Therapeutic Targeting of TFE3/IRS-1/PI3K/mTOR Axis in Translocation Renal Cell Carcinoma

Purpose: Translocation renal cell carcinoma (tRCC) represents a rare subtype of kidney cancer associated with various TFE3, TFEB, or MITF gene fusions that are not responsive to standard treatments for RCC. Therefore, the identification of new therapeutic targets represents an unmet need for this disease. Experimental Design: We have established and characterized a tRCC patient-derived xenograft, RP-R07, as a novel preclinical model for drug development by using next-generation sequencing and bioinformatics analysis. We then assessed the therapeutic potential of inhibiting the identified pathway using in vitro and in vivo models. Results: The presence of a SFPQ-TFE3 fusion [t(X;1) (p11.2; p34)] with chromosomal break-points was identified by RNA-seq and validated by RT-PCR. TFE3 chromatin immunoprecipitation followed by deep sequencing analysis indicated a strong enrichment for the PI3K/AKT/mTOR pathway. Consistently, miRNA microarray analysis also identified PI3K/AKT/mTOR as a highly enriched pathway in RP-R07. Upregulation of PI3/AKT/mTOR pathway in additional TFE3–tRCC models was confirmed by significantly higher expression of phospho-S6 (P < 0.0001) and phospho-4EBP1 (P < 0.0001) in established tRCC cell lines compared with clear cell RCC cells. Simultaneous vertical targeting of both PI3K/AKT and mTOR axis provided a greater antiproliferative effect both in vitro (P < 0.0001) and in vivo (P < 0.01) compared with single-node inhibition. Knockdown of TFE3 in RP-R07 resulted in decreased expression of IRS-1 and inhibited cell proliferation. Conclusions: These results identify TFE3/IRS-1/PI3K/AKT/mTOR as a potential dysregulated pathway in TFE3–tRCC, and suggest a therapeutic potential of vertical inhibition of this axis by using a dual PI3K/mTOR inhibitor for patients with TFE3–tRCC

Digital pathology for reporting histopathology samples, including cancer screening samples – definitive evidence from a multisite study

Aims To conduct a definitive multicentre comparison of digital pathology (DP) with light microscopy (LM) for reporting histopathology slides including breast and bowel cancer screening samples. Methods A total of 2024 cases (608 breast, 607 GI, 609 skin, 200 renal) were studied, including 207 breast and 250 bowel cancer screening samples. Cases were examined by four pathologists (16 study pathologists across the four speciality groups), using both LM and DP, with the order randomly assigned and 6 weeks between viewings. Reports were compared for clinical management concordance (CMC), meaning identical diagnoses plus differences which do not affect patient management. Percentage CMCs were computed using logistic regression models with crossed random-effects terms for case and pathologist. The obtained percentage CMCs were referenced to 98.3% calculated from previous studies. Results For all cases LM versus DP comparisons showed the CMC rates were 99.95% [95% confidence interval (CI) = 99.90–99.97] and 98.96 (95% CI = 98.42–99.32) for cancer screening samples. In speciality groups CMC for LM versus DP showed: breast 99.40% (99.06–99.62) overall and 96.27% (94.63–97.43) for cancer screening samples; [gastrointestinal (GI) = 99.96% (99.89–99.99)] overall and 99.93% (99.68–99.98) for bowel cancer screening samples; skin 99.99% (99.92–100.0); renal 99.99% (99.57–100.0). Analysis of clinically significant differences revealed discrepancies in areas where interobserver variability is known to be high, in reads performed with both modalities and without apparent trends to either. Conclusions Comparing LM and DP CMC, overall rates exceed the reference 98.3%, providing compelling evidence that pathologists provide equivalent results for both routine and cancer screening samples irrespective of the modality used

An insight into anticancer perspectives of chickpea bioactive compounds

Cancers of the lung, colon, liver, stomach, and breast are common worldwide and have significant fatality rates. Cachexia caused by cancer is the major cause of death in cancer patients, and malnutrition and metabolic illnesses have become more widespread in recent years. To combat these health conditions, proper nutrition is essential. Chickpeas include a variety of bioactive components, including antioxidants, phytochemicals, and bioactive peptides, all of which have preventative and protective health effects. This review summarizes the evidence-based studies on chickpeas’ ability to serve as a valuable source of bioactive chemicals that can help protect against many types of cancer. Chickpeas include secondary metabolites including quercetin and myricetin, as well as phenolic acids and vitamins A, B, and E, which may protect the body from free radicals. Chickpeas have the highest total phenolic content and essential amino acid concentration of any germinated seed. Chickpea storage proteins, such as globulins, glutelins, albumins, and prolamins, are high in protein and can help with cachexia. These proteins contain angiotensin-converting enzyme inhibitory and anti-proliferative capabilities, making them useful in the treatment of a wide range of cancers. As a result, this article provides advice to consumers on improving their eating habits to protect against and fight cancer and may serve as a foundation for future clinical studies