Adrian Wiestner - Academia.edu (original) (raw)

Papers by Adrian Wiestner

Cancer Research, 2018

A. Wiestner reports receiving commercial research grants from Acerta Pharma and Pharmacyclics, an... more A. Wiestner reports receiving commercial research grants from Acerta Pharma and Pharmacyclics, an Abbvie Company. No potential conflicts of interest were disclosed by the other authors. Word counts: Abstract: 240 (max 250); Manuscript: 4694 (max 5000) References: 55 (max 50) Number of Figures: 6 and 10 supplementary (max 7 including tables) Number of Tables: 1 and 3 supplementary (max 7 including figures) Research. on December 3, 2018.

Clinical Cancer Research, 2012

Purpose-Chronic Lymphocytic Leukemia (CLL), a malignancy of mature B-cells, is incurable with che... more Purpose-Chronic Lymphocytic Leukemia (CLL), a malignancy of mature B-cells, is incurable with chemotherapy. Signals from the microenvironment support leukemic cell survival and proliferation, and may confer chemotherapy resistance. ON 01910.Na (Rigosertib) a multikinase PI3K inhibitor is entering phase III trials for myelodysplastic syndrome. Our aim was to analyze the efficacy of ON 01910.Na against CLL cells in vitro and investigate the molecular effects of this drug on tumor biology.

$Research paper thumbnail of A Phase I/II Study of a Hybrid Schedule of Flavopiridol in Relapsed/Refractory Mantle Cell Lymphoma and Diffuse Large B-Cell Lymphoma$

Clinical Lymphoma Myeloma and Leukemia, 2010

Background: Continuous infusion and bolus schedules of flavopiridol in mantle cell lymphoma (MCL)... more Background: Continuous infusion and bolus schedules of flavopiridol in mantle cell lymphoma (MCL) have yielded disappointing results. However, a pharmacologically derived hybrid schedule of administration is effective in refractory, genetically high-risk chronic lymphocytic leukemia (CLL), though life-threatening tumor lysis syndrome (TLS) may occur in patients with very high lymphocyte counts. Because flavopiridol decreases cyclin D1 and Mcl-1 and induces apoptosis in MCL cells, is significantly toxic for cell lines derived from the activated B-cell-like type of diffuse large B-cell lymphoma (DLBCL; OCI-Ly3), and downregulates NF-κB, we investigated the hybrid schedule in MCL and DLBCL. Patients and Methods: Flavopiridol was administered as a 30-minute bolus (mg/m 2 ) followed by a 4-hour continuous infusion (mg/m 2 ), weekly for 4 doses every 6 weeks. Separate escalation rules applied to cycle 1 week 1 (C1W1) and all other weeks of treatment. Dose levels on C1W1 were DL1: 25/25 (4 patients), DL2: 30/30 (10 patients), and DL3: 30/50 (6 patients). Dose escalation on subsequent weeks was not possible due to toxicity, and all patients received 30/50. All patients received TLS prophylaxis. Paired biopsy samples obtained before and after the first dose were analyzed for CDK targets. Results: Patient (n = 20) characteristics: median age, 59 years (range, 24-80 years); male, 15 (75%); median prior regimens, 2 (range, 1-6). Ten patients had MCL, and 10 had DLBCL. Responses included partial response (PR) in 2 patients (1 MCL; 1 DLBCL; 10%), stable disease (SD) in 5 patients (25%), and progressive disease (PD) in 13 patients (65%). Dose-limiting toxicities (DLTs) included TLS and severe vomiting/diarrhea in 2 patients at DL3. The maximum tolerated dose (MTD) and phase II dose have not yet been defined. Other toxicities were grade 4 absolute neutrophil count (ANC; 10 patients) requiring prophylactic granulocyte colony-stimulating factor (G-CSF), TLS (1 patient), and bowel perforation (1 patient). Decreased Rb staining at the S807/811 phospho-site was noted in 8 of 9 paired samples analyzed (range, 20%-75%; P = .027) and at the S780 site in 7 of 8 paired samples (range, 38%-91%; P = .00016), suggestive of G1 CDK inhibition. In 1 sample in which p53 was detected, there was an increase post-treatment, suggestive of CDK9 inhibition. Conclusion: The hybrid schedule of flavopiridol has modest activity in relapsed MCL and DLBCL. TLS occurred infrequently and was reversible. DLTs were TLS and gastrointestinal toxicity. Accrual continues. Analysis of cell cycle and transcriptional CDK targets is ongoing.

Journal of immunology (Baltimore, Md. : 1950), 2015

Hiromi Kubagawa and John E. Coligan coordinated an online meeting to define an appropriate nomenc... more Hiromi Kubagawa and John E. Coligan coordinated an online meeting to define an appropriate nomenclature for the cell surface glycoprotein presently designated by different names: Toso, Fas apoptosis inhibitory molecule 3 (FAIM3), and IgM FcR (FcμR). FAIM3 and Faim3 are the currently approved symbols for the human and mouse genes, respectively, in the National Center for Biotechnology Information, Ensembl, and other databases. However, recent functional results reported by several groups of investigators strongly support a recommendation for renaming FAIM3/Faim3 as FCMR/Fcmr, a name better reflecting its physiological function as the FcR for IgM. Participants included 12 investigators involved in studying Toso/FAIM3(Faim3)/FμR, representatives from the Human Genome Nomenclature Committee (Ruth Seal) and the Mouse Genome Nomenclature Committee (Monica McAndrews), and an observer from the IgM research field (Michael Carroll). In this article, we provide a brief background of the key re...

mAbs

The selective cell surface expression of receptor tyrosine kinase-like orphan receptor 1 (ROR1) i... more The selective cell surface expression of receptor tyrosine kinase-like orphan receptor 1 (ROR1) in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) has made ROR1 a novel and promising target for therapeutic monoclonal antibodies (mAbs). Four mouse mAbs generated by hybridoma technology exhibited specific binding to human ROR1. Epitope mapping studies showed that two mAbs (2A2 and 2D11) recognized N-terminal epitopes in the extracellular region of ROR1 and the other two (1A1 and 1A7) recognized C-terminal epitopes. A ROR1- immunotoxin (BT-1) consisting of truncated Pseudomonas exotoxin A (PE38) and the VH and VL fragments of 2A2-IgG was made recombinantly. Both 2A2-IgG and BT-1 showed dose-dependent and selective binding to primary CLL and MCL cells and MCL cell lines. Kinetic analyses revealed 0.12-nM (2A2-IgG) to 65-nM (BT-1) avidity/affinity to hROR1, depicting bivalent and monovalent interactions, respectively. After binding to cell surface ROR1, 2A2-IgG and BT-1...

Seminars in hematology, 2003

Gene expression profiling of cancer began as a research tool but is rapidly moving towards clinic... more Gene expression profiling of cancer began as a research tool but is rapidly moving towards clinical application. The diagnostic category of diffuse large B-cell lymphoma (DLBCL) can now be viewed as an amalgam of several different diseases that have distinct gene expression profiles, oncogenic mechanisms, and clinical outcomes. Other diagnostic categories such as chronic lymphocytic leukemia (CLL) have a single gene expression signature that distinguishes them from other lymphoid malignancies. Nevertheless, elevated expression of a single gene, ZAP-70, is characteristic of a more aggressive subtype of CLL that may require novel treatment approaches. In mantle cell lymphoma (MCL), a quantitative measurement of gene expression associated with tumor proliferation is a powerful predictor of survival. Ultimately, the molecular diagnosis of these malignancies will identify molecular pathways that can be exploited for therapy. For example, one of the gene expression subgroups of DLBCL, ter...

Oncotarget, Jan 3, 2015

Bortezomib (BZM) is the first proteasome inhibitor approved for relapsed Mantle Cell Lymphoma (MC... more Bortezomib (BZM) is the first proteasome inhibitor approved for relapsed Mantle Cell Lymphoma (MCL) with durable responses seen in 30%-50% of patients. Given that a large proportion of patients will not respond, BZM resistance is a significant barrier to use this agent in MCL. We hypothesized that a subset of aberrantly methylated genes may be modulating BZM response in MCL patients. Genome-wide DNA methylation analysis using a NimbleGen array platform revealed a striking promoter hypomethylation in MCL patient samples following BZM treatment. Pathway analysis of differentially methylated genes identified molecular mechanisms of cancer as a top canonical pathway enriched among hypomethylated genes in BZM treated samples. Noxa, a pro-apoptotic Bcl-2 family member essential for the cytotoxicity of BZM, was significantly hypomethylated and induced following BZM treatment. Therapeutically, we could demethylate Noxa and induce anti-lymphoma activity using BZM and the DNA methytransferase...

Cancer research, Jan 15, 2014

Chronic lymphocytic leukemia (CLL) is a B-cell malignancy in need of new, effective, and safe the... more Chronic lymphocytic leukemia (CLL) is a B-cell malignancy in need of new, effective, and safe therapies. The recently identified IgM receptor FcμR is overexpressed on malignant B cells in CLL and mediates the rapid internalization and lysosomal shuttling of IgM via its Fc fragment (Fcμ). To exploit this internalization and trafficking pathway for targeted drug delivery, we engineered an IgM-derived protein scaffold (Fcμ) and linked it with the cytotoxic agent monomethylauristatin F. This Fcμ-drug conjugate was selectively toxic for FcμR-expressing cell lines in vitro and for CLL cells but not autologous normal T cells ex vivo. Notably, the cytotoxic activity of the Fcμ-drug conjugate was maintained in CLL cells carrying a 17p deletion, which predicts resistance to standard chemotherapy. Next, we tested the possible therapeutic application of the Fcμ-drug conjugate in immunodeficient NOD/SCID/IL-2Rγ(null) (NSG) mice engrafted with peripheral blood cells from patients with leukemia. T...

Proceedings of the National Academy of Sciences, 2009

This article contains supporting information online at www.pnas.org/cgi/content/full/ 0807611106/... more This article contains supporting information online at www.pnas.org/cgi/content/full/ 0807611106/DCSupplemental.

Proceedings of the National Academy of Sciences, 2003

To classify cancer specimens by their gene expression profiles, we created a statistical method b... more To classify cancer specimens by their gene expression profiles, we created a statistical method based on Bayes&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; rule that estimates the probability of membership in one of two cancer subgroups. We used this method to classify diffuse large B cell lymphoma (DLBCL) biopsy samples into two gene expression subgroups based on data obtained from spotted cDNA microarrays. The germinal center B cell-like (GCB) DLBCL subgroup expressed genes characteristic of normal germinal center B cells whereas the activated B cell-like (ABC) DLBCL subgroup expressed a subset of the genes that are characteristic of plasma cells, particularly those encoding endoplasmic reticulum and golgi proteins involved in secretion. We next used this predictor to discover these subgroups within a second set of DLBCL biopsies that had been profiled by using oligonucleotide microarrays [Shipp, M. A., et al. (2002) Nat. Med. 8, 68-74]. The GCB and ABC DLBCL subgroups identified in this data set had significantly different 5-yr survival rates after multiagent chemotherapy (62% vs. 26%; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; or = 0.0051), in accord with analyses of other DLBCL cohorts. These results demonstrate the ability of this gene expression-based predictor to classify DLBCLs into biologically and clinically distinct subgroups irrespective of the method used to measure gene expression.

Proceedings of the National Academy of Sciences, 1996

Leptin and its receptor, obese receptor (OB-R), comprise an important signaling system for the re... more Leptin and its receptor, obese receptor (OB-R), comprise an important signaling system for the regulation of body weight. Splice variants of OB-R mRNA encode proteins that differ in the length of their cytoplasmic domains. We cloned a long isoform of the wild-type leptin receptor that is preferentially expressed in the hypothalamus and show that it can activate signal transducers and activators of transcription (STAT)-3, STAT-5, and STAT-6. A point mutation within the OB-R gene of diabetic (db) mice generates a new splice donor site that dramatically reduces expression of this long isoform in homozygous db/db mice. In contrast, an OB-R protein with a shorter cytoplasmic domain is present in both db/db and wild-type mice. We show that this short isoform is unable to activate the STAT pathway. These data provide further evidence that the mutation in OB-R causes the db/db phenotype and identify three STAT proteins as potential mediators of the anti-obesity effects of leptin.

PLoS ONE, 2010

Background: Protein homeostasis in the endoplasmic reticulum (ER) has recently emerged as a thera... more Background: Protein homeostasis in the endoplasmic reticulum (ER) has recently emerged as a therapeutic target for cancer treatment. Disruption of ER homeostasis results in ER stress, which is a major cause of cell death in cells exposed to the proteasome inhibitor Bortezomib, an anti-cancer drug approved for treatment of multiple myeloma and Mantle cell lymphoma. We recently reported that the ERAD inhibitor Eeyarestatin I (EerI) also disturbs ER homeostasis and has anticancer activities resembling that of Bortezomib.

Nature Genetics, 1998

Essential thrombocythaemia (ET) is a chronic myeloproliferative syndrome due to sustained prolife... more Essential thrombocythaemia (ET) is a chronic myeloproliferative syndrome due to sustained proliferation of megakaryocytes, which results in elevated numbers of circulating platelets, thrombotic or haemorrhagic episodes and occasional leukaemic transformation. The cause of ET is unknown. Hereditary thrombocythaemia (HT) with autosomal-dominant transmission has been described with manifestations similar to those of sporadic ET. As the thrombopoietin gene (THPO) encodes a lineage-restricted growth factor with profound stimulatory effects on megakaryopoiesis and platelet production, we tested the hypothesis that HT results from a mutation in the human THPO gene. In a Dutch family with eleven affected individuals, the thrombopoietin protein (TPO) concentrations in serum were consistently elevated in individuals with HT. We derived an intragenic CA marker for the human THPO gene and performed linkage analysis in fourteen informative meioses in this family. This resulted in a lod score of 3.5 at theta=0. A G-->C transversion was found in the splice donor site of intron 3 of the THPO gene in all affected family members. This mutation leads to THPO mRNAs with shortened 5'-untranslated regions (UTR) that are more efficiently translated than the normal THPO transcripts. We conclude that a splice donor mutation in THPO leads to systemic overproduction of TPO and causes thrombocythaemia.

Modern Pathology, 2011

Increased numbers of T regulatory (T reg ) cells are found in B-chronic lymphocytic leukemia, but... more Increased numbers of T regulatory (T reg ) cells are found in B-chronic lymphocytic leukemia, but the nature and function of these T regs remains unclear. Detailed characterization of the T regs in chronic lymphocytic leukemia has not been performed and the degree of heterogeneity of among these cells has not been studied to date. Using 15-color flow cytometry we show that T reg cells, defined using CD4, CD25, and forkhead box P3 (FOXP3), can be divided into multiple complex subsets based on markers used for naïve, memory, and effector delineation as well as markers of T reg activation. Furthermore FOXP3 + cells can be identified among CD4 + CD25 − as well as CD8 + CD4 − populations in increased proportions in patients with chronic lymphocytic leukemia compared with healthy donors. Significantly different frequencies of naïve and effector T regs populations are found in healthy donor controls compared with donors with chronic lymphocytic leukemia. A population of CCR7 + CD39 + T regs was significantly associated with chronic lymphocytic leukemia. This population demonstrated slightly reduced suppressive activity compared with total T regs or T regs of healthy donors. These data suggest that FOXP3-expressing cells, particularly in patients with chronic lymphocytic leukemia are much more complex for T reg sub-populations and transitions than previously reported. These findings demonstrate the complexity of regulation of T-cell responses in chronic lymphocytic leukemia and illustrate the use of high-dimensional analysis of cellular phenotypes in facilitating understanding of the intricacies of cellular immune responses and their dysregulation in cancer.

Leukemia Research, 2006

The objectives of this study were foremost to further characterize pre-existing cell lines contai... more The objectives of this study were foremost to further characterize pre-existing cell lines containing the t(11;14)(q13;q32) translocation. This translocation along with cyclin D1 overexpression is characteristic of Mantle Cell Lymphoma (MCL), an aggressive B cell neoplasm. Considerable variation in the abundance of cyclin D1 expression was observed. mRNA levels were examined by RT-PCR as differences in cyclin D1 mRNA abundance have been shown to synergize with INK4A/Arf deletions to dictate proliferation rate and survival in MCL patient samples. In this study, the cell lines, Z-138 and HBL-2, which exhibited the fastest growth rates and the shortest survival times in Rag2-M mice, had high expression of either one or both cyclin D1 mRNA isoforms and had negligible expression of p16. On the other hand, NCEB-1 and JVM-2 had low expression of both mRNA isoforms, retained p16 expression, and had slower growth rates and exhibited longer survival times in Rag2-M mice. Furthermore, JVM-2, which was found to have the lowest expression of cyclin D1, was the only cell line that expressed cyclin D2. The results of the characterization of Z-138, HBL-2, NCEB-1 and JVM-2 reveal that this group of cell lines represents both classic and variant features of MCL.

Leukemia, 2014

Bortezomib therapy has shown promising clinical activity in mantle cell lymphoma (MCL), but the d... more Bortezomib therapy has shown promising clinical activity in mantle cell lymphoma (MCL), but the development of resistance to proteasome inhibition may limit its efficacy. To unravel the factors involved in the acquisition of bortezomib resistance in vivo, immunodeficient mice were engrafted with a set of MCL cell lines with different levels of sensitivity to the drug, followed by gene expression profiling of the tumors and functional validation of the identified gene signatures. We observed an increased tumorigenicity of bortezomib-resistant MCL cells in vivo, which was associated with plasmacytic differentiation features, like interferon regulatory factor 4 (IRF4) and Blimp-1 upregulation. Lenalidomide was particularly active in this subgroup of tumors, targeting IRF4 expression and plasmacytic differentiation program, thus overcoming bortezomib resistance. Moreover, repression of the IRF4 target gene MYC in bortezomib-resistant cells by gene knockdown or treatment with CPI203, a BET (bromodomain and extra terminal) bromodomain inhibitor, synergistically induced cell death when combined with lenalidomide. In mice, addition of CPI203 to lenalidomide therapy further decreased tumor burden, involving simultaneous MYC and IRF4 downregulation and apoptosis induction. Together, these results suggest that exacerbated IRF4/MYC signaling is associated to bortezomib resistance in MCL in vivo and warrant clinical evaluation of lenalidomide plus BET inhibitor combination in MCL cases refractory to proteasome inhibition.

Leukemia, 2007

We identified 19 persons with B-cell chronic lymphocytic leukemia (CLL) who received genetically ... more We identified 19 persons with B-cell chronic lymphocytic leukemia (CLL) who received genetically identical twin blood cell or bone marrow transplants after high-dose conditioning. Ten are alive (eight disease-free) with a median follow-up of 89 months (range, 31-171 months); 5-year relapse rate was 50% (95% confidence interval (CI), 26-73%). Estimated 5-year survival and disease-free survival were 61% (95% CI, 37-82%) and 45% (95% CI, 23-68%). In two of four patients tested at 12 and 21 months by polymerase chain reaction no evidence of residual CLL was detected post-transplant. In one recipient who relapsed at 6 years, molecular studies showed a different CLL clone from that detected pretransplant. This clone was subsequently identified in the donor suggesting transfer of occult leukemia at the time of transplant. Genetically identical twin transplants can result in long-term disease-free survival and molecular remissions, these data suggest the potential for CLL control in the absence of allogeneic graft-versus-leukemia effect. The case of leukemia transfer indicates the need for careful evaluation of donors prior to graft collection.