Validation of PRKCB Immunohistochemistry as a Biomarker for the Diagnosis of Ewing Sarcoma.

Ewing sarcoma (ES) can be confirmed by identifying the fusion transcript. This study is to investigate whether immunostaining (IHC) of PRKCB-a protein directly regulated by is a surrogate maker for diagnosing ES in routine practice. Microarray gene expression analyses were conducted.

A phase I/randomized phase II study of GM.CD40L vaccine in combination with CCL21 in patients with advanced lung adenocarcinoma.

The GM.CD40L vaccine, which recruits and activates dendritic cells, migrates to lymph nodes, activating T cells and leading to systemic tumor cell killing. When combined with the CCL21 chemokine, which recruits T cells and enhances T-cell responses, additive effects have been demonstrated in non-small cell lung cancer mouse models.

Microfluidic Biopsy Trapping Device for the Real-Time Monitoring of Tumor Microenvironment.

The tumor microenvironment is composed of cellular and stromal components such as tumor cells, mesenchymal cells, immune cells, cancer associated fibroblasts and the supporting extracellular matrix. The tumor microenvironment provides crucial support for growth and progression of tumor cells and affects tumor response to therapeutic interventions. To better understand tumor biology and to develop effective cancer therapeutic agents it is important to develop preclinical platforms that can faithfully recapitulate the tumor microenvironment and the complex interaction between the tumor and its surrounding stromal elements.

Identification of Synergistic, Clinically Achievable, Combination Therapies for Osteosarcoma.

Systemic therapy has improved osteosarcoma event-free and overall survival, but 30-50% of patients originally diagnosed will have progressive or recurrent disease, which is difficult to cure. Osteosarcoma has a complex karyotype, with loss of p53 in the vast majority of cases and an absence of recurrent, targetable pathways. In this study, we explored 54 agents that are clinically approved for other oncologic indications, agents in active clinical development, and others with promising preclinical data in osteosarcoma at clinically achievable concentrations in 5 osteosarcoma cell lines.

Special Technologies for Ex Vivo Analysis of Cancer.

Background: Predictive assays for cancer treatment are not new technology, but they have failed to meet the criteria necessary for standardized use in clinical decision-making.

Methods: The authors summarize the use of predictive assays and the challenges and values associated with these assays in the clinical setting.

Results: Predictive assays commercially available in the clinical setting are not standardized, have significant obstacles to overcome, and cannot be relied upon by health care professionals due to the limited value these assays provide to the decision-making process for the treatment of patients.

Advances in EGFR as a Predictive Marker in Lung Adenocarcinoma.

Background: Worldwide, lung cancer is the most common cause of mortality. Toxins from tobacco smoke are known to increase the risk of lung cancer; however, up to 15% of lung cancer-related deaths in men and up to 50% of lung cancer-related deaths in women occur in people who do not smoke. Despite the fact that chemotherapy generally provides a survival benefit for non-small-cell lung cancer, not every patient will respond to therapy and many experience therapy-related adverse events.

Annotation of human cancers with EGFR signaling-associated protein complexes using proximity ligation assays.

Strategies to measure functional signaling-associated protein complexes have the potential to augment current molecular biomarker assays, such as genotyping and expression profiling, used to annotate diseases. Aberrant activation of epidermal growth factor receptor (EGFR) signaling contributes to diverse cancers. We used a proximity ligation assay (PLA) to detect EGFR in a complex with growth factor receptor-bound protein 2 (GRB2), the major signaling adaptor for EGFR.

Antitumor efficacy of the anti-interleukin-6 (IL-6) antibody siltuximab in mouse xenograft models of lung cancer.

Introduction: Interleukin-6 (IL-6) can activate downstream signaling pathways in lung cancer cells, such as the STAT3 pathway, and is reported to be produced by tumor cells with activating EGFR mutations. We examined IL-6/STAT3 in lung cancer tumor tissues and the effects of siltuximab, a neutralizing antibody to human IL-6, in mouse models of lung cancer.

Methods: IL-6 and STAT3 activation levels were compared with tumor histology and presence of KRAS mutations in snap-frozen, non-small-cell lung cancer tumors.

A phase I, pharmacokinetic, and pharmacodynamic study of panobinostat, an HDAC inhibitor, combined with erlotinib in patients with advanced aerodigestive tract tumors.

Purpose: Panobinostat, a histone deacetylase (HDAC) inhibitor, enhances antiproliferative activity in non-small cell lung cancer (NSCLC) cell lines when combined with erlotinib. We evaluated this combination in patients with advanced NSCLC and head and neck cancer.

Experimental Design: Eligible patients were enrolled in a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD) of twice weekly panobinostat plus daily erlotinib at four planned dose levels (DL).

Diffusion MRI and novel texture analysis in osteosarcoma xenotransplants predicts response to anti-checkpoint therapy.

Combinations of targeted drugs have been employed to treat sarcomas, however, response rates have not improved notably, therefore emphasizing the need for novel treatments. In addition, imaging approaches to assess therapeutic response is lacking, as currently measurable indices, such as volume and/or diameter, do not accurately correlate with changes in tumor biology. In this study, quantitative and profound analyses of magnetic resonance imaging (MRI) were developed to evaluate these as imaging biomarkers for MK1775 and Gem in an osteosarcoma xenotransplant model at early time-points following treatment.

A miniaturized chemical proteomic approach for target profiling of clinical kinase inhibitors in tumor biopsies.

While targeted therapy based on the idea of attenuating the activity of a preselected, therapeutically relevant protein has become one of the major trends in modern cancer therapy, no truly specific targeted drug has been developed and most clinical agents have displayed a degree of polypharmacology. Therefore, the specificity of anticancer therapeutics has emerged as a highly important but severely underestimated issue. Chemical proteomics is a powerful technique combining postgenomic drug-affinity chromatography with high-end mass spectrometry analysis and bioinformatic data processing to assemble a target profile of a desired therapeutic molecule.

Wee1 inhibition by MK-1775 leads to tumor inhibition and enhances efficacy of gemcitabine in human sarcomas.

Sarcomas are rare and heterogeneous mesenchymal tumors affecting both pediatric and adult populations with more than 70 recognized histologies. Doxorubicin and ifosfamide have been the main course of therapy for treatment of sarcomas; however, the response rate to these therapies is about 10-20% in metastatic setting. Toxicity with the drug combination is high, response rates remain low, and improvement in overall survival, especially in the metastatic disease, remains negligible and new agents are needed.

Squamous cell carcinoma with rhabdoid phenotype of skin/soft tissue in a transplant patient: an exceptional case and review of the literature.

Squamous cell carcinoma with rhabdoid features (SCCRF) is a very rare and unusual cutaneous tumor. Here, we report an extraordinary case diagnosed by fine needle aspiration biopsy, in a 66-year-old man, status post multiple organ transplantation. The patient presented with a large ulcerating fungating mass in his forearm that had all the light microscopic and immunohistochemical features of a SCCRF.

The histogenic origin of melanoma arising in respiratory epithelium of a teratomatous germ cell tumor of the mediastinum: an enigma unraveled from an unlikely source.

Mixed germ cell tumors are rare neoplasms that are known to occur in the anterior mediastinum. Characterized by two or more types of germ cell components, these tumors comprise upwards of 25% of mediastinal germ cell tumors. Even rarer are those harboring somatic-type malignancies such as carcinoma, sarcoma, and hematopoietic malignancies.

Phase 2 randomized study of enzastaurin (LY317615) for lung cancer prevention in former smokers.

Background: Chemoprevention for lung cancer with nutraceutical or anti-inflammatory agents has had mixed clinical benefit. Novel targeted agents hold the promise of greater efficacy and selectivity. The authors of this report evaluated enzastaurin, a selective protein kinase C-β (PKC-β) inhibitor with antiproliferative and proapoptotic properties, in former smokers.

EGFR/Src/Akt signaling modulates Sox2 expression and self-renewal of stem-like side-population cells in non-small cell lung cancer.

Background: Cancer stem cells are thought to be responsible for the initiation and progression of cancers. In non-small cell lung cancers (NSCLCs), Hoechst 33342 dye effluxing side population (SP) cells are shown to have stem cell like properties. The oncogenic capacity of cancer stem-like cells is in part due to their ability to self-renew; however the mechanistic correlation between oncogenic pathways and self-renewal of cancer stem-like cells has remained elusive.

Autophagy induced by conventional chemotherapy mediates tumor cell sensitivity to immunotherapy.

Autophagy attenuates the efficacy of conventional chemotherapy but its effects on immunotherapy have been little studied. Here, we report that chemotherapy renders tumor cells more susceptible to lysis by CTL in vivo. Moreover, bystander tumor cells that did not express antigen were killed by CTL.

Phosphoproteomics identifies driver tyrosine kinases in sarcoma cell lines and tumors.

Driver tyrosine kinase mutations are rare in sarcomas, and patterns of tyrosine phosphorylation are poorly understood. To better understand the signaling pathways active in sarcoma, we examined global tyrosine phosphorylation in sarcoma cell lines and human tumor samples. Anti-phosphotyrosine antibodies were used to purify tyrosine phosphorylated peptides, which were then identified by liquid chromatography and tandem mass spectrometry.

Curcumin: a novel Stat3 pathway inhibitor for chemoprevention of lung cancer.

Multiple studies from independent groups find evidence for signal transducer and activator of transcription 3 (Stat3) activation in nearly 50% of lung cancers, suggesting a functional role for this target in subsets of lung cancer. On the basis of the existing evidence, we hypothesized that bioavailable curcuminoid complex may modulate lung carcinogenesis, primarily by inhibiting Stat3 activation. With the safety of this being botanically well established, the objective of these studies was to test our hypothesis in vitro and in vivo in an effort to inform the design of a phase II chemoprevention trial in former smokers.

MK1775, a selective Wee1 inhibitor, shows single-agent antitumor activity against sarcoma cells.

Wee1 is a critical component of the G(2)-M cell-cycle checkpoint control and mediates cell-cycle arrest by regulating the phosphorylation of CDC2. Inhibition of Wee1 by a selective small molecule inhibitor MK1775 can abrogate G(2)-M checkpoint, resulting in premature mitotic entry and cell death. MK1775 has recently been tested in preclinical and clinical studies of human carcinoma to enhance the cytotoxic effect of DNA-damaging agents.

Tumor-infiltrating myeloid cells induce tumor cell resistance to cytotoxic T cells in mice.

Cancer immunotherapeutic approaches induce tumor-specific immune responses, in particular CTL responses, in many patients treated. However, such approaches are clinically beneficial to only a few patients. We set out to investigate one possible explanation for the failure of CTLs to eliminate tumors, specifically, the concept that this failure is not dependent on inhibition of T cell function.

Metastatic soft tissue sarcoma chemotherapy: an opportunity for personalized medicine.

Background: Soft tissue sarcoma (STS) includes biologically and histologically diverse mesenchymal tumors that are relatively chemotherapy-resistant compared with other sarcoma subtypes.

Methods: The authors discuss the clinical challenges frequently encountered by medical oncologists and review the literature for predictive strategies to systematically approach chemotherapy decision making.

Results: There are no clinically validated predictive tests for chemotherapeutic response or resistance in STS.

The cyclin-dependent kinase inhibitor SCH 727965 (dinacliclib) induces the apoptosis of osteosarcoma cells.

Although rare, osteosarcoma is an aggressive cancer that often metastasizes to the lungs. Toward the goal of developing new treatment options for osteosarcoma, we show that the cyclin-dependent kinase (CDK) inhibitor SCH 727965 (SCH) induces the apoptosis of several osteosarcoma cell lines including those resistant to doxorubicin and dasatinib. Cell lines prepared in our laboratory from patients who had received adjuvant chemotherapy and explants derived from a human osteosarcoma xenograft in mice were also responsive to SCH.

Histone deacetylase inhibitors downregulate checkpoint kinase 1 expression to induce cell death in non-small cell lung cancer cells.

Background: Histone deacetylase inhibitors (HDACis) are promising anticancer drugs; however, the molecular mechanisms leading to HDACi-induced cell death have not been well understood and no clear mechanism of resistance has been elucidated to explain limited efficacy of HDACis in clinical trials.

Methods And Findings: Here, we show that protein levels of checkpoint kinase 1 (Chk1), which has a major role in G(2) cell cycle checkpoint regulation, was markedly reduced at the protein and transcriptional levels in lung cancer cells treated with pan-and selective HDACis LBH589, scriptaid, valproic acid, apicidin, and MS-275. In HDACi treated cells Chk1 function was impaired as determined by decreased inhibitory phosphorylation of cdc25c and its downstream target cdc2 and increased expression of cdc25A and phosphorylated histone H3, a marker of mitotic entry.