Phase I Study of Nintedanib Incorporating Dynamic Contrast‐Enhanced Magnetic Resonance Imaging in Patients With Advanced Solid Tumors

Background.

This open-label phase I dose-escalation study investigated the safety, efficacy, pharmacokinetics (PK), and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) effects of the oral angiokinase inhibitor nintedanib in patients with advanced solid tumors.

Methods.

Nintedanib was administered once daily continuously, starting at 100 mg and later amended to allow evaluation of 250 mg b.i.d. The primary endpoint was maximum tolerated dose (MTD). DCE-MRI studies were performed at baseline and on days 2 and 28.

Results.

Fifty-one patients received nintedanib 100–450 mg once daily (n = 40) or 250 mg b.i.d. (n = 11). Asymptomatic reversible liver enzyme elevations (grade 3) were dose limiting in 2 of 5 patients at 450 mg once daily. At 250 mg b.i.d., 2 of 11 patients experienced dose-limiting toxicity (grade 3 liver enzyme elevation and gastrointestinal symptoms). Common toxicities included fatigue, diarrhea, nausea, vomiting, and abdominal pain (mainly grade ≤2). Among 45 patients, 22 (49%) achieved stable disease; 7 remained on treatment for >6 months. DCE-MRI of target lesions revealed effects in some patients at 200 and ≥400 mg once daily.

Conclusion.

Nintedanib is well tolerated by patients with advanced solid malignancies, with MTD defined as 250 mg b.i.d., and can induce changes in DCE-MRI. Disease stabilization >6 months was observed in 7 of 51 patients.     

Patient-derived xenograft models of breast cancer and their predictive power

Despite advances in the treatment of patients with early and metastatic breast cancer, mortality remains high due to intrinsic or acquired resistance to therapy. Increased understanding of the genomic landscape through massively parallel sequencing has revealed somatic mutations common to specific subtypes of breast cancer, provided new prognostic and predictive markers, and highlighted potential therapeutic targets. Evaluating new targets using established cell lines is limited by the inexact correlation between responsiveness observed in cell lines versus that elicited in the patient. Patient-derived xenografts (PDXs) generated from fresh tumor specimens recapitulate the diversity of breast cancer and reflect histopathology, tumor behavior, and the metastatic properties of the original tumor. The high degree of genomic preservation evident across primary tumors and their matching PDXs over serial passaging validate them as important preclinical tools. Indeed, there is accumulating evidence that PDXs can recapitulate treatment responses of the parental tumor. The finding that tumor engraftment is an independent and poor prognostic indicator of patient outcome represents the first step towards personalized medicine. Here we review the utility of breast cancer PDX models to study the clonal evolution of tumors and to evaluate novel therapies and drug resistance.     

An integrated genomic analysis of papillary renal cell carcinoma type 1 uncovers the role of focal adhesion and extracellular matrix pathways

Papillary renal cell carcinoma (pRCC) is the second most common RCC subtype and can be further classified as type 1 (pRCC1) or 2 (pRCC2). There is currently minimal understanding of pRCC1 pathogenesis, and treatment decisions are mostly empirical. The aim of this study was to identify biological pathways that are involved in pRCC1 pathogenesis using an integrated genomic approach. By microarray analysis, we identified a number of significantly dysregulated genes and microRNAs (miRNAs) that were unique to pRCC1. Integrated bioinformatics analyses showed enrichment of the focal adhesion and extracellular matrix (ECM) pathways. We experimentally validated that many members of these pathways are dysregulated in pRCC1. We identified and experimentally validated the downregulation of miR‐199a‐3p in pRCC1. Using cell line models, we showed that miR‐199a‐3p plays an important role in pRCC1 pathogenesis. Gain of function experiments showed that miR‐199a‐3p overexpression significantly decreased cell proliferation (p = 0.013). We also provide evidence that miR‐199a‐3p regulates the expression of genes linked to the focal adhesion and ECM pathways, such as caveolin 2 (CAV2), integrin beta 8 (ITGB8), MET proto‐oncogene and mammalian target of rapamycin (MTOR). Using a luciferase reporter assay, we further provide evidence that miR‐199a‐3p overexpression decreases the expression of MET and MTOR. Using an integrated gene/miRNA approach, we provide evidence linking miRNAs to the focal adhesion and ECM pathways in pRCC1 pathogenesis. This novel information can contribute to the development of effective targeted therapies for pRCC1, for which there is none currently available in the clinic.     

Mesenchymal stem cells for treating ocular surface diseases

Mesenchymal stem cells (MSC) have become a promising tool for cell therapy in regenerative medicine. They are readily available, demonstrate powerful differentiation capabilities and present immunosuppressive properties that aid them in surviving from host immune rejection for its great potential use in allograft. Currently clinical trials are underway using MSC, both culture-expanded allogeneic and autologous, for the treatment of a range of diseases not treatable by conventional therapies. A vast array of studies has dedicated towards the use of MSC for treating corneal diseases with very promising outcomes. MSC have successfully differentiated into keratocytes both in vitro and in vivo, and corneal epithelial cells in vitro, but it is uncertain if MSC can assume corneal epithelial cells in vivo. However, to date few studies have unequivocally established the efficacy of MSC for treating corneal endothelial defects. Currently, the diversity in protocols of the isolation and expansion of MSC are hindering to the assessment of cell treatment ability and the further development of treatment regimens. Therefore, future studies should develop international standards for MSC isolation and characterization. In this review, we discuss recent advances in MSC for treating ocular surface diseases.     

Accuracy of the Emotion Thermometers (ET) Screening Tool in Patients Undergoing Surgery for Upper Gastrointestinal Malignancies

Distress is common in patients with gastrointestinal cancers. Most conventional scales are too long for routine clinic use. We tested the Emotion Thermometers (ET) tool, a brief visual-analogue scale. There are four emotional upset thermometers: distress, anxiety, depression, and anger. Sixty-nine surgical patients were recruited from an academic hospital clinic in 2012; 64 had complete data for Beck depression inventory and ET. The sample size was modest due to the specialist nature of the sample. We examined sensitivity, specificity, and area under the receiver-operator-curve. A dimensional multi-domain approach to screening for emotional disorders is preferable to using the distress thermometer alone and can be achieved with little extra time burden to clinicians. The ET is a diagnostic tool that is primarily designed for screening to identify cancer patients who would benefit by enhanced psychosocial care.