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.
Prostate Cancer Hepatocyte Growth Factor Tyrosine Kinase Inhibitor Maximum Tolerate Dose Medullary Thyroid Cancer
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Bean J et al (2007) MET amplification occurs with or without T790 M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci USA 104(52):20932–20937PubMedCentralPubMedCrossRefGoogle Scholar
Bussolino F et al (1992) Hepatocyte growth-factor is a potent angiogenic factor which stimulates endothelial-cell motility and growth. J Cell Biol 119(3):629–641PubMedCrossRefGoogle Scholar
Direnzo MF et al (1995) Overexpression and amplification of the Met/Hgf receptor gene during the progression of colorectal-cancer. Clin Cancer Res 1(2):147–154Google Scholar
Houldsworth J et al (1990) Gene amplification in gastric and esophageal adenocarcinomas. Cancer Res 50(19):6417–6422PubMedGoogle Scholar
Kurzrock R et al (2011) Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol 29(19):2660–2666PubMedCentralPubMedCrossRefGoogle Scholar
Matsumoto K, Nakamura T (2001) Hepatocyte growth factor: renotropic role and potential therapeutics for renal diseases. Kidney Int 59(6):2023–2038PubMedCrossRefGoogle Scholar
Mizuno S, Matsumoto K, Nakamura T (2001) Hepatocyte growth factor suppresses interstitial fibrosis in a mouse model of obstructive nephropathy. Kidney Int 59(4):1304–1314PubMedCrossRefGoogle Scholar
Nakagawa T et al (2012) Combined therapy with mutant-selective EGFR inhibitor and met kinase inhibitor for overcoming erlotinib resistance in EGFR-mutant lung cancer. Mol Cancer Ther 11(10):2149–2157PubMedCrossRefGoogle Scholar
Schmidt L et al (1997) Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet 16(1):68–73PubMedCrossRefGoogle Scholar
Schoffski P et al (2012) An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantinib (XL184) in medullary thyroid carcinoma (MTC) patients (pts) with documented RECIST progression at baseline. J Clin Oncol 30(15)Google Scholar
Sennino B et al (2012) Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov 2(3):270–287PubMedCentralPubMedCrossRefGoogle Scholar
Sirotnak FM et al (2004) Microarray analysis of progression to reduced prostate cancer androgen dependence: studies in unique models contrasts early and late molecular events. Mol Carcinog 41(3):150–163PubMedCrossRefGoogle Scholar
Smith DC et al (2013) Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol 31(4):412–419PubMedCrossRefGoogle Scholar
Soman NR et al (1991) The Tpr-Met oncogenic rearrangement is present and expressed in human gastric-carcinoma and precursor lesions. Proc Natl Acad Sci USA 88(11):4892–4896PubMedCentralPubMedCrossRefGoogle Scholar
Takayama H et al (1996) Scatter factor/hepatocyte growth factor as a regulator of skeletal muscle and neural crest development. Proc Natl Acad Sci USA 93(12):5866–5871PubMedCentralPubMedCrossRefGoogle Scholar
Trusolino L, Comoglio PM (2002) Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nat Rev Cancer 2(4):289–300PubMedCrossRefGoogle Scholar
Verras M et al (2007) The androgen receptor negatively regulates the expression of c-Met: implications for a novel mechanism of prostate cancer progression. Cancer Res 67(3):967–975PubMedCrossRefGoogle Scholar
Yakes FM et al (2011) Cabozantinib (XL184), a Novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther 10(12):2298–2308PubMedCrossRefGoogle Scholar