Showing papers by "Peter H. Schafer published in 2011"

Lenalidomide downregulates the cell survival factor, interferon regulatory factor-4, providing a potential mechanistic link for predicting response.

Abstract: Overexpression of the transcription factor interferon regulatory factor-4 (IRF4), which is common in multiple myeloma (MM), is associated with poor prognosis. Patients with higher IRF4 expression have significantly poorer overall survival than those with low IRF4 expression. Lenalidomide is an IMiD immunomodulatory compound that has both tumouricidal and immunomodulatory activity in MM. This study showed that lenalidomide downregulated IRF4 levels in MM cell lines and bone marrow samples within 8 h of drug exposure. This was associated with a decrease in MYC levels, as well as an initial G1 cell cycle arrest, decreased cell proliferation, and cell death by day 5 of treatment. In eight MM cell lines, high IRF4 levels correlated with increased lenalidomide sensitivity. The clinical significance of this observation was investigated in 154 patients with MM. Among MM patients with high levels of IRF4 expression, treatment with lenalidomide led to a significantly longer overall survival than other therapies in a retrospective analysis. These data confirm the central role of IRF4 in MM pathogenesis; indicate that this is an important mechanism by which lenalidomide exerts its antitumour effects; and may provide a mechanistic biomarker to predict response to lenalidomide.

Lenalidomide enhances antibody-dependent cellular cytotoxicity of solid tumor cells in vitro: influence of host immune and tumor markers

Abstract: We evaluated the effect of combining lenalidomide with therapeutic antibodies on antibody-dependant cell-mediated cytotoxicity (ADCC) of solid tumor cells, and the requirement for expression of natural killer (NK) cell-activating receptors and their solid tumor surface ligands. Twenty-three human tumor cell lines (colon, breast, lung, head and neck, ovary, and bone sarcoma) were analyzed. NK effector cells were isolated from healthy donors, pre-treated with and without lenalidomide, and incubated with antibody-coated tumor cells to determine ADCC. In blocking experiments, NK cells were pre-incubated with anti-DNAM-1 or anti-NKG2D antibodies, and target colorectal cells were pre-incubated with anti-CD155 (PVR), anti-MIC-A/B, or anti-ULBP 3 antibodies. Differences between groups were assessed using unpaired and paired Student’s t test and one-way ANOVA. Lenalidomide enhanced NK cell-mediated ADCC of trastuzumab- and cetuximab-coated tumor cells. Activity against colorectal cancer cells was dependent on target antigen expression, but independent of KRAS status and FcγRIIIa genotype. The extent of ADCC and its enhancement by lenalidomide correlated with NK cell expression of NKG2D and DNAM-1, and tumor cell expression of PVR and MIC-A. Blocking of NKG2D and, to a lesser extent, DNAM-1 inhibited ADCC. Anti-MIC-A/B monoclonal antibody blocked natural cytotoxicity, but not ADCC. Lenalidomide enhances the ability of IgG1-isotype antibodies to mediate ADCC of solid tumor cells, the extent of which is largely dependent on NKG2D–NKG2D ligand interactions, but appears to be independent of MIC-A/B. This provides a rationale for exploratory clinical studies and an assessment of potential biomarkers predictive of clinical benefit.

Disposition, metabolism and mass balance of [14C]apremilast following oral administration

Abstract: Apremilast is a novel, orally available small molecule that specifically inhibits PDE4 and thus modulates multiple pro- and anti-inflammatory mediators, and is currently under clinical development for the treatment of psoriasis and psoriatic arthritis. The pharmacokinetics and disposition of [14C]apremilast was investigated following a single oral dose (20 mg, 100 μCi) to healthy male subjects.Approximately 58% of the radioactive dose was excreted in urine, while faeces contained 39%. Mean Cmax, AUC0–∞ and tmax values for apremilast in plasma were 333 ng/mL, 1970 ng*h/mL and 1.5 h. Apremilast was extensively metabolized via multiple pathways, with unchanged drug representing 45% of the circulating radioactivity and 4% of the excreted radioactivity were O-demethylated apremilas...

Methods for the treatment of non-hodgkin's lymphomas using lenalidomide, and gene and protein biomarkers as a predictor

Abstract: Methods of treating or managing specific cancers, including non-Hodgkin's lymphoma, by the administration of 3-(4-amino-l-oxo-l,3-dihydro-isoindol-2-yl)- piperidine-2,6-dione are disclosed. Methods of using gene and protein biomarkers as a predictor of non-Hodgkin's lymphoma response to treatment with 3-(4-amino-l-oxo-l,3- dihydro-isoindol-2-yl)-piperidine-2,6-dione are also disclosed.

Biomarkers for the treatment of psoriasis

Abstract: Provided herein are the biomarkers for predicting or monitoring the efficacy of a treatment for psoriasis. The use of certain cell markers and mRNA levels as biomarkers to predict whether a psoriasis treatment is likely to be successful is also provided. Further, the expression of these genes or cell markers can be used to monitor progress of treatment effectiveness and patient compliance in psoriasis patients who are receiving treatment.

Biomarqueurs pour le traitement du psoriasis

Abstract: La presente invention a pour objet les biomarqueurs pour la prediction ou la surveillance de l'efficacite d'un traitement contre le psoriasis. La presente invention concerne egalement l'utilisation de certains marqueurs cellulaires et de niveaux d'ARNm en tant que biomarqueurs pour predire si un traitement contre le psoriasis est susceptible d'etre efficace. En outre, l'expression de ces genes ou de ces marqueurs cellulaires peut etre utilisee pour surveiller l'evolution de l'efficacite du traitement et de l'observance du patient chez des patients atteints de psoriasis qui recoivent un traitement.