Nutraceutical based SIRT3 activators as therapeutic targets in Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease, and its incidence is increasing worldwide with increased lifespan. Currently, there is no effective treatment to cure or prevent the progression of AD, which indicates the need to develop novel therapeutic targets and agents. Sirtuins, especially SIRT3, a mitochondrial deacetylase, are NAD-dependent histone deacetylases involved in aging and longevity. Accumulating evidence indicates that SIRT3 dysfunction is strongly associated with pathologies of AD, hence, therapeutic modulation of SIRT3 activity may be a novel application to ameliorate the pathologies of AD. Natural products commonly used in traditional medicine have wide utility and appear to have therapeutic benefits for the treatment of neurodegenerative diseases such as AD. The present review summarizes the currently available natural SIRT3 activators and their potentially neuroprotective molecular mechanisms of action that make them a promising agent in the treatment and management of neurodegenerative diseases such as AD.

Prognostic value of skeletal muscle mass during tyrosine kinase inhibitor (TKI) therapy in cancer patients: a systematic review and meta-analysis.

Low muscle mass has been associated with worse clinical outcomes in various cancers. This work investigated whether, during tyrosine kinases inhibitors (TKIs) therapy, low muscle mass was associated with treatment toxicity and survival outcomes. A systematic literature search was performed in Pubmed, Web of Science, and Scopus databases from inception to June 2020, based on fixed inclusion and exclusion criteria. Effect sizes were estimated with hazard ratios (HR) and odds ratios (OR) with 95% confidence interval (CI) and heterogeneity was assessed by measuring inconsistency (I2) based on the Chi squared test. A total of 24 retrospective studies were identified, enrolling patients treated with sorafenib (n = 12), sunitinib (n = 6), lenvatinib (n = 3), regorafenib (n = 2), gefitinib (n = 1), imatinib (n = 1), and pazopanib (n = 1). Thirteen studies were deemed eligible for pooled analyses. Meta-analyses found a significant effect of low muscle mass on dose-limiting toxicity (DLT) (OR 2.40, 95% CI 1.26-4.58, p = 0.008, I2 = 51%) in patients treated with TKI therapy. A subgroup analysis by treatment showed an association between DLT and low muscle during sorafenib or sunitinib, although not significant. A significant association between low skeletal muscle index and poorer overall survival was observed in HCC patients treated with sorafenib (HR 1.45, 95% CI 1.07-1.96, p = 0.02). For other TKIs, although some results showed an association between low muscle mass and worse outcomes, the number of studies for each TKI therapy was too small to reach conclusions. Skeletal muscle mass could influence the prognosis of some TKI-treated patients. This effect is demonstrated in sorafenib-treated HCC patients but remains almost unexplored in other cancer patients undergoing TKI therapy. Further prospective studies with large sample size and sufficient follow-up are needed to clarify the role of muscle mass in the metabolism of TKI-based cancer treatment, and its association with toxicity and survival.

Bioactivation of α,ß-Unsaturated Carboxylic Acids Through Acyl Glucuronidation.

After oral administration to monkeys of [14C]GDC-0810, an α,ß-unsaturated carboxylic acid, unchanged parent and its acyl glucuronide metabolite, M6, were the major circulating drug-related components. In addition, greater than 50% of circulating radioactivity in plasma was found to be nonextractable 12 hours post-dose, suggesting possible covalent binding to plasma proteins. In the same study, one of the minor metabolites was a cysteine conjugate of M6 (M11) that was detected in plasma and excreta (urine and bile). The potential mechanism for the covalent binding to proteins was further investigated using in vitro methods. In incubations with glutathione (GSH) or cysteine (5 mM), GSH and cysteine conjugates of M6 were identified, respectively. The cysteine reaction was efficient with a half-life of 58.6 minutes (k react = 0.04 1/M per second). Loss of 176 Da (glucuronic acid) followed by 129 Da (glutamate) in mass fragmentation analysis of the GSH adduct of M6 (M13) suggested the glucuronic acid moiety was not modified. The conjugation of N-glucuronide M4 with cysteine in buffer was >1000-fold slower than with M6. Incubations of GDC-0810, M4, or M6 with monkey or human liver microsomes in the presence of NADPH and GSH did not produce any oxidative GSH adducts, and the respective substrates were qualitatively recovered. In silico analysis quantified the inherent reactivity differences between the glucuronide and its acid precursor. Collectively, these results show that acyl glucuronidation of α,ß-unsaturated carboxylic acids can activate the compound toward reactivity with GSH, cysteine, or other biologically occurring thiols and should be considered during the course of drug discovery. SIGNIFICANCE STATEMENT: Acyl glucuronidation of the α,ß-unsaturated carboxylic acid in GDC-0810 activates the conjugated alkene toward nucleophilic addition by glutathione or other reactive thiols. This is the first example that a bioactivation mechanism could lead to protein covalent binding to α,ß-unsaturated carboxylic acid compounds.

SYK inhibitor entospletinib prevents ocular and skin GVHD in mice.

Graft-versus-host disease (GVHD) is a major complication of hematopoietic stem cell transplantation (HCT). The tyrosine kinase SYK contributes to both acute and chronic GVHD development, making it an attractive target for GVHD prevention. Entospletinib (ENTO) is a second-generation highly selective SYK inhibitor with a high safety profile. Potential utility of ENTO as GVHD prophylaxis in patients was examined using a preclinical mouse model of eye and skin GVHD and ENTO-compounded chow. We found that early SYK inhibition improved blood immune cell reconstitution in GVHD mice and prolonged survival, with 60% of mice surviving to day +120 compared with 10% of mice treated with placebo. Compared with mice receiving placebo, mice receiving ENTO had dramatic improvements in clinical eye scores, alopecia scores, and skin scores. Infiltrating SYK+ cells expressing B220 or F4/80, resembling SYK+ cells found in lichenoid skin lesions of chronic GVHD patients, were abundant in the skin of placebo mice but were rare in ENTO-treated mice. Thus, ENTO given early after HCT safely prevented GVHD.

Aortic Dissection and Cardiac Dysfunction Emerged Coincidentally During the Long-Term Treatment with Angiogenesis Inhibitors for Metastatic Renal Cell Carcinoma.

Angiogenesis inhibitors, such as sorafenib and axitinib, which target vascular endothelial growth factor (VEGF) signaling, are widely used for renal cell carcinoma, including metastasis. In this study, we report a case of cardiovascular adverse events of aortic dissection and cardiac dysfunction during treatment with sorafenib and axitinib for metastatic renal cell carcinoma. A 66-year-old man had been administered sorafenib for 2 years after nephrectomy due to renal cell carcinoma. To control the progression of metastatic lung tumor, axitinib was started after sorafenib for four years. During the treatment, angiotensin II type 1 receptor blockers and Ca antagonists were used to strictly control the axitinib-induced hypertension and proteinuria. Aortic dissection and cardiac dysfunction occurred coincidentally. Considering the critical role of VEGF signaling in the homeostasis of the cardiovascular system, we speculated that the long-term use of axitinib and sorafenib directly influenced the initiation of aortic dissection and cardiac dysfunction. Although the precise mechanisms underlying the aortic dissection and cardiac dysfunction induced by angiogenesis inhibition are still elusive, onco-cardiologists and oncologists should pay careful attention to cardiovascular toxicity and complications in patients with cancer, particularly patients undergoing long-term cancer treatment.

Micelle System Based on Molecular Economy Principle for Overcoming Multidrug Resistance and Inhibiting Metastasis.

The high mortality of cancer is mainly attributed to multidrug resistance (MDR) and metastasis. A simple micelle system was constructed here to codeliver doxorubicin (DOX), adjudin (ADD), and nitric oxide (NO) for overcoming MDR and inhibiting metastasis. It was devised based on the "molecular economy" principle as the micelle system was easy to fabricate and exhibited high drug loading efficiency, and importantly, each component of the micelles would exert one or more active functions. DOX acted as the main cell killing agent supplemented with ADD, NO, and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS). MDR was overcome by synergistic effects of mitochondria inhibition agents, TPGS and ADD. A TPGS-based NO donor can be used as a drug carrier, and it can release NO to enhance drug accumulation and penetration in tumor, resulting in a positive cycle of drug delivery. This DOX-ADD conjugate self-assembly system demonstrated controlled drug release, increased cellular uptake and cytotoxicity, enhanced accumulation at tumor site, and improved in vivo metastasis inhibition of breast cancer. The micelles can fully take advantage of the functions of each component, and they provide a potential strategy for nanomedicine design and clinical cancer treatment.

Everolimus Versus Axitinib as Second-line Therapy in Metastatic Renal Cell Carcinoma: Experience From Institut Gustave Roussy.

BACKGROUND: Everolimus (E) and axitinib (A) have been standard treatments for patients with metastatic renal cell carcinoma after failure of first-line therapy (1L) with vascular endothelial growth factor-targeted therapy. This study aims to compare both drugs in a large comprehensive cancer center. METHODS: Patient characteristics and outcome data from all patients with metastatic renal cell carcinoma who received E or A as second-line therapy at Gustave Roussy from April 2007 to May 2015 have been recorded. RESULTS: A total of 81 patients were treated with E and 45 patients with A. There were no major differences between the 2 groups. The most common 1L was sunitinib (79% in the E group and 82.2% in the A group). The median follow-up was 29 months; 26 months for A and 33 months for E (P = .046). The median overall survival (OS) was 21.5 months for E and 14.9 months for A (P = .23). The median progression-free survival (PFS) was 5.3 and 7.7 months for E and A, respectively (P = .39). Partial response was achieved in 4% and in 24% of patients (P = .002) in the E and A cohort, respectively. In the A group, the median PFS and OS were statistically different according to response, tumor burden, and 1L duration. No differences were found in the E arm. CONCLUSION: In this series, there are no significant differences for PFS and OS with E and A. A appears to provide more objective response. A appears to be more effective in patients with small tumor burden, responders to 1L, and 1L therapy > 12 months.

Real-world costs and outcomes in metastatic renal cell carcinoma patients treated with targeted therapies: a cohort study from the French health insurance database.

OBJECTIVES: The objective of this study was to describe treatment patterns, survival, healthcare use and costs in patients with metastatic renal cell carcinoma (mRCC) in a real-world setting. RESEARCH DESIGN AND METHODS: We used the National Health Insurance (NHI) claims database for the Ile-de-France region to perform a retrospective cohort analysis of patients with mRCC treated by a first-line targeted therapy. Treatment naïve patients were identified combining the 10th revision of the International Classification of Diseases (ICD-10) codes (C64 & C77-C79) and a first prescription of targeted therapies. Descriptive analyses were performed on treatment patterns and patients' characteristics. Progression free survival (PFS) and overall survival (OS) were determined using Kaplan-Meier actuarial survival analysis. All healthcare resource use and costs were estimated on a per patient per month (PPPM) basis (€2016). RESULTS: A total of 327 treatment naïve patients with mRCC were included. Median follow-up was 13.4 months. Sunitinib accounted for 73% of first-line treatments. The most frequently observed treatment sequence for the first two lines was sunitinib-everolimus (16%; n = 137) and for the first three lines sunitinib-everolimus-axitinib (20%; n = 49). First-line PFS for sunitinib, everolimus, pazopanib, sorafenib and other was 8.7, 6.2, 10.7, 5.7 and 11.2 months, respectively. Median OS for patients treated by first-line sunitinib, everolimus, pazopanib, sorafenib and other was respectively 14.7, 8.1, 21.1, 8.9 and 14.0 months. From the NHI's perspective, the mean PPPM was €5546. The average PPPM in pre-progression was €5597 compared to €5541 beyond progression of the disease. Oral targeted therapies accounted for 53% of the total PPPM. CONCLUSION: This descriptive study showed that the economic burden of mRCC is substantial with oral targeted therapies accounting for 53% of the PPPM. OS and PFS in real life are poorer than observed in clinical trials.

Real world prospective experience of axitinib in metastatic renal cell carcinoma in a large comprehensive cancer centre.

BACKGROUND: Axitinib has shown activity in metastatic renal cell carcinoma (mRCC) in a large phase III clinical trial and was approved in patients who failed first-line therapy. This drug has been available in France since November 2012. The objective is to report efficacy and safety of axitinib in mRCC outside of clinical trials. METHODS: A prospective evaluation of mRCC patients treated by axitinib in second or further next-line therapy at Gustave Roussy was conducted from 2012 to 2015. Objective response rate (ORR), progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS) and toxicities were analysed. The correlation between clinical markers and ORR, PFS, TTF and OS were explored. RESULTS: One-hundred and sixty patients with mRCC, received axitinib in second (40%) or further next-line therapy (60%). International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group classification was good, intermediate and poor in 13%, 54% and 32%, respectively. Dose titration (DT) to 7 mg twice a day (bid) was performed in 38% and to 10 mg bid in 19% of the patients. Hypertension was the most common adverse event, (grade (G)3: 39%; G4: 2%). ORR occurred in 32% (n = 33, only partial response). Median PFS, TTF and OS were 8.3, 5.8 and 16.4 months, respectively. IMDC risk group and DT at 2 weeks are associated to ORR while grade 3 hypertension is marginally associated. IMDC risk group and grade 3 hypertension are significantly associated with better PFS, TTF and OS while DT at 2 weeks is associated to PFS and TTF. CONCLUSION: Efficacy of axitinib in routine practice is similar to that previously reported, not only in second- but also in further next-lines of therapy.

Selective effects of oral antiangiogenic tyrosine kinase inhibitors on an animal model of hereditary hemorrhagic telangiectasia.

Essentials Antiangiogenic drugs are indicated as therapies for hereditary hemorrhagic telangiectasia. We interrogated the response to four antiangiogenic drugs for anemia and intestinal bleeding. Sorafenib and a pazopanib analog significantly improved while erlotinib worsened anemia. Some oral antiangiogenic drugs were effective in reducing intestinal bleeding. SUMMARY: Background Epistaxis and gastrointestinal (GI) tract hemorrhages are common symptoms of aged hereditary hemorrhagic telangiectasia (HHT) patients that result in anemia. Clinical as well as animal studies have suggested that vascular endothelial growth factor (VEGF) neutralizing antibodies lessen hemorrhage associated with adult-onset arteriovenous malformations (AVMs). Objectives The goal of this study is to evaluate potential therapeutic effects of oral delivery of four antiangiogenic tyrosine-kinase inhibitors (TKIs) in the development of adult-onset AVMs in a murine model of HHT. Methods An adult activin receptor-like kinase 1 (Alk1)-inducible knockout (iKO) model was utilized to evaluate the effect of oral administration of sorafenib, sunitinib, erlotinib and a pazopanib analog (GW771806) on hemoglobin level, GI hemorrhages and formation of wound-induced skin AVMs. Results and Conclusions Sorafenib and GW771806 significantly improved, yet erlotinib worsened, anemia and GI-bleeding in the Alk1-iKO model. However, none of these TKIs appeared to be effective for inhibiting the development of wound-induced skin AVMs. Taken together, these results suggest that oral delivery of antiangiogenic TKIs is selectively more effective for GI bleeding than mucocutaneous AVMs, and it may provide an experimental basis for selective therapeutic options depending on the symptoms of HHT.

Pituitary Metastasis from Renal Cell Carcinoma: Description of a Case Report.

BACKGROUND Pituitary metastasis is uncommon, breast and lung cancers being the most frequent primary tumors. Renal cell carcinoma (RCC) is a rare cause of pituitary metastases, with only a few cases described to date. CASE REPORT We report a case of a 61-year-old man who presented with a progressive deterioration of visual acuity and field associated with a bitemporal hemianopsia. Two years ago, he underwent radical right nephrectomy for a clear cell RCC (ccRCC). The biological tests showed pan-hypopituitarism and diabetes insipidus. Brain MRI revealed a large sellar tumor lesion bilaterally infiltrating the cavernous sinuses, which was surgically resected. Histology confirmed a ccRCC pituitary metastasis. The patient received post-surgical radiotherapy. Considering the presence of concomitant extra-pituitary metastases, treatment with sunitinib was started, followed by several lines of therapy with axitinib, everolimus, and sorafenib because of tumor progression. The patient also presented with a pituitary tumor recurrence, which was treated by stereotaxic radiotherapy. He died five years after the initial diagnosis of RCC and 30 months after the diagnosis of the pituitary metastasis.  CONCLUSIONS There are no standardized treatment guidelines for management of pituitary metastases. Pituitary surgery plays a role in symptom palliation, and it does not have any relevant impact on survival. Exclusive radiotherapy or stereotaxic radiotherapy could be an alternative to surgery in patients whose general condition is poor or who have concomitant extra-pituitary metastases.

Model-based prediction of progression-free survival in patients with first-line renal cell carcinoma using week 8 tumor size change from baseline.

PURPOSE: To assess the link between early tumor shrinkage (ETS) and progression-free survival (PFS) based on historical first-line metastatic renal cell carcinoma (mRCC) data. METHODS: Tumor size data from 921 patients with first-line mRCC who received interferon-alpha, sunitinib, sorafenib or axitinib in two Phase III studies were modeled. The relationship between model-based estimates of ETS at week 8 as well as the baseline prognostic factors and PFS was tested in multivariate log-logistic models. Model performance was evaluated using simulations of PFS distributions and hazard ratio (HR) across treatments for the two studies. In addition, an external validation was conducted using data from an independent Phase II RCC study. The relationship between expected HR of an investigational treatment vs. sunitinib and the differences in ETS was simulated. RESULTS: A model with a nonlinear ETS-PFS link was qualified to predict PFS distribution by ETS quartiles as well as to predict HRs of sunitinib vs. interferon-alpha and axitinib vs. sorafenib. The model also performed well in simulations of an independent study of axitinib (external validation). The simulations suggested that if a new investigational treatment could further reduce the week 8 ETS by 30 % compared with sunitinib, an expected HR [95 % predictive interval] of the new treatment vs. sunitinib would be 0.59 [0.46, 0.79]. CONCLUSION: A model has been developed that uses early changes in tumor size to predict the HR for PFS differences between treatment arms for first-line mRCC. Such a model may have utility in predicting the outcome of ongoing studies (e.g., as part of interim futility analyses), supporting early decision making and future study design for investigational agents in development for this indication.

Efficacy and Safety of Selective Vascular Endothelial Growth Factor Receptor Inhibitors Compared with Sorafenib for Metastatic Renal Cell Carcinoma: a Meta-analysis of Randomised Controlled Trials.

AIMS: Selective vascular endothelial growth factor receptor (VEGFR) inhibitors have the potential for greater potency and less off-target toxicity compared with multikinase tyrosine kinase inhibitors in the treatment of metastatic renal cell carcinoma. We carried out a meta-analysis to determine quantitatively the differences in comparative efficacy and tolerability between these newer, selective agents and the multikinase inhibitors. MATERIALS AND METHODS: We searched four electronic databases for published randomised controlled trials comparing selective VEGFR inhibitors with multikinase tyrosine kinase inhibitors for metastatic renal cell carcinoma and carried out a meta-analysis. Outcomes of interest were progression-free survival, objective response rate (ORR), overall survival, discontinuation of treatment due to adverse events (DAE) and occurrence of specific toxicities. RESULTS: Four trials involving the selective VEGFR inhibitors axitinib, tivozanib and dovitinib were analysed, all using sorafenib as the comparator. There was a 22% reduction in risk of disease progression with selective VEGFR inhibitors (relative risk 0.78; 95% confidence interval 0.69-0.87) compared with sorafenib, the tyrosine kinase inhibitor in all trials, and similar whether the agents were first-line or subsequent therapy. ORR was improved with selective VEGFR inhibitors, with 91% increased odds over sorafenib (odds ratio 1.91; 95% confidence interval 1.35-2.69). Overall survival was similar between groups (relative risk 1.03; 95% confidence interval 0.88-1.21) and DAE differed only in sensitivity analysis with exclusion of dovitinib (odds ratio 0.62; 95% confidence interval 0.41-0.94). Frequencies of the most common toxicities were overall similar, but differences included more frequent grade 3 or 4 fatigue and less frequent palmar-plantar erythrodysesthesia with selective VEGFR therapy. CONCLUSION: Although selective VEGFR inhibitors are associated with similar overall survival as multikinase inhibitor sorafenib, they show significant improvement in progression-free survival, regardless of first-line or later use, and ORR compared with sorafenib. Tolerability due to toxicities is similar.

Comparative effectiveness of everolimus and axitinib as second targeted therapies for metastatic renal cell carcinoma in the US: a retrospective chart review.

Background Second targeted therapies for metastatic renal cell carcinoma (mRCC) include mammalian target of rapamycin inhibitors (mTORis) and tyrosine kinase inhibitors (TKIs). This observational study compares overall survival (OS) and progression-free survival (PFS) of patients treated with everolimus (an mTORi) and axitinib (a TKI) following first TKI, and assesses the impact of type and duration of first TKI on the relative effectiveness of these second targeted therapies. Methods Retrospective reviews of medical records were conducted by medical oncologists or hematologists/oncologists recruited from a nationwide panel. Included patients with mRCC were required to have discontinued a first TKI (sunitinib, sorafenib, or pazopanib) for medical reasons, and to have initiated everolimus or axitinib as second targeted therapy between February 2012 and January 2013. OS and PFS were compared between patients treated with everolimus vs. axitinib using multivariable Cox proportional hazards regression models. Comparative results were also stratified by type and duration of first TKI. Results Included patients (n = 325 for everolimus and n = 127 for axitinib) had a mean age of 61 years and 31% were female. Sunitinib was the most commonly used first TKI (73%). After adjusting for patient characteristics, no statistically significant differences were observed in OS or PFS between everolimus and axitinib. When stratifying by type and duration of first TKI, there was no statistically significant difference in OS between everolimus and axitinib in all subgroups except for patients with <6 months on sunitinib or sorafenib as first TKI. No significant difference in PFS was observed in any subgroup. Limitations Important limitations include potential missing or inaccurate data in medical charts, and confounding due to unobserved factors. Conclusions In this retrospective chart review, no significant differences were detected in OS or PFS between axitinib and everolimus as second targeted therapy. Longer duration of first TKI was not associated with increased effectiveness of subsequent axitinib compared to everolimus.

Risk factors and model for predicting toxicity-related treatment discontinuation in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted therapy: Results from the International Metastatic Renal Cell Carcinoma Database Consortium.

BACKGROUND: Vascular endothelial growth factor (VEGF)-targeted therapies are standard treatment for metastatic renal cell carcinoma (mRCC); however, toxicities can lead to drug discontinuation, which can affect patient outcomes. This study was aimed at identifying risk factors for toxicity and constructing the first model to predict toxicity-related treatment discontinuation (TrTD) in mRCC patients treated with VEGF-targeted therapies. METHODS: The baseline characteristics, treatment outcomes, and toxicity data were collected for 936 mRCC patients receiving first-line VEGF-targeted therapy from the International Metastatic Renal Cell Carcinoma Database Consortium. A competing risk regression model was used to identify risk factors for TrTD, and it accounted for other causes as competing risks. RESULTS: Overall, 198 (23.8%) experienced TrTD. Sunitinib was the most common VEGF-targeted therapy (77%), and it was followed by sorafenib (18.4%). The median time on therapy was 7.1 months for all patients and 4.4 months for patients with TrTD. The most common toxicities leading to TrTD included fatigue, diarrhea, and mucositis. In a multivariate analysis, significant predictors for TrTD were a baseline age ≥60 years, a glomerular filtration rate (GFR) <30 mL/min/1.73 m(2) , a single metastatic site, and a sodium level <135 mmol/L. A risk group model was developed that used the number of patient risk factors to predict the risk of TrTD. CONCLUSIONS: In the largest series to date, age, GFR, number of metastatic sites, and baseline sodium level were found to be independent risk factors for TrTD in mRCC patients receiving VEGF-targeted therapy. Based on the number of risk factors present, a model for predicting TrTD was built to be used as a tool for toxicity monitoring in clinical practice.

TOKIO rationale and protocol: a phase II study to evaluate the activity and safety of third-line tyrosine kinase inhibitor after 2 tyrosine kinase inhibitors in patients with metastatic renal cell carcinoma.

AIMS AND BACKGROUND: The introduction of agents targeting vascular endothelial growth factor has radically changed the approach to metastatic renal cell carcinoma (mRCC): sunitinib and pazopanib are now the standard first-line therapy in mRCC. At sunitinib failure, second-line axitinib or everolimus or sorafenib should be considered to improve the clinical outcome. No data are available for a third-line tyrosine kinase inhibitor (TKI) after 2 previous lines of therapy with TKIs. At pazopanib failure, no prospective data are available. STUDY DESIGN: The TOKIO study was designed to evaluate progression-free survival, safety, and efficacy of third-line therapy with TKI in 44 patients already treated with 2 previous lines of TKIs in 10 Italian centers, and relapsed from sunitinib-axitinib (group A) or pazopanib-sorafenib (group B). Standard treatment is sorafenib in group A and sunitinib in group B, administered until disease progression or unacceptable toxicity. Secondary endpoints include the evaluation of overall survival, safety, and quality of life.

Prolonging survival in metastatic renal cell carcinoma patients treated with targeted anticancer agents: a single-center experience of treatment strategy modifications.

INTRODUCTION: We investigated therapeutic outcomes in consecutive patients with metastatic renal cell carcinoma treated with targeted anticancer agents from 2008 to 2014 in order to determine the efficacy of adverse event management for such agents and the best sequence in which to use them. MATERIALS AND METHODS: We analyzed 132 consecutive patients who had taken targeted anticancer agents for metastatic renal cell carcinoma. Of these, 101 patients received therapy between 2008 and 2011 (pioneer group) and 31 patients received therapy between 2011 and 2014 (contemporary group). Patients of the contemporary group were provided with aggressive adverse event management and education on such management, were treated according to a standard therapeutic strategy, and were able to receive axitinib as a second-line drug. We analyzed the incidence of hand-foot syndrome. Furthermore, we compared relative dose intensity between patients in the pioneer and contemporary groups who took sunitinib as first-line therapy. We also compared overall survival between the two groups to determine whether adverse event management improved prognosis. RESULTS: The incidence of hand-foot syndrome was significantly reduced by aggressive adverse event management. Relative dose intensity was significantly higher in the contemporary group than in the pioneer group. Median survival time was significantly longer in the contemporary group than in the pioneer group. CONCLUSION: Our results suggest that aggressive management of adverse events associated with targeted drugs, the use of sunitinib as a first-line therapy, and the availability of axitinib as a second-line therapy all contribute to prolonged survival for metastatic renal cell carcinoma patients.

ABCB1 and ABCG2 restrict the brain penetration of a panel of novel EZH2-Inhibitors.

Enhancer of Zeste Homolog 2 (EZH2) has emerged as a promising therapeutic target for treatment of a broad spectrum of tumors including gliomas. We explored the interactions of five novel, structurally similar EZH2 inhibitors (EPZ005687, EPZ-6438, UNC1999, GSK343 and GSK126) with P-glycoprotein (P-gp/ABCB1) and breast cancer resistance protein (BCRP/ABCG2). The compounds were screened by in vitro transwell assays and EPZ005687, EPZ-6438 and GSK126 were further tested in vivo using wild-type (WT), Abcb1 and/or Abcg2 knockout mice. All EZH2 inhibitors are transported by P-gp and BCRP, although in vitro the transporter affinity of GSK126 was obscured by very low membrane permeability. Both P-gp and Bcrp1 restrict the brain penetration of EPZ005687 and GSK126, whereas the brain accumulation of EPZ-6438 is limited by P-gp only and efflux of EPZ-6438 was completely abrogated by elacridar. Intriguingly, an unknown factor present in all knockout mouse strains causes EPZ005687 and EPZ-6438 retention in plasma relative to WT mice, a phenomenon not seen with GSK126. In WT mice, the GSK126 tissue-to-plasma ratio for all tissues is lower than for EPZ005687 or EPZ-6438. Moreover, the oral bioavailability of GSK126 is only 0.2% in WT mice, which increases to 14.4% in Abcb1;Abcg2 knockout mice. These results are likely due to poor membrane permeability and question the clinical usefulness of GSK126. Although all tested EZH2 inhibitors are substrates of P-gp and BCRP, restricting the brain penetration and potential utility for treatment of glioma, EPZ-6438 would be the most suitable candidate of this series.

Clinical observation of liver cancer patients treated with axitinib and cabozantinib after failed sorafenib treatment: a case report and literature review.

Hepatocellular carcinoma (HCC) is a major pathological type of primary liver cancer. Sorafenib has demonstrated definite efficacy in targeted therapy for HCC. However, when treatment with sorafenib fails, suitable drugs must be found for further treatment. This article reports a case of an HCC patient who was treated with angiogenesis inhibitor axitinib and c-Met inhibitor cabozantinib following treatment with sorafenib. The report focuses on clinical treatment and toxicity. Rational application of targeted therapy is also explored.

Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial.

PURPOSE: This open-label phase III trial evaluated efficacy and tolerability of linifanib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC) without prior systemic therapy. PATIENTS AND METHODS: Patients were randomly assigned in a 1:1 ratio to linifanib 17.5 mg once daily or sorafenib 400 mg twice daily. Patients were stratified by region (Outside Asia, Japan, and rest of Asia), Eastern Cooperative Oncology Group performance score (ECOG PS; 0 or 1), vascular invasion or extrahepatic spread (yes or no), and hepatitis B virus (HBV) infection (yes or no). The primary end point of the study was overall survival (OS). Secondary end points were time to progression (TTP) and objective response rate (ORR) per RECIST v1.1. RESULTS: We randomly assigned 1,035 patients (median age, 60 years; Asian, 66.6%; ECOG PS 0, 65.2%; HBV, 49.1%; vascular invasion or extrahepatic spread, 70.1%). Median OS was 9.1 months on the linifanib arm (95% CI, 8.1 to 10.2) and 9.8 months on the sorafenib arm (95% CI, 8.3 to 11.0; hazard ratio [HR], 1.046; 95% CI, 0.896 to 1.221). For prespecified stratification subgroups, OS HRs ranged from 0.793 to 1.119 and the 95% CI contained 1.0. Median TTP was 5.4 months on the linifanib arm (95% CI, 4.2 to 5.6) and 4.0 months on the sorafenib arm (95% CI, 2.8 to 4.2; HR, 0.759; 95% CI, 0.643 to 0.895; P = .001). Best response rate was 13.0% on the linifanib arm versus 6.9% on the sorafenib arm. Grade 3/4 adverse events (AEs); serious AEs; and AEs leading to discontinuation, dose interruption, and reduction were more frequent with linifanib (all P < .001). CONCLUSION: Linifanib and sorafenib had similar OS in advanced HCC. Predefined superiority and noninferiority OS boundaries were not met for linifanib and the study failed to meet the primary end point. TTP and ORR favored linifanib; safety results favored sorafenib.