The endoplasmic reticulum (ER), a multifunctional organelle, plays a central role in cellular signaling, development, and stress response. Dysregulation of ER homeostasis has been associated with human diseases, such as cancer, inflammation, and diabetes. A broad spectrum of stressful stimuli including hypoxia as well as a variety of pharmacological agents can lead to the ER stress response. In this study, we have developed a stable ER stress reporter cell line that stably expresses a β-lactamase reporter gene under the control of the ER stress response element (ESRE) present in the glucose-regulated protein, 78 kDa (GRP78) gene promoter. This assay has been optimized and miniaturized into a 1536-well plate format. In order to identify clinically used drugs that induce ER stress response, we screened approximately 2800 drugs from the NIH Chemical Genomics Center Pharmaceutical Collection (NPC library) using a quantitative high-throughput screening (qHTS) platform. From this study, we have identified several known ER stress inducers, such as 17-AAG (via HSP90 inhibition), as well as several novel ER stress inducers such as AMI-193 and spiperone. The confirmed drugs were further studied for their effects on the phosphorylation of eukaryotic initiation factor 2α (eIF2α), the X-box-binding protein (XBP1) splicing, and GRP78 gene expression. These results suggest that the ER stress inducers identified from the NPC library using the qHTS approach could shed new lights on the potential therapeutic targets of these drugs.

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We aimed to investigate the feasibility of droplet digital PCR (ddPCR) for the quantitative and dynamic detection of EGFR mutations and next generation sequencing (NGS) for screening EGFR-tyrosine kinase inhibitors (EGFR-TKIs) resistance-relevant mutations in circulating tumor DNA (ctDNA) from advanced lung adenocarcinoma (ADC) patients.
Detection limit of EGFR mutation in ctDNA by ddPCR was 0.04%. Taking the EGFR mutation in tumor tissue as the golden standard, the concordance of EGFR mutations detected in ctDNA was 74% (54/73). Patients with EGFR mutation in ctDNA (n = 54) superior progression-free survival (PFS, median, 12.6 vs. 6.7 months, P < 0.001) and overall survival (OS, median, 35.6 vs. 23.8 months, P = 0.028) compared to those with EGFR wild type in ctDNA (n = 19). Patients with high EGFR-mutated abundance in ctDNA (> 5.15%) showed better PFS compared to those with low EGFR mutated abundance (≤ 5.15%) (PFS, median, 15.4 vs. 11.1 months, P = 0.021). NGS results showed that 66.6% (8/12) total mutational copy number were elevated and 76.5% (26/34) mutual mutation frequency increased after disease progression.
Seventy-three advanced ADC patients with tumor tissues carrying EGFR mutations and their matched pre- and post-EGFR-TKIs plasma samples were enrolled in this study. Absolute quantities of plasma EGFR mutant and wild-type alleles were measured by ddPCR. Multi-genes testing was performed using NGS in 12 patients.
Dynamic and quantitative analysis of EGFR mutation in ctDNA could guide personalized therapy for advanced ADC. NGS shows good performance in multiple genes testing especially novel and uncommon genes.

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Hepatocellular carcinoma (HCC) remains a significant clinical challenge with few therapeutic options available to cancer patients. MicroRNA 21-5p (miR-21) has been shown to be upregulated in HCC, but the contribution of this oncomiR to the maintenance of tumorigenic phenotype in liver cancer remains poorly understood. We have developed potent and specific single-stranded oligonucleotide inhibitors of miR-21 (anti-miRNAs) and used them to interrogate dependency on miR-21 in a panel of liver cancer cell lines. Treatment with anti-miR-21, but not with a mismatch control anti-miRNA, resulted in significant derepression of direct targets of miR-21 and led to loss of viability in the majority of HCC cell lines tested. Robust induction of caspase activity, apoptosis, and necrosis was noted in anti-miR-21-treated HCC cells. Furthermore, ablation of miR-21 activity resulted in inhibition of HCC cell migration and suppression of clonogenic growth. To better understand the consequences of miR-21 suppression, global gene expression profiling was performed on anti-miR-21-treated liver cancer cells, which revealed striking enrichment in miR-21 target genes and deregulation of multiple growth-promoting pathways. Finally, in vivo dependency on miR-21 was observed in two separate HCC tumor xenograft models. In summary, these data establish a clear role for miR-21 in the maintenance of tumorigenic phenotype in HCC in vitro and in vivo.
miR-21 is important for the maintenance of the tumorigenic phenotype of HCC and represents a target for pharmacologic intervention.
©2015 American Association for Cancer Research (AACR) (Free AACR Whitepaper).

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Compared to normal kidney, renal clear cell carcinomas (ccRCC) contain increased numbers of interstitial, non-hematopoietic CD133+cells that express stem cell markers and exhibit low rates of proliferation. These cells fail to form tumors upon transplantation but support tumor formation by differentiated malignant cells. We hypothesized that killing of ccRCC CD133+ (RCCCD133+) cells by cytotoxic agents might be enhanced by inducing them to divide. Since tumor necrosis factor-alpha (TNF), signalling through TNFR2, induces proliferation of malignant renal tubular epithelial cells, we investigated whether TNFR2 might similarly affect RCCCD133+cells. We compared treating organ cultures of ccRCC vs adjacent nontumour kidney (NK) and RCCCD133+vs NK CD133+ (NKCD133+) cell cultures with wild-type TNF (wtTNF) or TNF muteins selective for TNFR1 (R1TNF) or TNFR2 (R2TNF). In organ cultures, R2TNF increased expression of TNFR2 and promoted cell cycle entry of both RCCCD133+ and NKCD133+ but effects were greater in RCCCD133+. In contrast, R1TNF increased TNFR1 expression and promoted cell death. Importantly, cyclophosphamide triggered much more cell death in RCCCD133+ and NKCD133+cells pre-treated with R2TNF as compared to untreated controls. We conclude that selective engagement of TNFR2 by TNF can drives RCCCD133+ proliferation and thereby increase sensitivity to cell cycle-dependent cytotoxicity.

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On March 18, 2016 Myriad Genetics, Inc. (NASDAQ:MYGN), a leader in molecular diagnostics and personalized medicine, reported it will present two important new studies at the 2016 Society for Gynecologic Oncology annual meeting in San Diego, Calif (Press release, Myriad Genetics, MAR 18, 2016, View Source [SID:1234509630]).

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The data demonstrate the ability of the myRisk Hereditary Cancer test to identify deleterious mutations in patients with endometrial cancer. Additionally, a different study showed the superior ability of the combined three biomarker myChoice HRD test to predict survival in patients with platinum treated ovarian cancer.

"Endometrial cancer is the most frequent gynecologic cancer and a significant number of these cases are due to mutations in hereditary cancer genes," said Johnathan Lancaster, M.D., Ph.D., chief medical officer, Myriad Genetic Laboratories. "Our new data show that gene panel testing can identify many more patients with harmful mutations than testing Lynch Syndrome genes alone. The additional information provided by the myRisk Hereditary Cancer test will help physicians optimize care for their patients."

Details about the featured Myriad presentations at SGO are below. Follow Myriad on Twitter via @MyriadGenetics and stay up-to-date with the meeting by using the hashtag #SGOMtg.

myRisk Hereditary Cancer Presentation — Endometrial Cancer

Title: Hereditary cancer panel testing in an unselected endometrial carcinoma cohort.
Date: Saturday, March 19, 2016: 7:50 to 9:55 a.m. PT.
Location: Podium — Abstract 6261.
Presenter: Kari Ring, MD Anderson Cancer Center.

This study evaluated the prevalence of cancer predisposition gene mutations in 381 endometrial cancer patients who had previously undergone tumor testing to screen for Lynch Syndrome. Patients were tested for mutations in 25 cancer genes using the myRisk Hereditary Cancer test. The results showed that 9.2 percent of endometrial cancer patients had a deleterious mutation, including 5.8 percent with a mutation in a Lynch Syndrome gene and 3.4 percent in 10 non-Lynch genes. Multi-gene panel testing with myRisk demonstrated the ability to identify 60 percent more mutations, several of which are associated with ovarian and uterine cancers. These findings support gene panel testing to identify patients who may be missed by current Lynch Syndrome testing alone.

myChoice HRD Presentation

Title: Homologous recombination deficiency (HRD) score shows superior association with outcome compared to its individual score components (LOH, TAI and LST) in platinum treated serous ovarian cancer.
Date: Saturday, March 19, 2016: 7:50 to 9:55 a.m. PT.
Location: Podium — Abstract 6286.
Presenter: Gordon B. Mills, M.D., Ph.D., MD Anderson Cancer Center.

This study compared the predictive ability of the combined three biomarker myChoice HRD score to the three independent measures of homologous recombination deficiency that comprise the assay including: loss of heterozygosity (LOH) score, telomeric-allelic imbalance (TAI) score, and large-scale state transitions (LST) score. The results showed that the combined myChoice HRD score predicted progression-free survival (p=2.2×10-6) and overall survival (p=1.0×10-8) in patients with platinum-treated ovarian cancer. In a bivariate analysis none of the individual biomarkers (LOH, TAI and LST) reached statistical significance for either progression free survival or overall survival. In this study, myChoice HRD was shown to be a superior predictor of clinical outcomes to any of the individual score components including LOH, TAI and LST.

About Myriad myRisk Hereditary Cancer Testing
The Myriad myRisk Hereditary Cancer test uses next-generation sequencing technology to evaluate 25 clinically significant genes associated with eight hereditary cancer sites including: breast, colon, ovarian, endometrial, pancreatic, prostate and gastric cancers and melanoma. For more information visit: myriad.com.

About myChoice HRD
Myriad’s myChoice HRD is the first homologous recombination deficiency test that can detect when a tumor has lost the ability to repair double-stranded DNA breaks, resulting in increased susceptibility to DNA-damaging drugs such as platinum drugs or PARP inhibitors. High myChoice HRD scores reflective of DNA repair deficiencies are prevalent in all breast cancer subtypes, ovarian and most other major cancers. In previously published data, Myriad showed that the myChoice HRD test predicted drug response to platinum therapy in certain patients with triple-negative breast and ovarian cancers. It is estimated that 1.8 million people in the United States and Europe who are diagnosed with cancers annually may be candidates for treatment with DNA-damaging agents. For more information visit: myriad.com.