CD90 expression controls migration and predicts dasatinib response in glioblastoma.

Purpose: CD90 (Thy-1) is a glycophosphatidylinositol-anchored glycoprotein considered as a surrogate marker for a variety of stem cells including glioblastoma (GBM) stem cells (GSCs). However, the molecular and cellular functions of CD90 remain unclear. Experimental design: The function of CD90 in GBM was addressed using cellular models from immortalized and primary GBM lines, in vivo orthotopic mouse models, GBM specimens' transcriptome associated with MRI features from GBM patients. CD90 expression was silenced in U251 and GBM primary cells; and complemented in CD90 negative U87 cells. Results: We showed that CD90 is not only expressed on GSCs but also on more differentiated GBM cancer cells. In GBM patients, CD90 expression was associated with an adhesion/migration gene signature and with invasive tumor features. Modulation of CD90 expression in GBM cells dramatically impacted on their adhesion and migration properties. Moreover, orthotopic xenografts revealed that CD90 expression induced invasive phenotypes in vivo. Indeed, CD90 expression led to enhanced SRC and FAK signaling in our GBM cellular models and GBM patients' specimens. Pharmacologic inhibition of these signaling nodes blunted adhesion and migration in CD90 positive cells. Remarkably, dasatinib blunted CD90 dependent GBM cell invasion in vivo and killed CD90high primary GSC lines. Conclusion: Our data demonstrate that CD90 is an actor of GBM invasiveness through SRC dependent mechanisms and could be used as a predictive factor for dasatinib response in CD90high GBM patients.

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A novel Breast Cancer Index for prediction of distant recurrence in HR+ early stage breast cancer with 1 to 3 positive nodes

Purpose: Study objective was to characterize the prognostic performance of a novel Breast Cancer Index model (BCIN+), an integration of BCI gene expression, tumor size, and grade, specifically developed for assessment of distant recurrence (DR) risk in HR+ breast cancer patients with 1-3 positive lymph nodes (pN1). <br><br> Experimental Design: Analysis was conducted in a well-annotated retrospective series of pN1 patients (N=402) treated with adjuvant endocrine therapy with or without chemotherapy using a pre-specified model. The primary endpoint was time-to-DR. Results were determined blinded to clinical outcome. Kaplan-Meier estimates of overall (0-15y) and late (≥5y) DR, hazard ratios and 95% CIs were estimated. Likelihood ratio statistics assessed relative contributions of prognostic information. <br><br> Results: BCIN+ classified 81 patients (20%) as low risk with a 15-year DR rate of 1.3% (95%CI: 0.0-3.7%) vs 321 patients as high risk with a DR rate of 29.0% (23.2-34.4%). In patients DR-free for ≥5y (n=349), the late DR rate was 1.3% (95%CI: 0.0-3.7%) and 16.1% (10.6-21.3%) in low- and high-risk groups, respectively. BCI gene expression alone was significantly prognostic (LR-2=20.12, P<0.0001). Addition of tumor size (LR-2=13.29, P=0.0003) and grade (LR-2=12.72, P=0.0004) significantly improved prognostic performance. BCI added significant prognostic information to tumor size (LR-2=17.55, P<0.0001); addition to tumor grade was incremental (LR-2=2.38, P=0.1) with considerable overlap between prognostic values (LR-2=17.74). <br><br> Conclusions: The integrated BCIN+ identified 20% of pN1 patients with limited risk of recurrence over 15y, in whom extended endocrine treatment may be spared. Ongoing studies will characterize combined clinical-genomic risk assessment in node-positive patients.

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Phase III clinical trial (RERISE study) results of Efficacy and safety of radotinib compared with imatinib in newly diagnosed chronic phase chronic myeloid leukemia

Purpose: Radotinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor (TKI) approved in Korea for CML-CP in patients newly diagnosed or with insufficient response to other TKIs. This study was conducted to evaluate the efficacy and safety of radotinib as first-line therapy for CML-CP. Methods: This multinational, open-label study assigned patients (1:1:1) to one of two twice-daily (bid) radotinib doses, or imatinib daily (qd). The primary endpoint was major molecular response (MMR) by 12 months. Results: Two hundred forty-one patients were randomized to receive radotinib 300 mg (n = 79) or 400 mg bid (n = 81), or imatinib 400 mg qd (n = 81). MMR rates by 12 months were higher in patients receiving radotinib 300 mg (52%) or radotinib 400 mg bid (46%) versus imatinib (30%; P = 0.0044 and P = 0.0342, respectively). Complete cytogenetic response (CCyR) rates by 12 months were higher for radotinib 300 mg (91%) versus imatinib (77%; P = 0.0120). Early molecular response at 3 months occurred in 86% and 87% of patients receiving radotinib 300 mg and radotinib 400 mg, respectively, and 71% of those receiving imatinib. By 12 months, no patients had progression to accelerated phase or blast crisis. Most adverse events were manageable with dose reduction. Conclusion: Radotinib demonstrated superiority over imatinib in CCyR and MMR in patients newly diagnosed with Philadelphia chromosome-positive CML-CP. This trial was registered at http://ift.tt/PmpYKN as NCT01511289.

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In-depth genetic analysis of sclerosing epithelioid fibrosarcoma reveals recurrent genomic alterations and potential treatment targets

Purpose: Sclerosing epithelioid fibrosarcoma (SEF) is a highly aggressive soft tissue sarcoma closely related to low-grade fibromyxoid sarcoma (LGFMS). Some tumors display morphological characteristics of both SEF and LGFMS, so called hybrid SEF/LGFMS. Despite the overlap of gene fusion variants between these two tumor types, SEF is much more aggressive. The present study aimed to further characterize SEF and hybrid SEF/LGFMS genetically in order to better understand the role of the characteristic fusion genes and possible additional genetic alterations in tumorigenesis. Experimental Design: We performed whole exome sequencing, single nucleotide polymorphism (SNP) array analysis, RNA-sequencing (RNA-seq), global gene expression analyses and/or IHC on a series of 13 SEFs and 6 hybrid SEF/LGFMS. We also expressed the FUS-CREB3L2 and EWSR1-CREB3L1 fusion genes conditionally in a fibroblast cell line; these cells were subsequently analyzed by RNA-seq and expression of the CD24 protein was assessed by FACS analysis. Results: The SNP array analysis detected a large number of structural aberrations in SEF and SEF/LGFMS, many of which were recurrent, notably DMD microdeletions. RNA-seq identified FUS-CREM and PAX5-CREB3L1 as alternative fusion genes in one SEF each. CD24 was strongly upregulated, presumably a direct target of the fusion proteins. This was further confirmed by the gene expression analysis and FACS analysis on Tet-On 3G cells expressing EWSR1-CREB3L1. Conclusions: While gene fusions are the primary tumorigenic events in both SEF and LGFMS, additional genomic changes explain the differences in aggressiveness and clinical outcome between the two types. CD24 and DMD constitute potential therapeutic targets.

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Radiomics Analysis for Evaluation of Pathological Complete Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer

Purpose: To develop and validate a radiomics model for evaluating pathological complete response (pCR) to neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer (LARC). Experimental Design: We enrolled 222 patients (152 in the primary cohort and 70 in the validation cohort) with clinicopathologically confirmed LARC who received chemoradiotherapy before surgery. All patients underwent T2-weighted and diffusion-weighted imaging before and after chemoradiotherapy; 2252 radiomic features were extracted from each patient pre- and post-treatment imaging. The 2-sample t-test and the least absolute shrinkage and selection operator regression were used for feature selection, whereupon a radiomics signature was built with support vector machines. Multivariable logistic regression analysis was then used to develop a radiomics model incorporating the radiomics signature and independent clinicopathological risk factors. The performance of the radiomics model was assessed by its calibration, discrimination, and clinical usefulness with independent validation. Results: The radiomics signature comprised 30 selected features and showed good discrimination performance in both the primary and validation cohorts. The individualized radiomics model, which incorporated the radiomics signature and tumor length, also showed good discrimination, with an area under the receiver operating characteristic curve of 0.9756 (95% confidence interval: 0.9185-0.9711) in the validation cohort, and good calibration. Decision curve analysis confirmed the clinical utility of the radiomics model. Conclusion: Using pre- and post-treatment MRI data, we developed a radiomics model with excellent performance for individualized, non-invasive prediction of pCR. This model may be used to identify LARC patients who can omit surgery after chemoradiotherapy.

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Phospholipase D1 inhibition linked to upregulation of ICAT blocks colorectal cancer growth hyperactivated by Wnt/{beta}-catenin and PI3K/Akt Signaling

Purpose: Dysregulated expression of PLD1 has emerged as a hallmark feature of colorectal cancer (CRC), which remains a major cause of mortality worldwide. Aberrant activation of Wnt/β-catenin signaling is a critical event in the development of CRC. Here, we investigated molecular crosstalk between the Wnt/β-catenin and PI3K/Akt pathways via ICAT, a negative regulator of Wnt/β-catenin signaling. We also explored the effect of PLD1 inhibition on growth of CRC hyperactivated by Wnt/β-catenin and PI3K/Akt signaling. Experimental design: Expression of ICAT via targeting of PLD1 was assessed in vivo in ApcMin/+ mice, an AOM/DSS model, and in vitro using various CRC cells. The relationship between ICAT/PLD1 expression and prognostic survival value of 153 CRC patients was examined. The therapeutic efficacy of PLD1 inhibitor was determined using a patient-derived xenograft model carrying APC and PI3K mutations. Results: PLD1 promoted the Wnt/β-catenin signaling pathway by selectively down-regulating ICAT via the PI3K/Akt-TopBP1-E2F1 signaling pathways. Low PLD1 expression and high ICAT expression were significantly associated with increased survival in CRC patients and vice versa. Furthermore, PLD1 inhibition suppressed growth of CRC activated by the Wnt/β-catenin and PI3K signaling pathways. Conclusion: These results suggest that PLD1 linked to ICAT mediates molecular crosstalk between the Wnt/β-catenin and PI3K/Akt pathways and thus could be proposed as a novel CRC prognostic biomarker. These results may assist in the clinical development of a PLD1 inhibitor for treatment of CRC patients carrying APC and PI3KCA mutations.

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A pilot trial of humanized anti-GD2 monoclonal antibody (hu14.18K322A) with chemotherapy and natural killer cells in children with recurrent/refractory neuroblastoma

Purpose: Anti-GD2 monoclonal antibodies (mAb), acting via antibody-dependent cell-mediated cytotoxicity, may enhance the effects of chemotherapy. This pilot trial investigated a fixed dose of a unique anti-GD2 mAb, hu14.18K322A, combined with chemotherapy, cytokines and haploidentical natural killer (NK) cells. Experimental Design: Children with recurrent/refractory neuroblastoma received up to six courses of hu14.18K322A (40mg/m2/dose, days 2-5), GMCSF and IL-2 with chemotherapy: cyclophosphamide/topotecan (courses 1,2), irinotecan/temozolomide (courses 3,4) and ifosfamide/carboplatin/etoposide (courses 5,6). Parentally-derived NK cells were administered with courses 2, 4 and 6. Serum for pharmacokinetic studies of hu14.18K322A, soluble IL-2 receptor alpha (sIL-2Ra) levels and human anti-human antibodies (HAHA) were obtained. Results: Thirteen heavily pretreated patients (9 with prior anti-GD2 therapy) completed 65 courses. One patient developed an unacceptable toxicity (grade 4 thrombocytopenia >35 days). Four patients discontinued treatment for adverse events (hu14.18K322A allergic reaction, viral infection, surgical death, second malignancy). Common toxicities included grade 3/4 myelosuppression (13/13 patients) and grade 1/2 pain (13/13 patients). Eleven patients received 29 NK cell infusions. The response rate was 61.5% (4 CR, 1 VGPR, 3 PR) and 5 had stable disease. The median time to progression was 274 days (range, 239-568 days); 10 of 13 patients (77%) survived one year. Hu14.18K322A pharmacokinetics were not affected by chemotherapy or HAHA. All patients had increased sIL-2Ra levels, indicating immune activation. Conclusions: Chemotherapy plus hu14.18K322A, cytokines and NK cells is feasible and resulted in clinically meaningful responses in patients with refractory/recurrent neuroblastoma. Further studies of this approach are warranted in patients with relapsed and newly-diagnosed neuroblastoma.

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