2b or Not 2b: How Opposing FGF Receptor Splice Variants Are Blocking Progress in Precision Oncology.

More than ten thousand peer-reviewed studies have assessed the role of fibroblast growth factors (FGFs) and their receptors (FGFRs) in cancer, but few patients have yet benefited from drugs targeting this molecular family. Strategizing how best to use FGFR-targeted drugs is complicated by multiple variables, including RNA splicing events that alter the affinity of ligands for FGFRs and hence change the outcomes of stromal-epithelial interactions. The effects of splicing are most relevant to FGFR2; expression of the FGFR2b splice isoform can restore apoptotic sensitivity to cancer cells, whereas switching to FGFR2c may drive tumor progression by triggering epithelial-mesenchymal transition. The differentiating and regulatory actions of wild-type FGFR2b contrast with the proliferative actions of FGFR1 and FGFR3, and may be converted to mitogenicity either by splice switching or by silencing of tumor suppressor genes such as CDH1 or PTEN. Exclusive use of small-molecule pan-FGFR inhibitors may thus cause nonselective blockade of FGFR2 isoforms with opposing actions, undermining the rationale of FGFR2 drug targeting. This splice-dependent ability of FGFR2 to switch between tumor-suppressing and -driving functions highlights an unmet oncologic need for isoform-specific drug targeting, e.g., by antibody inhibition of ligand-FGFR2c binding, as well as for more nuanced molecular pathology prediction of FGFR2 actions in different stromal-tumor contexts.

How aging of the global population is changing oncology.

Population aging is causing a demographic redistribution with implications for the future of healthcare. How will this affect oncology? First, there will be an overall rise in cancer affecting older adults, even though age-specific cancer incidences continue to fall due to better prevention. Second, there will be a wider spectrum of health functionality in this expanding cohort of older adults, with differences between "physiologically older" and "physiologically younger" patients becoming more important for optimal treatment selection. Third, greater teamwork with supportive care, geriatric, mental health and rehabilitation experts will come to enrich oncologic decision-making by making it less formulaic than it is at present. Success in this transition to a more nuanced professional mindset will depend in part on the development of user-friendly computational tools that can integrate a complex mix of quantitative and qualitative inputs from evidence-based medicine, functional and cognitive assessments, and the personal priorities of older adults.

[Combined effects of genetic polymorphisms in cytochrome P450s and GSTM1 on lung cancer susceptibility].

OBJECTIVE: To investigate the relationship between the gene polymorphism of metabolizing enzymes and the genetic susceptibility to lung cancer as well as to study the synergistic effects between smoking and the genes. METHODS: Peripheral blood samples were collected from 279 patients with primary lung cancer and 684 age-, nationality-, and native place-matched controls, including patients with benign diseases and healthy volunteers. PCR-RELP was used to detect the distribution of CYP1A1, 2D6, 2E1, and GSTM1 genotypes. The correlation of these genes with the sensibility to lung cancer was analyzed. RESULTS: The CYP1A1 variant allele frequency of the lung cancer group was 67.4%, significantly higher than that of the control group (55.7%, P = 0.001). GSTM1-null genotype was found to be associated with lung cancer (OR = 1.58, P = 0.002). The risk of lung cancer in the individuals carrying GSTM1-null genotype and CYP1A1 (w/m, m/m) genotype was 2.75 times that of the individuals not carrying these genotypes (P < 0.01). There were no significant differences in the frequencies of CYP2D6 and CYP2E1 genotypes between these two groups. In the heavy smokers GSTM1-null, CYP1A1, CYP2D6, and CYP2E1 genotypes increased the risk of lung cancer by 5.71 - 11.67 times (P = 0.000). CONCLUSION: The individuals who carry GSTM1-null genotype and CYP1A1 (m) genotype have an increase risk of lung cancer. The combined effect of I phase metabolizing enzymes and II phase metabolizing enzymes is observed. In heavy smokers the polymorphism of GSTM1 and CYPs affects the susceptibility to lung cancer.

miR-30b and miR-30c expression predicted response to tyrosine kinase inhibitors as first line treatment in non-small cell lung cancer.

BACKGROUND: Aberrantly expressed microRNAs are a hallmark of cancer, and microRNA expression profiling is associated with tumor progression and response to chemotherapy, suggesting their potential application as prognostic and predictive biomarkers. The role of microRNAs in lung cancer remains elusive. It has been recently reported that epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (MET) tyrosine kinase can regulate expression of specific microRNAs including miR-30b, miR-30c, miR-221, miR-222, miR-103 and miR-203, and induce tumorigenesis and gefitinib resistance in lung cancers. We intend to study the role of miR-30b and miR-30c expression in predicting response to tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). METHODS: We have therefore retrospectively examined expression of miR-30b miR-30c in 41 formalin fixed paraffin embedded tissue samples from NSCLC patients when TKIs were used as first line therapy. RESULTS: We found a significant correlation between expression of miR-30b and miR-30c. Furthermore, miR-30b and miR-30c expression correlated with short-term response. Kaplan-Meier analysis further revealed that the expression of miR-30b and miR-30c predicted progression free survival and the overall survival rate in the examined cohort. CONCLUSION: Our study identified miR-30b and miR-30c as useful prognostic predictors in NSCLC patients who underwent first line treatment with TKIs.