Antitumor effects of the multi-target tyrosine kinase inhibitor cabozantinib: a comprehensive review of the preclinical evidence.

INTRODUCTION: Altered receptor tyrosine kinase (RTK) signaling contributes to tumorigenesis and suppression of immune-mediated destruction of cancer cells. Cabozantinib is an oral tyrosine kinase inhibitor that inhibits several RTKs involved in tumorigenesis, and is approved for the treatment of patients with progressive metastatic medullary thyroid cancer, advanced renal cell carcinoma, and hepatocellular carcinoma that has been previously treated with sorafenib. AREAS COVERED: We present an up-to-date evaluation of preclinical evidence for RTK inhibition with cabozantinib, specifically VEGFR, MET, KIT, RET, AXL, FLT3, and associated antitumor effects. Preclinical investigations of cabozantinib in combination with other anticancer drugs are also reviewed. EXPERT OPINION: Preclinical evidence shows that cabozantinib has antitumor activity against various cancer cells and exhibits synergy with other anticancer agents, including immune checkpoint inhibitors and hormone receptor or metabolic pathway inhibitors. Further optimization of cabozantinib treatment requires the identification of biomarkers of response and resistance, and exploration of complementary drug targets. Investigation of mechanisms of adaptive resistance, such as epithelial to mesenchymal transition (cancer intrinsic) and immunomodulation by the tumor microenvironment (cancer extrinsic), as well as identification of novel drug targets based on characterization of cancer stem cell metabolomic phenotypes, appear to be promising approaches.

A melanoma subtype with intrinsic resistance to BRAF inhibition identified by receptor tyrosine kinases gene-driven classification.

Dysregulation of receptor tyrosine kinases (RTKs) contributes to several aspects of oncogenesis including drug resistance. In melanoma, distinct RTKs have been involved in BRAF inhibitors (BRAFi) resistance, yet the utility of RTKs expression pattern to identify intrinsically resistant tumors has not been assessed. Transcriptional profiling of RTKs and integration with a previous classification, reveals three robust subtypes in two independent datasets of melanoma cell lines and one cohort of melanoma samples. This classification was validated by Western blot in a panel of patient-derived melanoma cell lines. One of the subtypes identified here for the first time displayed the highest and lowest expression of EGFR and ERBB3, respectively, and included BRAF-mutant tumors all intrinsically resistant to BRAFi PLX4720, as assessed by analysis of the Cancer Cell Line Encyclopedia pharmacogenomic study and by in vitro growth inhibition assays. High levels of EGFR were detected, even before therapy, in tumor cells of one of three melanoma patients unresponsive to BRAFi. Use of different pharmacological inhibitors highlighted the relevance of PI3K/mTOR signaling for growth of this PLX4720-resistant subtype. Our results identify a specific molecular profile of melanomas intrinsically resistant to BRAFi and suggest the PI3K/mTOR pathway as a potential therapeutic target for these tumors.

Mammalian target of rapamycin expression in poorly differentiated endocrine carcinoma: clinical and therapeutic future challenges.

While the mammalian target of rapamycin (mTOR) signaling pathway is a promising target for well-differentiated endocrine carcinoma therapy with the mTOR inhibitor everolimus (RAD001), poorly differentiated endocrine carcinomas (PDECs) are usually excluded from clinical trials due to their aggressiveness. So far, mTOR activity in PDECs has only been tested in cell lines. This study reviewed 36 mono-institutional PDECs to determine mTOR expression. Slides of normal kidney as positive control were used to optimize mTOR staining. To ensure antibody specificity, consecutive sections were incubated in the absence of primary antibody. Immunoreactivity was evaluated on a semi-quantitative scale scoring the extent and intensity of staining. The product of these two scores was used to obtain a total immunostaining score. The main primary site of disease was the pancreas, and 83% of patients had stage IV disease. In 80% of samples, mTOR expression was maintained at similar levels, with no relationship to tumor origin or proliferation rate determined by MIB-1. This study seems to demonstrate that mTOR is expressed in human PDECs regardless of tumor site. Its role in relation to the activity of everolimus in this subset of patients needs to be confirmed.

Elevated chromogranin A (CgA) serum levels in the patients with advanced pancreatic cancer.

The neuroendocrine differentiation in PC could potentially represent a new finding with diagnostic, prognostic and therapeutic implications. This study aimed at evaluating the clinical usefulness of CgA as a neuroendocrine (NE) serum-marker. We investigated the role of the serum concentration of CgA in a study group of patients with PC. CgA was significantly higher in the patients affected by PC as compared with the group of healthy subjects (HS) and those with chronic pancreatitis (CHP) (p<0.001). Also the HS group differed significantly from the CHP control group in the serum CgA levels (p<0.001). The serum carbohydrate antigen (CA19-9) level displayed a significant difference (p<0.001) between the PC and the HS group. The PC and CHP groups, as well as the HS and CHP groups showed also significant differences in the CA19-9 levels (p<0.001). One can conclude that the patients with higher CgA levels had poorer prognosis and survival, as compared to those with lower CgA levels. These results support the notion that the determination of serum CgA level before treatment may be a potential prognostic factor for PC.

L-carnitine treatment reduces steatosis in patients with chronic hepatitis C treated with alpha-interferon and ribavirin.

BACKGROUND: Hepatic steatosis is a common presentation in patients with chronic hepatitis C. Interferon alpha exerts both antiviral and immunomodulating actions, and influences on lipid metabolism. The aim of our study was to test whether L-carnitine reduces steatosis in patients treated with interferon and ribavirin. PATIENTS AND METHODS: A total of 70 patients were randomly assigned to receive either leucocyte IFN alpha at a dose of 3 MIU thrice a week plus 1,000 mg ribavirin per day for 12 months (group A) or IFN alpha and ribavirin at the same dose plus 2 g carnitine per day (group B). RESULTS: Comparison of the two treatments showed significant differences between the mean values of the following parameters at the end of the treatment: ALT -68 vs -95 IU/ml (P < 0.05), total cholesterol 0.08 vs -0.91 mmol/l (P < 0.05) and triglycerides +0.25 vs -20 mmol/l (P < 0.05); and at the follow-up: AST -35 vs -65 IU/ml (P < 0.05) and ALT -55 vs -84 IU/ml (P < 0.05). All values were lower in group B (IFN + Ribavirin + Carnitine) than in group A (IFN plus Ribavirin). When comparing those patients treated with IFN + ribavirin with those treated with IFN plus ribavirin plus carnitine, the response at the end of the treatment was 48% vs 56%, and the sustained response 39% vs 46%, respectively. CONCLUSIONS: Combined treatment with L: -carnitine, ribavirin and IFN alpha resulted in greater antihyperlipidaemic effects and than with ribavirin and IFN alpha alone. The results of this study suggest that L: -carnitine may have a role among the reduction of steatosis strategies in patients with hepatitis C treated with IFN alpha and ribavirin.

Acetyl L-carnitine (ALC) treatment in elderly patients with fatigue.

Fatigue is one of the conditions most frequently complained by the elderly. There are few effective treatment options for patients with chronic fatigue syndrome. To determine the efficacy, tolerability and impact on the fatigue, as well as on cognitive and functional status of elderly subjects with acetyl L-carnitine (ALC), 96 aged subjects (>70 years, range 71-88) were investigated (50 females and 46 males; mean age 76.2+/-7.6 and 78.4+/-6.4 years, respectively). They met four or more of the Holmes major criteria or at least six of Fukuda minor criteria. Fatigue was measured with the Wessely and Powell [Wessely, S., Powell, R., 1989. Fatigue syndromes: a comparison of chronic postviral fatigue with neuromuscular and affective disorders. J. Neurol. Neurosurg. Psychiatry 52, 940-948] scores, with the fatigue severity scale. At the end of the treatment, we observed a decrease of physical fatigue: 6.2 (p<0.001), of mental fatigue: 2.8 (p<0.001), of severity fatigue: 21.0 (p<0.001) and improvements in functional status: 16.1 (p<0.001) and cognitive functions: 2.7 (p<0.001). By the end of the treatment, significant differences between the two groups were found for the following parameters: muscle pain -27% versus -3% (p<0.05); prolonged fatigue after exercise: 51% versus -4% (p<0.0001); sleep disorders: 28% versus 4% (p<0.05); physical fatigue: 7 versus -0.5 (p<0.0001); mental fatigue: -3.3 versus 0.6 (p<0.0001); fatigue severity scale: -22.5 versus 1.2 (p<0.0001); functional status 17.1 versus 0.6 (p<0.0001); mini mental state examination (MMSE) improvements: 3.4 versus 0.5 (p<0.0001). Our data show that administering ALC may reduce both physical and mental fatigue in elderly and improves both the cognitive status and physical functions.

L-Carnitine treatment reduces severity of physical and mental fatigue and increases cognitive functions in centenarians: a randomized and controlled clinical trial.

BACKGROUND: Centenarians are characterized by weakness, decreasing mental health, impaired mobility, and poor endurance. L-Carnitine is an important contributor to cellular energy metabolism. OBJECTIVE: This study evaluated the efficacy of L-carnitine on physical and mental fatigue and on cognitive functions of centenarians. DESIGN: This was a placebo-controlled, randomized, double-blind, 2-phase study. Sixty-six centenarians with onset of fatigue after even slight physical activity were recruited to the study. The 2 groups received either 2 g levocarnitine once daily (n = 32) or placebo (n = 34). Efficacy measures included changes in total fat mass, total muscle mass, serum triacylglycerol, total cholesterol, HDL cholesterol, LDL cholesterol, Mini-Mental State Examination (MMSE), Activities of Daily Living, and a 6-min walking corridor test. RESULTS: At the end of the study period, the levocarnitine-treated centenarians, compared with the placebo group, showed significant improvements in the following markers: total fat mass (-1.80 compared with 0.6 kg; P < 0.01), total muscle mass (3.80 compared with 0.8 kg; P < 0.01), plasma concentrations of total carnitine (12.60 compared with -1.70 mumol; P < 0.05), plasma long-chain acylcarnitine (1.50 compared with -0.1 micromol; P < 0.001), and plasma short-chain acylcarnitine (6.0 compared with -1.50 micromol; P < 0.001). Significant differences were also found in physical fatigue (-4.10 compared with -1.10; P < 0.01), mental fatigue (-2.70 compared with 0.30; P < 0.001), fatigue severity (-23.60 compared with 1.90; P < 0.001), and MMSE (4.1 compared with 0.6; P < 0.001). CONCLUSIONS: Our study indicates that oral administration of levocarnitine produces a reduction of total fat mass, increases total muscular mass, and facilitates an increased capacity for physical and cognitive activity by reducing fatigue and improving cognitive functions.