Judith Loeffler-Ragg

EGFR inhibition as a therapy for head and neck squamous cell carcinoma

Background: Improved understanding of disease biology of head and neck squamous cell carcinoma (HNSCC) with nearly universal expression of EGFR has led to the introduction of targeted therapies to interrupt signalling of this negative prognostic marker. Objective: We performed a literature review on the mechanisms and efficacy of anti-EGFR antibodies and EGFR tyrosine kinase inhibitors in patients with locally advanced or recurrent/metastatic HNSCC. Results/conclusion: Clinical trials in HNSCC have administered EGFR directed drugs as single agents, in combination with chemotherapy or radiotherapy and demonstrated a good safety profile with antitumour activity in a subgroup of patients. The biology of responsiveness is still unclear, although there is growing evidence of an association of skin toxicity or presence of shorter EGFR intron 1 cytosine–adenine repeats with positive outcome.

Identification of the rare EGFR mutation p.G796S as somatic and germline mutation in white patients with squamous cell carcinoma of the head and neck

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) are involved in tumorigenesis and response to targeted therapies in distinct cancer types. Squamous cell carcinomas of the head and neck (HNSCC) show an incidence of EGFR mutations varying from 7% in Asians to 0% to 4% in white patients. Mutational screening predominantly focuses on the analysis of hotspot regions of EGFR (exons 19 and 21).

AKR1B10 expression is associated with less aggressive hepatocellular carcinoma: a clinicopathological study of 168 cases

Background/Aims: The detoxification enzyme AKR1B10, a member of the aldo‐keto reductase superfamily, is discussed as a new biomarker candidate for hepatocellular carcinoma (HCC). Only rare clinicopathological data on AKRB1B10 in HCC exist. This retrospective study determines the diagnostic and prognostic relevance of AKR1B10 expression in HCC and its relationship to a series of clinicopathological parameters including underlying aetiological factors.

Targeted Therapies in Non-Small Cell Lung Cancer: Proven Concepts and Unfulfilled Promises.

Targeted therapies focus on signaling pathways in cancer cells and other molecular processes involved in oncogenesis. Recent approaches affect the following major groups: the epidermal growth factor receptor (EGFR)-family, angiogenesis, the eicosanoid pathway, the PKC/ Ras/ MAPK pathway, the proteasome and inducers of apoptosis. Numerous phase I and II trials have provided promising results and recently, anti-EGFR and anti-VEGF treatments have proven their efficacy in phase III trials. However, others failed in phase III settings (e.g. PKC- and matrix metalloproteinase inhibitors) and it is a moot point, whether patients have been selected properly. The huge amount of new medications raises questions like when to use which strategy in which sequence. The successful implementation of targeted agents into clinical routine will depend on the verification of sufficient predictive markers, allowing their economically reasonable usage. In the current review the up-to-date knowledge concerning targeted therapies in NSCLC is summarized and their therapeutical potential is discussed.

Proteomic identification of aldo-keto reductase AKR1B10 induction after treatment of colorectal cancer cells with the proteasome inhibitor bortezomib

Targeting the ubiquitin-proteasome pathway with the proteasome inhibitor bortezomib has emerged as a promising approach for the treatment of several malignancies. The cellular and molecular effects of this agent on colorectal cancer cells are poorly characterized. This study investigated the antiproliferative effect of bortezomib on colorectal cancer cell lines (Caco-2 and HRT-18). In order to define the proteins potentially involved in the mechanisms of action, proteome profiling was applied to detect the proteins altered by bortezomib. The in vitro efficacy of bortezomib as a single agent in colorectal cancer cell lines was confirmed. Proteome profiling with two-dimensional PAGE followed by mass spectrometry revealed the up-regulation of the major inducible isoform of heat shock protein 70 (hsp72) and lactate dehydrogenase B in both cell lines, as well as the induction of aldo-keto reductase family 1 member B10 (AKR1B10) in HRT-18 cells. Both AKR1B10 and hsp72 exert cell-protective functions. This study shows for the first time a bortezomib-induced up-regulation of AKR1B10. Small interfering RNA–mediated inhibition of this enzyme with known intracellular detoxification function sensitized HRT-18 cells to therapy with the proteasome inhibitor. To further characterize the relevance of AKR1B10 for colorectal tumors, immunohistochemical expression was shown in 23.2% of 125 tumor specimens. These findings indicate that AKR1B10 might be a target for combination therapy with bortezomib. [Mol Cancer Ther 2009;8(7):1995–2006]

Irreversible pan-ErbB tyrosine kinase inhibitor CI-1033 induces caspase-independent apoptosis in colorectal cancer DiFi cell line

The epidermal growth factor receptor (EGFR) is overexpressed in the majority of colorectal carcinomas and represents a target for therapeutic interventions with signal transduction inhibitors. We investigated the ability of CI-1033 to induce apoptosis and inhibition of proliferation in the colorectal cancer cell lines DiFi and Caco-2, which both express high levels of EGFR. While in Caco-2 cells CI-1033 treatment at a concentration 0.1 μ M for 72 hours demonstrated only antiproliferative (53.7 ± 4.3%) but no pro-apoptotic effects, treatment of DiFi cells resulted in a reduced proliferation rate (31.4 ± 3.1%) and in apoptosis (44.2 ± 8.9%). In order to define proteins involved in the regulation of apoptosis, we aimed to determine differences in the proteome profile of both cell lines before and after treatment with CI-1033. Cellular proteins were analyzed by 2-D gel electrophoresis followed by computational image analysis and mass spectrometry. Our data show that DiFi cells differ from Caco-2 cells in nine significantly upregulated proteins, and their potential role in apoptosis is described. We demonstrate that induction of apoptosis was triggered via caspase-independent pathways. Overexpression of leukocyte elastase inhibitor (LEI) and translocation of cathepsin D to the cytosol accompanied by upregulation of other defined proteins resulted in Bax-independent AIF translocation from mitochondria into the nucleus and apoptosis. Definition of these proteins can pave the way for functional studies and contribute to a better understanding of the effects of CI-1033 and the pathways of caspase-independent cell death.

Diagnostic and therapeutic challenges of a large pleural inflammatory myofibroblastic tumor.

We report a 48-year-old woman with a pleural pseudoneoplasm requiring different diagnostic and therapeutic strategies. After initial presentation with increasing dyspnoea, temperature, dry cough, and interscapular pain diagnostic processing showed a large mediastinal mass with marked pleural effusion and high metabolic activity in the 18F-FDG-PET/CT. Extensive CT-guided biopsy of the tumor reaching from the visceral pleura into the right upper lobe revealed no malignancy, but a marked inflammatory tissue reaction containing foam cells. Initial empiric antibiotic therapy was temporarily successful. However, in the further course the mass relapsed and was resistant to antibiotics and a corticosteroid trial. With the working hypothesis of an inflammatory myofibroblastic tumor the patient underwent surgical tumor resection, finally confirming the suspected diagnosis. Due to residual disease intravenous immunoglobulins were administered leading to sustained response. This case with a pleural localisation of a large inflammatory pseudotumor with responsiveness to immunomodulation after incomplete resection extends the reported spectrum of thoracopulmonary manifestations of this rare entity.

Increase in antibody-dependent cellular cytotoxicity (ADCC) in a patient with advanced colorectal carcinoma carrying a KRAS mutation under lenalidomide therapy

The failure of EGFR inhibitors in colorectal tumors with KRAS mutations requires the development of alternative treatment strategies for this patient subgroup. Among the hallmarks of cancer the disturbed immunosurveillance and cancer immune evasion have become emerging targets for cancer therapy. Due to their pleiotropic functions immunomodulatory drugs (IMiDs) are interesting agents for combination therapies in solid tumors. However, their possible contribution and a way of monitoring their biological effects have yet to be revealed. In a heavily pretreated patient with advanced colorectal cancer carrying mutations in APC and KRAS genes, we show an early metabolic response and enhanced NK cell activity to monotherapy with lenalidomide. After subsequent lenalidomide/cetuximab combination treatment, the patient had progressive disease. At the same time a reduced performance status, complicated by febrile neutropenia, occurred, as well as a slight increase in metabolic activity. Concordantly NK cell activity dropped back to baseline. Thus, laboratory measurements and metabolic response assessment correlated with clinical conditions. This case report describes the feasibility and potential of a functional assessment of patient derived immune competent cells in combination with functional imaging for the detection of a biological response.

Elevated levels of serum CD44 and E-cadherin predict an unfavourable outcome in myelodysplastic syndromes

Elevated levels of serum CD44 and E-cadherin predict an unfavourable outcome in myelodysplastic syndromes

R001: Novel Mutations in the EGFR Kinase Domain in Patients

PROBLEM: Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are associated with increased sensitivity to tyrosine kinase inhibitors (TKIs) and are present in 10% to 30% of nonsmall cell lung carcinoma depending on ethnic origin. EGFR protein is also overexpressed in about 90% of squamous cell carcinoma of head and neck (HNSCC), and treatment with TKIs has shown clinical benefit in a subgroup of these patients. Recently, EGFR mutations were described in three Asian patients with larynx cancer. METHODS: The presenters screened for EGFR tyrosine kinase mutations in tumor DNA of 100 patients of Caucasian origin with HNSCC by direct sequencing of the hotspot regions. Two patients displayed a novel, somatic EGFR missense mutation, K745R, affecting a highly conserved residue within the ATP cleft. RESULTS: Similar to reports in lung cancer, EGFR kinase domain mutations in HNSCC patients seem to show a lower incidence in patients of Caucasian origin. CONCLUSION: Altough EGFR kinase domain mutations in HNSCC are rare, an exact evaluation of these mutations might help to stimulate further investigations in the field of specific tumor therapy. SIGNIFICANCE: However, for individualized cancer therapy screening for such specific mutations could be one rationale for clinical applicability of gefitinib to a subset of patients.