Cancers are heterogeneous at the cell level, and the mechanisms leading to cancer heterogeneity could be clonal evolution or cancer stem cells. Cancer stem cells are resistant to most anti-cancer treatments and could be preferential targets to reverse this resistance, either targeting stemness pathways or cancer stem cell surface markers. Gold nanoparticles have emerged as innovative tools, particularly for photo-thermal therapy since they can be excited by laser to induce hyperthermia. Gold nanoparticles can be functionalized with antibodies to specifically target cancer stem cells. Preclinical studies using photo-thermal therapy have demonstrated the feasibility of targeting chemo-resistant cancer cells to reverse clinical chemoresistance. Here, we review the data linking cancer stem cells and chemoresistance and discuss the way to target them to reverse resistance. We particularly focus on the use of functionalized gold nanoparticles in the treatment of chemo-resistant metastatic cancers.

Introduction: Molecular apocrine (MA) tumors are estrogen receptor (ER) negative breast cancers characterized by androgen receptor (AR) expression. We analyzed a group of 58 transcriptionally defined MA tumors and proposed a new tool to identify these tumors. Methods: We performed quantitative reverse transcription PCR (qRT-PCR) for ESR1, AR, FOXA1 and AR-related genes, and immunohistochemistry (IHC) for ER, PR, Human Epidermal Growth Factor Receptor 2 (HER2), CK5/6, CK17, EGFR, Ki67, AR, FOXA1 and GCDFP15 and we analyzed clinical features. Results: MA tumors were all characterized by ESR1(-) AR(+) FOXA1(+) and AR-related genes positive mRNA profile. IHC staining on these tumors showed 93% ER(-), only 58% AR(+) and 90% FOXA1(+). 67% and 57% MA tumors were HER2(3+) and GCDFP15(+), respectively. Almost all MA tumors (94%) had the IHC signature HER2(3+) or GCDFP15(+) but none of the 13 control basal-like (BL) tumors did. Clinically, MA tumors were rather aggressive, with poor prognostic factors. Conclusion: MA tumors could be better defined by their qRT-PCR-AR profile than by AR IHC. In addition, we found that HER2 or GCDFP15 protein overexpression is a sensitive and specific tool to differentiate MA from BL in the context of ER negative tumors. A composite molecular and IHC signature could, therefore, help to identify MA tumors in daily practice.

Anemia in β-thalassemia is related to ineffective erythropoiesis and reduced red cell survival. Excess free heme and accumulation of unpaired α-globin chains impose substantial oxidative stress on β-thalassemic erythroblasts and erythrocytes, impacting cell metabolism. We hypothesized that increased pyruvate kinase activity induced by mitapivat (AG-348) in the Hbb^th3/+ mouse model for β-thalassemia would reduce chronic hemolysis and ineffective erythropoiesis through stimulation of red cell glycolytic metabolism. Oral mitapivat administration ameliorated ineffective erythropoiesis and anemia in Hbb^th3/+ mice. Increased ATP, reduced reactive oxygen species production, and reduced markers of mitochondrial dysfunction associated with improved mitochondrial clearance suggested enhanced metabolism following mitapivat administration in β-thalassemia. The amelioration of responsiveness to erythropoietin resulted in reduced soluble erythroferrone, increased liver Hamp expression, and diminished liver iron overload. Mitapivat reduced duodenal Dmt1 expression potentially by activating the pyruvate kinase M2-HIF2α axis, representing a mechanism additional to Hamp in controlling iron absorption and preventing β-thalassemia–related liver iron overload. In ex vivo studies on erythroid precursors from patients with β-thalassemia, mitapivat enhanced erythropoiesis, promoted erythroid maturation, and decreased apoptosis. Overall, pyruvate kinase activation as a treatment modality for β-thalassemia in preclinical model systems had multiple beneficial effects in the erythropoietic compartment and beyond, providing a strong scientific basis for further clinical trials.

The incidence of brain metastases has increased in the last 10 years. However, the survival of patients with brain metastases remains poor and challenging in daily practice in medical oncology. One of the mechanisms suggested for the persistence of a high incidence of brain metastases is the failure to cross the blood–brain barrier of most chemotherapeutic agents, including the more recent targeted therapies. Therefore, new pharmacological approaches are needed to optimize the efficacy of anticancer drug protocols. In this article, we present recent findings in molecular data on brain metastases. We then discuss published data from pharmacological studies on the crossing of the blood–brain barrier by anticancer agents. We go on to discuss future developments to facilitate drug penetration across the blood–brain barrier for the treatment of brain metastases among cancer patients, using physical methods or physiological transporters.

Human tissue biobanking encompasses a wide range of activities and study designs and is critical for application of a wide range of new technologies (-“omics”) to the discovery of molecular patterns of disease and for implementation of novel biomarkers into clinical trials. Pathology is the cornerstone of hospital-based tissue biobanking. Pathologists not only provide essential information identifying the specimen but also make decisions on what should be biobanked, making sure that the timing of all operations is consistent with both the requirements of clinical diagnosis and the optimal preservation of biological products. This document summarizes the conclusions of a Pathology Expert Group Meeting within the European Biological and Biomolecular Research Infrastructure (BBMRI) Program. These recommendations are aimed at providing guidance for pathologists as well as for institutions hosting biobanks on how to better integrate and support pathological activities within the framework of biobanks that fulfill international standards.