Specific cellular signal-transduction responses to in vivo combination therapy with ATRA, valproic acid and theophylline in acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) frequently comprises mutations in genes that cause perturbation in intracellular signaling pathways, thereby altering normal responses to growth factors and cytokines. Such oncogenic cellular signal transduction may be therapeutic if targeted directly or through epigenetic regulation. We treated 24 selected elderly AML patients with all-trans retinoic acid for 2 days before adding theophylline and the histone deacetylase inhibitor valproic acid (ClinicalTrials.gov NCT00175812; EudraCT no. 2004-001663-22), and sampled 11 patients for peripheral blood at day 0, 2 and 7 for single-cell analysis of basal level and signal-transduction responses to relevant myeloid growth factors (granulocyte-colony-stimulating factor, granulocyte/macrophage-colony-stimulating factor, interleukin-3, Flt3L, stem cell factor, erythropoietin, CXCL-12) on 10 signaling molecules (CREB, STAT1/3/5, p38, Erk1/2, Akt, c-Cbl, ZAP70/Syk and rpS6). Pretreatment analysis by unsupervised clustering and principal component analysis divided the patients into three distinguishable signaling clusters (non-potentiated, potentiated basal and potentiated signaling). Signal-transduction pathways were modulated during therapy and patients moved between the clusters. Patients with multiple leukemic clones demonstrated distinct stimulation responses and therapy-induced modulation. Individual signaling profiles together with clinical and hematological information may be used to early identify AML patients in whom epigenetic and signal-transduction targeted therapy is beneficial.

Discovery and development of the Polo-like kinase inhibitor volasertib in cancer therapy

“… 32 , 63 In this regard, it is noteworthy that a proteomics study in AML identified a signature of four phosphorylated proteins that act as predictors for response to the FLT3-targeted tyrosine kinase inhibitor, quizartinib. 64 Proteomics of AML is still in its infancy, 65 but may allow delineation of defined signal transduction and tumor suppressor pathways in single cells or cell extract assay: 66 , 67 sample formats that may be relevant for future clinical trials of Plk1-targeting therapy. Relevant markers might be also identified based on comprehensive genomic, epigenomic and transcriptomic analyses.…”

Opening Lecture

“…The algorithm used for the digital analysis was developed using MATLAB (MathWorks, Natick, Massachusetts). The patients were randomly selected from a previously characterized cohort (n = 97) where the ultrasound findings correlated with objective findings such as reduced saliva secretion, minor salivary gland inflammation and elevated autoantibody titers, as well as sicca symptoms of the mouth (3). Results: Preliminary findings show an excellent correlation between the scores obtained with the simplified grading system (0-3) and the automated digital evaluation of local variability in grayscale values (P < 0.05, r = 0.816, n = 26).…”

“…34.5% pts (29/84): 7 pts with systemic manifestations, 15 with MALT lymphoma, seven with hypergammaglobulinemia) were under RTX maintenance therapy for median 48 (33-60) months. Median RTX cumulative dose of during it was 2.5 gr (2)(3)(4). Results: At month three after RTX induction therapy, there was significant improvement in pSS (see Table 1).…”

“…Serum cryoglobulins (SC) (1) may be found in many diseases, and SC are a known risk factor for lymphoma evolution in some non-malignant diseases. The aim of this study was to distinguish the role of cryoglobulinemic vasculitis (CV), classified according to the validated criteria (2,3), and primary Sjögren's syndrome (pSS) as risk factors of lymphoma in patients with SC. Importantly, SC, CV and pSS may occur together.…”

“…Tertiary lymphoid organs (TLOs) are organized clusters of immune cells that preferentially form in the salivary glands (sg) of patients with Sjogren's syndrome (SS). Recent observational studies have proposed a relationship between IL22 expression, B cell infiltration and humoral autoimmunity in SS but failed to provide a molecular mechanism for this relationship (1,2,3). Objective: To investigate the functional role of IL22 in TLO formation within the sg.…”