Issue Information - Ed Board

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A parent-directed intervention for addressing academic risk in latino survivors of childhood leukemia: results of a pilot study

Key Points

Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk for treatment-related neurocognitive dysfunction, which may be exacerbated by factors related to low socio-economic status and linguistic disparities.

1. Approximately half of childhood ALL survivors at our institution are Latino and exhibit multiple socio-demographic risk factors that threaten academic functioning.
2. To better serve these survivors, we developed a culturally competent, parent-directed intervention to improve academic success that is feasible to deliver, shows preliminary evidence of efficacy, and is valued by families.
3. The approach outlined here enables pediatric cancer treatment centers to provide culturally competent assessment and academic support that exceed published guidelines for survivors at neurocognitive risk.

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Comparison of KRAS mutation status between primary tumor and metastasis in Chinese colorectal cancer patients

Abstract

Detection of KRAS mutation status is a routine clinical procedure for predicting response to anti-EGFR therapy in colorectal cancer (CRC) patients. Previous studies showed high concordance of KRAS mutation status in primary lesion and corresponding metastatic sites in CRC. However, the data were mostly from Caucasians. The aim of this study is to compare KRAS mutation and other molecules mutation status between primary tumor and corresponding metastatic lesion in Chinese patients with CRC. In this retrospective study, Chinese CRC patients with paired samples of primary tumor and metastatic site were detected for KRAS codon 12 and 13 with quantitative real-time PCR, or detected for OncoCarta™ panel of 19 genes with MassARRAY^® technique, including KRAS, BRAF, NRAS and PIK3CA et al. Forty-eight paired CRC samples were analyzed for KRAS codon 12 and 13 using quantitative real-time PCR. Ten paired samples were analyzed by 19 genes OncoCarta™ Panel with MassARRAY^® technique. KRAS mutation was found in 15 (25.9 %) primary tumors and 18 (31.0 %) metastases. The discordance of KRAS was observed in 11 (19.0 %) patients. Alteration of mutation points in primary site with mutant KRAS was not observed. In the 10 patients with multiple gene detection, PIK3CA mutation showed concordant mutation status in primary tumor and metastatic site, whereas discordance in BRAF, NRAS and AKT1 was detected. A concordance rate of 81.0 % was detected in KRAS mutation between primary tumor and metastatic lesion in Chinese patients with CRC. Discordance of BRAF, NRAS and AKT1 mutation status in primary tumor and metastases was observed.

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The Genomic Data Commons Launches

Making genomic and clinical data about cancer accessible to the cancer research community is imperative for our success in applying precision medicine to clinical oncology. The NCI Genomic Data Commons (GDC), released today, brings us a step closer to realizing this goal.

By analyzing large sets of shared data with the cutting-edge bioinformatics tools, we can improve our ability discover the genomic changes that drive rare cancers, puzzle out the complexity of tumor growth and drug resistance, and identify robust targets for therapy. The GDC is a data sharing platform to facilitate these types of discoveries. The GDC initially contains NCI-generated datasets including some of the most comprehensive cancer genomic datasets in the world, The Cancer Genome Atlas (TCGA), and the pediatric equivalent, TARGET.

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Tumor Microenvironment Influences Metabolism of Cancer Cells

When we think about tumor heterogeneity, we often imagine variation that originates from genetic and/or epigenetic mechanisms. However, there is increasing evidence that variation exists at the level of cellular metabolism and that this intratumoral heterogeneity could be important to tumor progression. The vast majority of RAS-driven tumors are notoriously aggressive and do not respond to chemotherapies, and it is conceivable that the metabolic heterogeneity found within these tumors could be contributing to their aggressiveness or to chemoresistance. Variations in metabolic wiring could allow some cancers cells within the tumor to be better positioned to survive specific stresses within the harsh tumor microenvironment. Moreover, metabolic adaptation to these stresses might also impact signaling pathways that regulate macropinocytosis and autophagy, both critical routes of nutrient supply in RAS-driven tumors^{1, 2}.

In rapidly proliferating RAS-mutated pancreatic cancer cells, cellular metabolism comes in at least two broad flavors – cells that are glycolytic and those that are lipogenic³. Interestingly, the glycolytic cells, which have elevated levels of various components of glycolysis, are associated with more mesenchymal properties, while lipogenic cells that are enriched for various lipid metabolites are associated with a classical, more epithelial cell type^{3, 4}. This is a great example of how metabolic heterogeneity within RAS-driven tumors might be contributing to tumor aggressiveness and/or invasion. In my lab we have observed that in addition to the differential usage of various metabolic pathways, RAS-mutated pancreatic cancers also exhibit intratumoral variation in how they obtain nutrients, with some cells depending on nutrient transporters and other cells relying on protein scavenging pathways, such as macropinocytosis. Altogether, it looks like it will be imperative to take into account this heterogeneity when designing novel therapeutic strategies for this disease.

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Patient-Derived Antibody Appears to Selectively Target Tumor Cells, Spur Immune Attack

Researchers have developed an antibody, derived from patients with early-stage lung cancer, that enlists the immune system to destroy cancer cells.

The antibody killed tumor cells in cell lines of several different cancer types and slowed tumor growth in mouse models of brain and lung cancer without obvious evidence of side effects, the researchers reported May 5 in Cell Reports.

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Roles of acid-extruding ion transporters in regulation of breast cancer cell growth in a 3-dimensional microenvironment

Abstract

Background

The 3-dimensional (3D) microenvironment of breast carcinomas is characterized by profoundly altered pH homeostasis, reflecting increased metabolic acid production and a confined extracellular space characterized by poor diffusion, yet the relative contributions of specific pH-regulatory transporters to 3D growth are poorly understood. The aim of this work was to determine how 3D spheroid growth of breast cancer cells impacts the expression and spatial organization of major acid extruding proteins, and how these proteins in turn are required for spheroid growth.

Methods

MCF-7 (Luminal-A) and MDA-MB-231 (Triple-negative) human breast cancer cells were grown as ~700-950 μm diameter spheroids, which were subjected to Western blotting for relevant transporters (2- and 3D growth), quantitative immunohistochemical analysis, and spheroid growth assays. Individual transporter contributions were assessed (i) pharmacologically, (ii) by stable shRNA- and transient siRNA-mediated knockdown, and (iii) by CRISPR/Cas9 knockout.

Results

In MCF-7 spheroids, expression of the lactate-H⁺ cotransporter MCT1 (SLC16A1) increased from the spheroid periphery to its core, the Na⁺,HCO₃⁻ cotransporter NBCn1 (SLC4A7) was most highly expressed at the periphery, and the Na⁺/H⁺ exchanger NHE1 (SLC9A1) and MCT4 (SLC16A3) were evenly distributed. A similar pattern was seen in MDA-MB-231 spheroids, except that these cells do not express MCT1. The relative total expression of NBCn1 and NHE1 was decreased in 3D compared to 2D, while that of MCT1 and MCT4 was unaltered. Inhibition of MCT1 (AR-C155858) attenuated MCF-7 spheroid growth and this was exacerbated by addition of S0859, an inhibitor of Na⁺,HCO₃⁻ cotransporters and MCTs. The pharmacological data was recapitulated by stable knockdown of MCT1 or NBCn1, whereas knockdown of MCT4 had no effect. CRISPR/Cas9 knockout of NHE1, but neither partial NHE1 knockdown nor the NHE1 inhibitor cariporide, inhibited MCF-7 spheroid growth. In contrast, growth of MDA-MB-231 spheroids was inhibited by stable or transient NHE1 knockdown and by NHE1 knockout, but not by knockdown of NBCn1 or MCT4.

Conclusions

This work demonstrates the distinct expression and localization patterns of four major acid-extruding transporters in 3D spheroids of human breast cancer cells and reveals that 3D growth is dependent on these transporters in a cell type-dependent manner, with potentially important implications for breast cancer therapy.

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