cabozantinib and Carcinoma

Incidence of bone metastases is very high in advanced prostate cancer patients. Bone metastases likely have a significant impact on functional status and quality of life, not only related to pain, but also to the relevant risk of skeletal-related events. A better understanding of mechanisms associated with bone metastatic disease secondary to prostate cancer and more specifically to the cross-talk between tumor cells and bone microenvironment in metastatic progression represented the background for the development of new effective bone-targeted therapies. Furthermore, a better knowledge of biological mechanisms driving disease progression led to significant advances in the treatment of castration-resistant prostate cancer, with the development and approval of new effective drugs. Aim of this review is to outline the physiopathology of bone metastases in prostate cancer and summarize the main results of clinical trials conducted with different drugs to control morbidity induced by skeletal metastases and bone disease progression. For each agent, therapeutic effect on bone metastases has been measured in terms of pain control and/or incidence of skeletal-related events, usually defined as a composite endpoint, including the need for local treatment (radiation therapy or surgery), spinal cord compression, pathological bone fractures. In details, data obtained with chemotherapy (mitoxantrone, docetaxel, cabazitaxel), new generation hormonal agents (abiraterone, enzalutamide), radium-223, bone-targeted agents (zoledronic acid, denosumab) and with several experimental agents (cabozantinib, dasatinib, anti-endothelin and other agents) in patients with castration-resistant prostate cancer are reviewed.

Topics: Androstenes; Anilides; Antineoplastic Agents; Benzamides; Bone Density Conservation Agents; Bone Neoplasms; Carcinoma; Dasatinib; Denosumab; Diphosphonates; Docetaxel; Humans; Imidazoles; Male; Mitoxantrone; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Pyridines; Radioisotopes; Radium; Taxoids; Zoledronic Acid

Improved understanding of mechanisms underlying metastatic castration-resistant prostate cancer (mCRPC) progression has led to the recognition of multiple molecular targets and advances in the therapeutic landscape. The addition of abiraterone acetate, sipuleucel-T, cabazitaxel, and denosumab to the therapeutic armamentarium and the impending addition of MDV-3100 and radium-223 underscore the importance of androgen pathway inhibition, immunotherapy, tubulin antagonism, and pathophysiology of bone metastasis.. Review the next generation of molecular targets in mCRPC.. Medline databases were searched for >100 original articles published as of October 18, 2011, with the search terms metastatic castration-resistant prostate cancer, targeted therapy, biologic agents, and immunotherapy. Proceedings from the last 5 yr of conferences of the American Society of Clinical Oncology, American Urological Association, European Society of Medical Oncology, and the European Association of Urology were also searched. We included novel and promising drugs that have reached clinical trial evaluation.. The major findings were addressed in an evidence-based fashion. Prospective trials and important preclinical data were analyzed.. mCRPC is a disease with multiple molecular drivers. Molecular pathways being targeted in ongoing phase 3 trials are androgen signaling (MDV3100, TAK700), immunoregulatory pathways (ipilimumab, Prostvac-VF-TRICOM), Src (dasatinib), Met (cabozantinib), clusterin (custirsen), and angiogenesis (aflibercept, tasquinimod). The strides made in identifying multiple other novel molecular targets offer potential opportunities for further improving outcomes.

Topics: Abiraterone Acetate; Androstadienes; Anilides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzamides; Bone Neoplasms; Cancer Vaccines; Carcinoma; Clinical Trials, Phase III as Topic; Clusterin; Dasatinib; Denosumab; Humans; Ipilimumab; Male; Nitriles; Orchiectomy; Phenylthiohydantoin; Prostatic Neoplasms; Pyridines; Pyrimidines; Quinolines; Quinolones; Radium; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Taxoids; Thiazoles; Tissue Extracts; Treatment Outcome; Vaccines, Synthetic

Cabozantinib (XL184), an orally bioavailable inhibitor of vascular endothelial growth factor receptor 2 and MET, was assessed in a cohort of ovarian carcinoma patients as part of a phase 2 randomised discontinuation trial (RDT) with cohorts from nine different tumour types.. Patients received 100-mg cabozantinib daily. Those with stable disease (SD) per Response Evaluation Criteria in Solid Tumors at week 12 were randomised to cabozantinib or placebo. Primary end-points were objective response rate (ORR) at week 12 and progression-free survival (PFS) after random assignment.. Seventy patients with ovarian carcinoma, 50% of whom were platinum refractory/resistant, were enrolled in this RDT. Median PFS from day 1 was 5.5 months for all patients. The ORR at week 12 was 21%; one patient achieved a complete response (CR), and 14 patients (20%) achieved a confirmed partial response (PR). The overall disease control rate (CR + PR + SD) at week 12 was 50%. Throughout the study, 70% of the patients with ≥1 postbaseline scan had tumour regression, and randomisation was discontinued early. For patients with SD randomised to cabozantinib, PFS was 5.9 months after randomisation. The most common grade 3/4 adverse events were diarrhoea (14%), palmar-plantar erythrodysesthesia syndrome (6%), asthenia (6%), hypertension (6%) and neutropenia (6%). Dose reductions were required in 37% of the patients during the first 12 weeks.. Cabozantinib demonstrates clinical activity, with acceptable toxicities, in patients with ovarian carcinoma based on ORR and regression of tumour target lesions.. This trial is registered at ClinicalTrial.gov (NCT00940225).

Topics: Adult; Aged; Anilides; Antineoplastic Agents; Carcinoma; Female; Humans; Middle Aged; Ovarian Neoplasms; Protein Kinase Inhibitors; Pyridines; Survival Analysis

Cabozantinib targets tyrosine kinases including MET, vascular endothelial growth factor (VEGF) receptor 2, and rearranged during transfection (RET). Differentiated thyroid cancer (DTC) is a tumor type that may be sensitive to cabozantinib. Therefore, we evaluated cabozantinib in a cohort of heavily pretreated patients with metastatic DTC.. This single-arm open-label phase I trial assessed the safety, tolerability, and antitumor activity of cabozantinib in DTC patients taking part in a drug-drug interaction study. Adult patients with histologically confirmed metastatic or surgically unresectable DTC (including papillary, follicular, or Hürthle cell) were enrolled. Patients received daily oral dosing of 140 mg cabozantinib. Safety was assessed by evaluation of adverse events (AEs), vital signs, electrocardiograms, laboratory tests, and concomitant medications. Tumor response by magnetic resonance imaging or computed tomography scan was investigator assessed using Response Evaluation Criteria In Solid Tumors (RECIST) v1.0.. The study enrolled 15 patients who had failed standard radioactive iodine therapy. Patients had received a median of two prior systemic agents, and 11 patients (73%) had previously received at least one VEGF pathway inhibiting therapy. Common AEs included diarrhea, nausea, fatigue, and decreased appetite. Partial response was reported in eight patients (53%). Median progression-free survival and median overall survival were not reached.. Cabozantinib demonstrates a safety profile similar to other multitargeted VEGFR inhibitors in advanced DTC patients. The antitumor activity observed in this study warrants further investigation of cabozantinib in patients with advanced DTC.

Topics: Administration, Oral; Adult; Aged; Anilides; Antineoplastic Agents; Carcinoma; Cell Differentiation; Disease-Free Survival; Drug Administration Schedule; Humans; Kaplan-Meier Estimate; Magnetic Resonance Imaging; Male; Middle Aged; Protein Kinase Inhibitors; Pyridines; Thyroid Neoplasms; Time Factors; Tomography, X-Ray Computed; Treatment Outcome; United States

Local or metastatic relapse following surgery, radiotherapy, and cisplatin is the leading cause of death in patients with head and neck squamous cell carcinoma (HNSCC). Our study shows overexpression of c-MET and AXL in HNSCC cells and patients resistant to radiotherapy and cisplatin. We demonstrate that cabozantinib, an inhibitor of vascular endothelial growth factor receptor (VEGFR), c-MET, and AXL, decreases migration, invasion, and proliferation and induces mitotic catastrophe and apoptotic cell death of naive and radiotherapy- and cisplatin-resistant HNSCC cells. Cabozantinib inhibits the growth and metastatic spread of experimental HNSCC in zebrafish and the growth of experimental HNSCC in mice by blocking tumor cell proliferation and angiogenesis. The efficacy of cabozantinib is also confirmed on viable sections of surgically removed specimens of human HNSCC and on a patient who relapses after five lines of treatment. These results suggest that cabozantinib is relevant for the treatment of patients with HNSCC after relapse under radiotherapy and cisplatin.

Topics: Anilides; Animals; Carcinoma; Cell Line, Tumor; Cisplatin; Head and Neck Neoplasms; Humans; Mice; Neoplasm Recurrence, Local; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-met; Pyridines; Receptor Protein-Tyrosine Kinases; Squamous Cell Carcinoma of Head and Neck; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays; Zebrafish

Although epidermal growth factor receptor (EGFR) has been identified as a potent "oncogenic driver" in various tumors of epithelial origin, EGFR-targeted therapies are often of limited success. One of the challenges of improving targeted therapies is to overcome bypassing signaling pathways. Analysis of RNA-seq data of 1006 cell lines from the Cancer Cell Line Encyclopedia (CCLE) revealed that more than 12% of carcinoma cell lines expressed markedly elevated mRNA levels of colony-stimulating factor (CSF)-1 receptor (CSF-1R). Since epithelial cells also express CSF-1, elevated levels of CSF-1R may participate in providing alternative growth and survival signals under targeted therapies. To address this question, we ectopically expressed CSF-1R in A431 cells that express EGFR at high levels, but no biologically relevant level of CSF-1R. In the presence of EGFR inhibitor gefitinib, CSF-1R provided a significant growth advantage in A431 cells. As expected, activation of both receptors, EGFR or CSF-1R, induced phosphorylation of extracellular signal-regulated kinase (Erk)1/2, Akt, protein kinase C (PKC) and signal transducer and activator of transcription (STAT)3. However, EGFR, but not CSF-1R, also induced STAT5 phosphorylation. Inhibitor of phosphatidylinositol 3-kinase (PI3K) (AZD8186), MAPK/ERK kinase (MEK)1/2 (U0126), PKCs (Bisindolylmaleimide I or Gö6976) or STAT3 (Stattic) partially reduced proliferation of CSF-1R expressing A431 cells in the presence of gefitinib. Moreover, multi-kinase inhibitor, cabozantinib, suppressed CSF-1R activation and drastically reduced cell growth when combined with gefitinib. These data suggest that CSF-1R has the potential to reduce sensitivity to gefitinib and may be involved in resistance development.

Topics: Anilides; Animals; Antineoplastic Agents; Carcinoma; Cell Proliferation; Databases, Genetic; Drug Resistance, Neoplasm; ErbB Receptors; Gefitinib; HeLa Cells; Hep G2 Cells; Humans; Macrophage Colony-Stimulating Factor; Macrophages; Mice; Mice, Inbred C57BL; Phosphorylation; Pyridines; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; Signal Transduction; Skin Neoplasms

MET has gained interest as a therapeutic target for a number of malignancies because of its involvement in tumorigenesis, invasion and metastasis. At present, a number of inhibitors, both antibodies against MET or its ligand hepatocyte growth factor, and small molecule MET tyrosine kinase inhibitors are in clinical trials. We here describe a novel variant of MET that is expressed in 6% of high-grade gliomas. Characterization of this mutation in a glioma cell line revealed that it consists of an intronic deletion, resulting in a splice event connecting an intact splice donor site in exon 6 with the next splice acceptor site being that of exon 9. The encoded protein lacks parts of the extracellular IPT domains 1 and 2, encoded by exons 7 and 8, resulting in a novel pseudo-IPT and is named MET(Δ7-8). MET(Δ7-8) is located predominantly in the cytosol and is constitutively active. The auto-activating nature of MET(Δ7-8), in combination with a lack of transmembrane localization, renders MET(Δ7-8) not targetable using antibodies, although the protein is efficiently deactivated by MET-specific tyrosine kinase inhibitors. Testing of MET-expressing tumors for the presence of this variant may be important for treatment decision making.

Topics: Anilides; Animals; Antibodies; Carcinoma; Cell Line, Tumor; Female; Glioma; Hepatocyte Growth Factor; Humans; Male; Mice; Neoplasm Grading; Neoplasm Transplantation; Prostatic Neoplasms, Castration-Resistant; Protein Conformation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyridines; RNA, Messenger; Sarcoma; Sequence Deletion

Adrenocortical carcinoma is a rare malignancy with poor prognosis and limited response to chemotherapy. Hepatocyte growth factor (HGF) and its receptor cMET augment cancer growth and resistance to chemotherapy, but their role in adrenocortical carcinoma has not been examined. In this study, we investigated the association between HGF/cMET expression and cancer hallmarks of adrenocortical carcinoma. Transcriptomic and immunohistochemical analyses indicated that increased HGF/cMET expression in human adrenocortical carcinoma samples was positively associated with cancer-related biologic processes, including proliferation and angiogenesis, and negatively correlated with apoptosis. Accordingly, treatment of adrenocortical carcinoma cells with exogenous HGF resulted in increased cell proliferation in vitro and in vivo while short hairpin RNA-mediated knockdown or pharmacologic inhibition of cMET suppressed cell proliferation and tumor growth. Moreover, exposure of cells to mitotane, cisplatin, or radiation rapidly induced pro-cMET expression and was associated with an enrichment of genes (e.g., CYP450 family) related to therapy resistance, further implicating cMET in the anticancer drug response. Together, these data suggest an important role for HGF/cMET signaling in adrenocortical carcinoma growth and resistance to commonly used treatments. Targeting cMET, alone or in combination with other drugs, could provide a breakthrough in the management of this aggressive cancer.

Topics: Adenoma; Adrenal Cortex Neoplasms; Adult; Aged; Aged, 80 and over; Anilides; Animals; Antineoplastic Agents; Carcinoma; Cell Division; Cell Line, Tumor; Cisplatin; Drug Resistance, Neoplasm; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Hepatocyte Growth Factor; Humans; Male; Mice; Mice, Nude; Middle Aged; Mitotane; Molecular Targeted Therapy; Neoplasm Proteins; Neovascularization, Pathologic; Proto-Oncogene Proteins c-met; Pyridines; RNA Interference; RNA, Small Interfering; Signal Transduction; Transcriptome; Xenograft Model Antitumor Assays

Topics: Anilides; Antineoplastic Agents; Carcinoma; Carcinoma, Neuroendocrine; Clinical Trials as Topic; Cohort Studies; Genotype; Humans; Medical Oncology; Mutation; Phenotype; Pyridines; Thyroid Neoplasms; Treatment Outcome