BAL101553 activity on glioblastoma stem-like cells

Glioblastoma (GBM) patients have limited treatment options. Cancer stem-like cells (CSLCs) contribute to GBM invasiveness and repopulation; hence, they represent promising targets for novel therapies. BAL101553 is a prodrug of BAL27862, a novel microtubule-destabilizing agent inhibiting tumor cell proliferation through activation of the Spindle Assembly Checkpoint, which is currently in Phase 1/2 clinical development. Broad anti-cancer activity has been demonstrated against human cancer models, including tumors refractory to conventional treatments. We have shown that overexpression of microtubule +End-binding 1-protein (EB1) correlates with GBM progression and poor survival. Here, we show that BAL27862 inhibits the growth of two GBM CSLCs. As EB1 is overexpressed in the CSLCs line GBM6, that display a high tumorigenicity and infiltrative pattern of migration in vivo, we investigated drug activity on GBM6 according to EB1 expression. BAL27862 inhibited migration and colony formation at sub-cytotoxic concentrations in EB1-expressing control cells (GBM6-sh0) but only at cytotoxic concentrations in EB1-down-regulated (GBM-shE1) cells. Three administrations of BAL101553 were sufficient to provoke an EB1-dependent survival benefit in tumor-bearing mice. Patterns of invasion and quantification of tumor cells in brain, demonstrated that GBM6-sh0 cells were more invasive than GBM6-shEB1 cells, and that the anti-proliferative and anti-invasive effects of BAL101553 were more potent in mice bearing control tumors than EB1-down-regulated tumors. This was associated with inhibition of stem-cell properties in the GBM6-sh0 model. Finally, BAL27862 triggered astrocytic differentiation of GBM6 in an EB1-dependent manner. These results support the potential of BAL101553 for GBM treatment, with EB1 expression as a predictive biomarker of response.

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Applying a RapidPlan model trained on a technique and orientation to another: a feasibility and dosimetric evaluation

The development of a dose-volume-histogram (DVH) estimation model for knowledge-based planning is very time-consuming and it could be inefficient if it was only used for similar upcoming cases as supposed. It ...

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Minimally invasive and robotic esophagectomy: Evolution and evidence

Esophageal cancer has a poor prognosis, with little improvement in outcomes in recent years. Surgery maintains its pivotal role in cure, but this involves two or three compartment dissection with associated high risks. Chiefly, pulmonary complications following surgery are most common, and can be life-threatening. As a consequence, minimally invasive and robotic esophagectomy have been performed with improving efficacy and equivalent oncological outcomes. This is a review of the pertinent literature regarding these techniques. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

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Medullary Thyroid Carcinoma: Recent Advances Including MicroRNA Expression

Abstract

Medullary thyroid carcinoma (MTC) is an uncommon neuroendocrine tumor arising from the C cells in the thyroid and accounts for about 5 % of all thyroid cancers. MTC exhibits more aggressive behavior than follicular tumors, with the majority of cases presenting with lymph node metastasis. It is particularly common among patients carrying germline RET mutations with almost 100 % penetrance. Because activating RET mutations occur in over 90 % of hereditary and 40 % of sporadic MTC, clinical trials of several RET-targeting multikinase inhibitors (MKIs) have resulted in FDA approval of vandetanib and cabozantinib for the treatment of MTC. Nevertheless, in light of significant individual differences in tumor behavior and treatment responses, there has been a persistent need for research efforts to decipher the molecular events within RET-driven or non-RET-driven tumors. Recently, the gene regulatory roles of microRNAs (miRNAs) in MTC have been studied extensively. Multiple miRNA deregulations have been discovered in MTC with potential prognostic and therapeutic implications. This review provides an overview of the basic pathology of MTC and an update on recent investigational progress.

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Truth-Telling in Taiwanese Cancer Care: Patients’ and Families’ Preferences and their Experiences of Doctors’ Practices

Abstract

Objective

Despite the significant role played by cancer patients' families in medical decision-making in Asian countries, inconsistencies have hitherto not been evaluated between patients' and families' preferences and doctors' actual practices with regard to cancer truth telling.

Methods

For this quantitative comparative study of cancer patients' and families' truth-telling preferences and their experiences of doctors' practices, 532 patients, 551 family members, and 127 doctors (N = 1,210) were enrolled from five hospitals across Taiwan over 2 years. Truth telling was assessed using the Taiwanese version of a modified Japanese truth-telling scale.

Results

Patients' truth-telling preferences and their experiences of doctors' truth-telling practices differed significantly in scores on the overall truth-telling scale and each subscale, including method of disclosure, emotional support, additional information, and setting (p < 0.001). Similar findings were obtained for families' preferences and doctors' actual practices (p < 0.001). Patients' and families' truth-telling preference scores were higher than doctors' actual practice scores. Multiple regression analysis revealed a dose-dependent effect of doctors' monthly truth-telling frequency on their truth-telling preferences, but this effect was only borderline significant (p = 0.08). This multiple regression model explained 30% of the total variance in doctors' truth-telling preferences (F = 1.38, p = 0.22).

Conclusions

Taiwanese medical educational policies need to be revised to better equip doctors to practice truth telling in accordance with the preferences of cancer patients and families. Communication skills training should be prioritized for doctors who refrain from truth telling in actual practice.

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The pivotal role of mammalian target of rapamycin inhibition in the treatment of patients with neuroendocrine tumors

Abstract

Significant advances have been made toward understanding the biology of neuroendocrine tumors (NET) in terms of defining prognosis and improving clinical management; however, many unmet needs remain. The treatment landscape for NET has evolved, with the approval of the targeted agents everolimus and sunitinib for the treatment of advanced pancreatic NET in 2011 followed by the approval of everolimus for the treatment of advanced nonfunctional gastrointestinal and lung NET in 2016. Mammalian target of rapamycin (mTOR) and components of the mTOR pathway play pivotal roles in NET pathogenesis. Effects of the mTOR inhibitor everolimus have been well documented in preclinical and clinical studies, both as monotherapy and combination therapy. mTOR inhibition as backbone therapy within the NET treatment landscape is a focus of continuing research, which includes evaluation of the growing armamentarium of approved and investigational agents as potential combination partners. Data evaluating the clinical benefits of agents targeting mTOR and related pathways (alone and in combination) in the treatment of patients with NET continue to increase. Many of the findings to date are encouraging.

Mammalian target of rapamycin (mTOR) and components of the mTOR pathway play pivotal roles in neuroendocrine tumor (NET) pathogenesis. mTOR inhibition as backbone therapy within the NET treatment landscape is an ongoing focus. Data evaluating the clinical benefits of agents targeting mTOR and related pathways (alone and in combination) in the treatment of patients with pancreatic NET continues to emerge, and many of the findings to date are encouraging.

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The hedgehog pathway in triple-negative breast cancer

Abstract

Treatment of triple-negative breast cancer (TNBC) remains challenging due to the underlying heterogeneity of this disease coupled with the lack of predictive biomarkers and effective targeted therapies. Intratumoral heterogeneity, particularly enrichment for breast cancer stem cell-like subpopulations, has emerged as a leading hypothesis for systemic therapy resistance and clinically aggressive course of poor prognosis TNBC. A growing body of literature supports the role of the stem cell renewal Hedgehog (Hh) pathway in breast cancer. Emerging preclinical data also implicate Hh signaling in TNBC pathogenesis. Herein, we review the evidence for a pathophysiologic role of Hh signaling in TNBC and explore mechanisms of crosstalk between the Hh pathway and other key signaling networks as well as their potential implications for Hh-targeted interventions in TNBC.

Given the increasingly recognized role of aberrant Hedgehog signaling in breast tumorigenesis as a whole and TNBC in particular, we sought to review all relevant preclinical data and provide a concise summary of the mechanisms of Hedgehog signaling in this breast cancer subtype. Further, we extend our review to recent findings of both established and potential crosstalk with other key signaling pathways which may potentially impact the efficacy of agents targeting the Hedgehog pathway in TNBC.

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