitoxantrone, SN-38, and topotecan. Our results indicate that cabozantinib reverses ABCG2-mediated multidrug resistance by antagonizing the drug efflux function of the ABCG2 transporter instead of downregulating its expression. The molecular docking analysis indicates that cabozantinib binds to the drug-binding site of the ABCG2 transporter. Overall, our findings demonstrate that cabozantinib inhibits the ABCG2 transporter function and consequently enhances the effect of the antineoplastic agents that are substrates of ABCG2. Cabozantinib may be a useful agent in anticancer treatment regimens for patients who are resistant to ABCG2 substrate drugs.

Topics: Anilides; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily G, Member 2; Cell Line, Tumor; Drug Resistance, Neoplasm; HEK293 Cells; Humans; Mitoxantrone; Molecular Docking Simulation; Neoplasms; Pyridines; Topoisomerase I Inhibitors; Topotecan

Growing awareness of the complexity of carcinogenesis has made multimodal therapies for cancer increasingly compelling and relevant. In recent years, immunotherapy has gained acceptance as an active therapeutic approach to cancer treatment, even though cancer is widely considered an immunosuppressive disease. Combining immunotherapy with targeted agents that have immunomodulatory capabilities could significantly improve its efficacy.. We evaluated the ability of cabozantinib, a receptor tyrosine kinase inhibitor, to modulate the immune system in vivo as well as alter the phenotype of tumor cells in vitro in order to determine if this inhibitor could act synergistically with a cancer vaccine.. Our studies indicated that cabozantinib altered the phenotype of MC38-CEA murine tumor cells, rendering them more sensitive to immune-mediated killing. Cabozantinib also altered the frequency of immune sub-populations in the periphery as well as in the tumor microenvironment, which generated a more permissive immune environment. When cabozantinib was combined with a poxviral-based cancer vaccine targeting a self-antigen, the combination significantly reduced the function of regulatory T cells and increased cytokine production from effector T cells in response to the antigen. These alterations to the immune landscape, along with direct modification of tumor cells, led to markedly improved antitumor efficacy.. These studies support the clinical combination of cabozantinib with immunotherapy for the treatment of cancer.

Topics: Anilides; Animals; Biomarkers, Tumor; Cancer Vaccines; Cell Line, Tumor; Cell Proliferation; Combined Modality Therapy; Cytotoxicity, Immunologic; Female; Immunotherapy; Lymphocyte Subsets; Mice, Inbred C57BL; Mice, Transgenic; Neoplasms; Phenotype; Pyridines; Small Molecule Libraries; T-Lymphocytes; Tumor Microenvironment

The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a number of human malignancies and has been associated with tumorigenesis. Cabozantinib (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. Treatment with cabozantinib inhibited MET and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro. In mouse models, cabozantinib dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target MET. Collectively, these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling.

Topics: Angiogenesis Inhibitors; Anilides; Animals; Cell Growth Processes; Cell Line, Tumor; Drug Evaluation, Preclinical; Female; Humans; Mice; Mice, Nude; Models, Biological; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyridines; Vascular Endothelial Growth Factor Receptor-2