Publications by authors named "Martin J S Dyer"

144 Publications

Pooled analysis of safety data from clinical trials evaluating acalabrutinib monotherapy in mature B-cell malignancies.

Leukemia 2021 Nov 27;35(11):3201-3211. Epub 2021 Apr 27.

Willamette Valley Cancer Institute/US Oncology, Eugene, OR, USA.

Bruton tyrosine kinase (BTK) inhibition is an effective therapy for many B-cell malignancies. Acalabrutinib is a next-generation, potent, highly selective, covalent BTK inhibitor. To characterize acalabrutinib tolerability, we pooled safety data from 1040 patients with mature B-cell malignancies treated with acalabrutinib monotherapy in nine clinical studies (treatment-naïve: n = 366 [35%], relapsed/refractory: n = 674 [65%]; median [range] age: 67 [32-90] years; median [range] prior treatments: 1 [0-13]; median [range] duration of exposure: 24.6 [0.0-58.5] months). The most common adverse events (AEs) were headache (38%), diarrhea (37%), upper respiratory tract infection (22%), contusion (22%), nausea (22%), fatigue (21%), and cough (21%). Serious AEs (SAEs) occurred in 39% of patients; pneumonia (6%) was the only SAE that occurred in ≥2%. Deaths due to AEs occurred in 52 patients (5%); pneumonia (n = 8) was the only fatal AE to occur in ≥3 patients. AEs led to treatment discontinuation in 9%. Rates for the AEs of interest (all grades) included infections (67%), hemorrhages (46%), neutropenia (16%), anemia (14%), second primary malignancies (12%), thrombocytopenia (9%), hypertension (8%), and atrial fibrillation (4%). This pooled analysis confirmed acalabrutinib's tolerability and identified no newly emerging late toxicities, supporting acalabrutinib as a long-term treatment for patients with mature B-cell malignancies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-021-01252-yDOI Listing
November 2021

A Phase 1b Study to Evaluate the Safety and Efficacy of Durvalumab in Combination With Tremelimumab or Danvatirsen in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma.

Clin Lymphoma Myeloma Leuk 2021 05 17;21(5):309-317.e3. Epub 2020 Dec 17.

Division of Hematology & Oncology, MUSC Health Hollings Cancer Center, Charleston, SC.

Background: Despite recent advances, outcomes in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) remain poor. Immune checkpoint inhibitors have shown limited efficacy in this setting, but combinations with novel agents may enhance benefit. Combination therapy with durvalumab, an anti-programmed death ligand 1 (PD-L1) antibody, and danvatirsen (AZD9150; an antisense oligonucleotide inhibiting signal transducer and activator of transcription 3 [STAT3]) or tremelimumab (an anti-cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] antibody) may augment endogenous antitumor activity.

Patients And Methods: In this phase 1b dose escalation and dose expansion study, we evaluated durvalumab 20 mg/kg every 4 weeks plus either tremelimumab 1 mg/kg every 4 weeks or danvatirsen 2 or 3 mg/kg (administered on days 1, 3, 5, 8, 15, and 22, then every week). Treatment continued until disease progression. The primary endpoint was safety; secondary endpoints included efficacy, pharmacokinetics, and immunogenicity.

Results: As of April 4, 2019, 32 patients were enrolled and treated, receiving a median of 2 prior lines of systemic therapy. Treatment-related adverse events occurred in 21 patients (65.6%), most commonly alanine aminotransferase/aspartate aminotransferase increased (grade 1-3), anemia (grade 1-3), and fatigue (grade 1). The overall objective response rate was 6.3%, with 2 partial responses. Median time to response was 11.0 weeks (range, 7.7-14.3 weeks). Median progression-free survival was 7.4 weeks (range, 0.1-31.4 weeks), and median overall survival was 28.0 weeks (range, 1.9-115.4 weeks).

Conclusion: The primary endpoint was met, with durvalumab plus tremelimumab/danvatirsen generally well tolerated in patients with relapsed/refractory DLBCL; however, antitumor activity was limited.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clml.2020.12.012DOI Listing
May 2021

Mantle cell lymphomas with concomitant MYC and CCND1 breakpoints are recurrently TdT positive and frequently show high-grade pathological and genetic features.

Virchows Arch 2021 Jul 2;479(1):133-145. Epub 2021 Feb 2.

Hematopathology Section, Christian-Albrechts-University, Kiel, Germany.

Chromosomal breakpoints involving the MYC gene locus, frequently referred to as MYC rearrangements (MYC - R+), are a diagnostic hallmark of Burkitt lymphoma and recurrent in many other subtypes of B-cell lymphomas including follicular lymphoma, diffuse large B-cell lymphoma and other high-grade B-cell lymphomas and are associated with an aggressive clinical course. In remarkable contrast, in MCL, only few MYC - R+ cases have yet been described. In the current study, we have retrospectively analysed 16 samples (MYC - R+, n = 15, MYC - R-, n = 1) from 13 patients and describe their morphological, immunophenotypic and (molecular) genetic features and clonal evolution patterns. Thirteen out of fifteen MYC - R+ samples showed a non-classical cytology including pleomorphic (centroblastic, immunoblastic), anaplastic or blastoid. MYC translocation partners were IG-loci in 4/11 and non-IG loci in 7/11 analysed cases. The involved IG-loci included IGH in 3 cases and IGL in one case. PAX5 was the non-IG partner in 2/7 patients. The MYC - R+ MCL reported herein frequently displayed characteristics associated with an aggressive clinical course including high genomic-complexity (6/7 samples), frequent deletions involving the CDKN2A locus (7/10 samples), high Ki-67 proliferation index (12/13 samples) and frequent P53 expression (13/13 samples). Of note, in 4/14 samples, SOX11 was not or only focally expressed and 3/13 samples showed focal or diffuse TdT-positivity presenting a diagnostic challenge as these features could point to a differential diagnosis of diffuse large B-cell lymphoma and/or lymphoblastic lymphoma/leukaemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00428-021-03022-8DOI Listing
July 2021

Genome-wide association study identifies risk loci for progressive chronic lymphocytic leukemia.

Nat Commun 2021 01 28;12(1):665. Epub 2021 Jan 28.

Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, Hull, UK.

Prognostication in patients with chronic lymphocytic leukemia (CLL) is challenging due to heterogeneity in clinical course. We hypothesize that constitutional genetic variation affects disease progression and could aid prognostication. Pooling data from seven studies incorporating 842 cases identifies two genomic locations associated with time from diagnosis to treatment, including 10q26.13 (rs736456, hazard ratio (HR) = 1.78, 95% confidence interval (CI) = 1.47-2.15; P = 2.71 × 10) and 6p (rs3778076, HR = 1.99, 95% CI = 1.55-2.55; P = 5.08 × 10), which are particularly powerful prognostic markers in patients with early stage CLL otherwise characterized by low-risk features. Expression quantitative trait loci analysis identifies putative functional genes implicated in modulating B-cell receptor or innate immune responses, key pathways in CLL pathogenesis. In this work we identify rs736456 and rs3778076 as prognostic in CLL, demonstrating that disease progression is determined by constitutional genetic variation as well as known somatic drivers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-20822-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843618PMC
January 2021

Phase Ib Study of Tirabrutinib in Combination with Idelalisib or Entospletinib in Previously Treated Chronic Lymphocytic Leukemia.

Clin Cancer Res 2020 06 10;26(12):2810-2818. Epub 2020 Mar 10.

University Hospital of Wales, Cardiff, United Kingdom.

Purpose: Bruton tyrosine kinase (BTK) inhibition alone leads to incomplete responses in chronic lymphocytic leukemia (CLL). Combination therapy may reduce activation of escape pathways and deepen responses. This open-label, phase Ib, sequential dose-escalation and dose-expansion study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the selective BTK inhibitor tirabrutinib alone, in combination with the PI3K delta (PI3Kδ) inhibitor idelalisib, or with the spleen tyrosine kinase (SYK) inhibitor entospletinib in patients with relapsed/refractory CLL.

Patients And Methods: Patients received either tirabrutinib monotherapy (80 mg every day) or tirabrutinib 20-150 mg every day in combination with either idelalisib (50 mg twice a day or 100 mg every day) or entospletinib (200 mg or 400 mg every day).

Results: Fifty-three patients were included. Systemic tirabrutinib exposure was comparable between monotherapy and combination therapy. No MTD was identified. Across all treatment groups, the most common adverse event was diarrhea (43%, 1 patient grade ≥3); discontinuation due to adverse events was uncommon (13%). Objective response rates were 83%, 93%, and 100%, and complete responses were 7%, 7%, and 10% in patients receiving tirabrutinib, tirabrutinib/idelalisib, and tirabrutinib/entospletinib, respectively. As of February 21, 2019, 46 of 53 patients continue to receive treatment on study.

Conclusions: Tirabrutinib in combination with idelalisib or entospletinib was well tolerated in patients with CLL, establishing an acceptable safety profile for concurrent selective inhibition of BTK with either PI3Kδ or SYK. This small study did not establish a superior efficacy of the combinations over tirabrutinib alone. This trial is registered at www.clinicaltrials.gov (NCT02457598).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-3504DOI Listing
June 2020

Reconstruction of rearranged T-cell receptor loci by whole genome and transcriptome sequencing gives insights into the initial steps of T-cell prolymphocytic leukemia.

Genes Chromosomes Cancer 2020 04 29;59(4):261-267. Epub 2019 Nov 29.

Institute of Human Genetics, University of Ulm and University of Ulm Medical Center, Ulm, Germany.

T-cell prolymphocytic leukemia (T-PLL) is an aggressive tumor with leukemic presentation of mature T-lymphocytes. Here, we aimed at characterizing the initial events in the molecular pathogenesis of T-PLL and particularly, at determining the point in T-cell differentiation when the hallmark oncogenic events, that is, inv(14)(q11q32)/t(14;14)(q11;q32) and t(X;14)(q28;q11) occur. To this end, we mined whole genome and transcriptome sequencing data of 17 and 11 T-PLL cases, respectively. Mapping of the 14q32.1 locus breakpoints identified only TCL1A, which was moreover significantly overexpressed in T-PLL as compared to benign CD4+ and CD8+ T-cells, as the only common oncogenic target of aberrations. In cases with t(14;14), the breakpoints mapped telomeric and in cases with inv(14) centromeric or in the 3'-untranslated region of TCL1A. Regarding the T-cell receptor alpha (TRA) locus-TCL1A breakpoint junctions, all 17 breakpoints involved recombination signal sequences and 15 junctions contained nontemplated (N-) nucleotides. All T-PLL cases studied carried in-frame TRA rearrangements on the intact allele, which skewed significantly toward usage of distal/central TRAV/TRAJ gene segments as compared to the illegitimate TRA rearrangements. Our findings suggest that the oncogenic TRA-TCL1A/MTCP1 rearrangements in T-PLL occur during opening of the TRA locus, that is, during the progression from CD4+ immature single positive to early double positive thymocyte stage, just before physiologic TCL1A expression is silenced. The cell carrying such an oncogenic event continues maturation and rearranges the second TRA allele to achieve a functional T-cell receptor. Thereafter, it switches off RAG and DNTT expression in line with the mature T-cell phenotype at presentation of T-PLL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gcc.22821DOI Listing
April 2020

Specific interactions of BCL-2 family proteins mediate sensitivity to BH3-mimetics in diffuse large B-cell lymphoma.

Haematologica 2020 08 10;105(8):2150-2163. Epub 2019 Oct 10.

Department of Molecular and Cell Biology, University of Leicester, Leicester, UK

The BCL-2-specific inhibitor, ABT-199 (venetoclax) has exhibited remarkable clinical activity in nearly all cases of chronic lymphocytic leukemia. In contrast, responses are usually much less in diffuse large B-cell lymphoma (DLBCL), despite high level expression of BCL-2 in over 40% of cases, indicating that co-expression of related anti-apoptotic BCL-2 family proteins may limit the activity of ABT-199. We have investigated the roles of BCL-2 proteins in DLBCL cells using a panel of specific BCL-2 homology 3 (BH3)-mimetics and identified subgroups of these cells that exhibited marked and specific dependency on either BCL-2, BCL-X or MCL-1 for survival. Dependency was associated with selective sequestration of the pro-apoptotic proteins BIM, BAX and BAK by the specific anti-apoptotic BCL-2 protein which was important for cellular survival. Sensitivity to BH3-mimetics was independent of genetic alterations involving the BCL-2 family and only partially correlated with protein expression levels. Treatment with ABT-199 displaced BAX and BIM from BCL-2, subsequently leading to BAK activation and apoptosis. In contrast, apoptosis induced by inhibiting BCL-X with A1331852 was associated with a displacement of both BAX and BAK from BCL-X and occurred independently of BIM. Finally, the MCL-1 inhibitor S63845 induced mainly BAX-dependent apoptosis mediated by a displacement of BAK, BIM and NOXA from MCL-1. In conclusion, our study indicates that in DLBCL, the heterogeneous response to BH3-mimetics is mediated by selective interactions between BAX, BAK and anti-apoptotic BCL-2 proteins.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2019.220525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395267PMC
August 2020

Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia.

Blood 2019 06 12;133(26):2765-2775. Epub 2019 Mar 12.

School of Medicine, University of California, San Diego, CA.

This single-arm, open-label, phase 1b study evaluated the maximum tolerated dose (MTD) of venetoclax when given with obinutuzumab and its safety and tolerability in patients with relapsed/refractory (R/R) or previously untreated (first line [1L]) chronic lymphocytic leukemia (CLL). Venetoclax dose initially was escalated (100-400 mg) in a 3 + 3 design to define MTD combined with standard-dose obinutuzumab. Patients received venetoclax (schedule A) or obinutuzumab (schedule B) first to compare safety and determine dose/schedule for expansion. Venetoclax-obinutuzumab was administered for 6 cycles, followed by venetoclax monotherapy until disease progression (R/R) or fixed duration 1-year treatment (1L). Fifty R/R and 32 1L patients were enrolled. No dose-limiting toxicities were observed. Safety, including incidence of tumor lysis syndrome (TLS), did not differ between schedules (2 laboratory TLSs per schedule). Schedule B and a 400-mg dose of venetoclax were chosen for expansion. The most common grade 3-4 adverse event was neutropenia (R/R, 58% of patients; 1L, 53%). Rates of grade 3-4 infections were 29% (R/R) and 13% (1L); no fatal infections occurred in 1L. All infusion-related reactions were grade 1-2, except for 2 grade 3 events. No clinical TLS was observed. Overall best response rate was 95% in R/R (complete response [CR]/CR with incomplete marrow recovery [CRi], 37%) and 100% in 1L (CR/CRi, 78%) patients. Rate of undetectable (<10) minimal residual disease (uMRD) in peripheral blood for R/R and 1L patients, respectively, was 64% and 91% ≥3 months after last obinutuzumab dose. Venetoclax and obinutuzumab therapy had an acceptable safety profile and elicited durable responses and high rates of uMRD. This trial was registered at www.clinicaltrials.gov as #NCT01685892.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2019-01-896290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6706803PMC
June 2019

Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology.

Blood Cancer J 2018 12 21;9(1). Epub 2018 Dec 21.

German Cancer Research Center, 69120, Heidelberg, Germany.

The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (R = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChIP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41408-018-0162-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315026PMC
December 2018

Kinetics of T-cell subset reconstitution following treatment with bendamustine and rituximab for low-grade lymphoproliferative disease: a population-based analysis.

Br J Haematol 2019 03 13;184(6):957-968. Epub 2018 Dec 13.

Department of Clinical Haematology, Nottingham University Hospitals NHS Trust, Nottingham, UK.

Delayed lymphocyte and T-cell immune reconstitution following bendamustine-rituximab (BR) for indolent non-Hodgkin lymphoma (iNHL) has been described, but no information is available for chronic lymphocytic leukaemia (CLL). We present a population-based retrospective analysis of immune reconstitution and risk of infection following BR. Outcomes included timing/correlates of CD4+ recovery and risk of ≥grade 3 infections. Consecutively treated patients (1 April 2014 to 31 January 2017) were included (n = 295),with a median age of 65 years (range 33-92); 57% were 1st line treatments. Median cumulative bendamustine dose was 1080 mg/m (range 140-1440 mg/m ). CD4/CD8/CD19/NK subsets were available for 148 patients. Median follow-up was 24 months. Median times to lymphocyte count (ALC) recovery (≥1 × 10 /l) and CD4+ recovery (≥0·2 × 10 /l) were 26 and 24 months, respectively. Bendamustine total dose >1080 mg/m (hazard ratio [HR] 0·4; 95% confidence interval [CI]: 0·2-0·8), end-of-treatment ALC ≤0·4 × 10 /l (HR 0·53; 95% CI: 0·3-0·9) and CD4+ <0·1 × 10 /l 1-year post-BR (HR 0·03; 95% CI: 0·008-0·15) were covariables for delayed CD4+ recovery. ALC-recovery ≥1 × 10 /l was an unreliable predictor of CD4+ recovery (negative predictive vale 74%, positive predictive value 86%, likelihood ratio 3·3). CD4+ lymphopenia >3 years was a significant risk factor for ≥grade 3 infections (Odds ratio 3·4; 95% CI: 1·4-6·9). CD4+ recovery after BR is unexpectedly delayed and late recovery is associated with risk of serious infections. Monitoring CD4+ following BR could identify patients at high risk of delayed infections.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.15722DOI Listing
March 2019

Targeting intermediary metabolism enhances the efficacy of BH3 mimetic therapy in hematologic malignancies.

Haematologica 2019 05 22;104(5):1016-1025. Epub 2018 Nov 22.

Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, UK

BH3 mimetics are novel targeted drugs with remarkable specificity, potency and enormous potential to improve cancer therapy. However, acquired resistance is an emerging problem. We report the rapid development of resistance in chronic lymphocytic leukemia cells isolated from patients exposed to increasing doses of navitoclax (ABT-263), a BH3 mimetic. To mimic such rapid development of chemoresistance, we developed simple resistance models to three different BH3 mimetics, targeting BCL-2 (ABT-199), BCL-X (A-1331852) or MCL-1 (A-1210477), in relevant hematologic cancer cell lines. In these models, resistance could not be attributed to either consistent changes in expression levels of the anti-apoptotic proteins or interactions among different pro- and anti-apoptotic BCL-2 family members. Using genetic silencing, pharmacological inhibition and metabolic supplementation, we found that targeting glutamine uptake and its downstream signaling pathways, namely glutaminolysis, reductive carboxylation, lipogenesis, cholesterogenesis and mammalian target of rapamycin signaling resulted in marked sensitization of the chemoresistant cells to BH3 mimetic-mediated apoptosis. Furthermore, our findings highlight the possibility of repurposing widely used drugs, such as statins, to target intermediary metabolism and improve the efficacy of BH3 mimetic therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2018.204701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518917PMC
May 2019

CUDC-907 blocks multiple pro-survival signals and abrogates microenvironment protection in CLL.

J Cell Mol Med 2019 01 24;23(1):340-348. Epub 2018 Oct 24.

Mechanisms of Cancer and Ageing Laboratory, Department of Molecular and Cell Biology, University of Leicester, Leicester, UK.

CUDC-907, a dual PI3K/HDAC inhibitor, has been proposed to have therapeutic potential in hematopoietic malignancies. However, the molecular mechanisms of its effects in chronic lymphocytic leukaemia (CLL) remain elusive. We show that CLL cells are sensitive to CUDC-907, even under conditions similar to the protective microenvironment of proliferation centres. CUDC-907 inhibited PI3K/AKT and HDAC activity, as expected, but also suppressed RAF/MEK/ERK and STAT3 signalling and reduced the expression of anti-apoptotic BCL-2 family proteins BCL-2, BCL-xL, and MCL-1. Moreover, CUDC-907 downregulated cytokines BAFF and APRIL and their receptors BAFFR, TACI, and BCMA, thus blocking BAFF-induced NF-κB signalling. T cell chemokines CCL3/4/17/22 and phosphorylation of CXCR4 were also reduced by CUDC-907. These data indicated that CUDC-907 abrogates different protective signals and suggested that it might sensitize CLL cells to other drugs. Indeed, combinations of low concentrations of CUDC-907 with inhibitors of BCL2, BTK, or the NF-κB pathway showed a potent synergistic effect. Our data indicate that, apart from its known functions, CUDC-907 blocks multiple pro-survival pathways to overcome microenvironment protection in CLL cells. This provides a rationale to evaluate the clinical relevance of CUDC-907 in combination therapies with other targeted inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jcmm.13935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307843PMC
January 2019

SRC/ABL inhibition disrupts CRLF2-driven signaling to induce cell death in B-cell acute lymphoblastic leukemia.

Oncotarget 2018 May 1;9(33):22872-22885. Epub 2018 May 1.

M. Tettamanti Research Center, Pediatric Clinic, University of Milano Bicocca, Monza, Italy.

Children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) overexpressing the gene () have poor prognosis. CRLF2 protein overexpression leads to activated JAK/STAT signaling and trials are underway using JAK inhibitors to overcome treatment failure. Pre-clinical studies indicated limited efficacy of single JAK inhibitors, thus additional pathways must be targeted in cells. To identify additional activated networks, we used single-cell mass cytometry to examine 15 BCP-ALL primary patient samples. We uncovered a coordinated signaling network downstream of CRLF2 characterized by co-activation of JAK/STAT, PI3K, and CREB pathways. This CRLF2-driven network could be more effectively disrupted by SRC/ABL inhibition than single-agent JAK or PI3K inhibition, and this could be demonstrated even in primary minimal residual disease (MRD) cells. Our study suggests SCR/ABL inhibition as effective in disrupting the cooperative functional networks present in 2 BCP-ALL patients, supporting further investigation of this strategy in pre-clinical studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.25089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5955419PMC
May 2018

S55746 is a novel orally active BCL-2 selective and potent inhibitor that impairs hematological tumor growth.

Oncotarget 2018 Apr 13;9(28):20075-20088. Epub 2018 Apr 13.

Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, UK.

Escape from apoptosis is one of the major hallmarks of cancer cells. The B-cell Lymphoma 2 (BCL-2) gene family encodes pro-apoptotic and anti-apoptotic proteins that are key regulators of the apoptotic process. Overexpression of the pro-survival member BCL-2 is a well-established mechanism contributing to oncogenesis and chemoresistance in several cancers, including lymphoma and leukemia. Thus, BCL-2 has become an attractive target for therapeutic strategy in cancer, as demonstrated by the recent approval of ABT-199 (Venclexta™) in relapsed or refractory Chronic Lymphocytic Leukemia with 17p deletion. Here, we describe a novel orally bioavailable BCL-2 selective and potent inhibitor called S55746 (also known as BCL201). S55746 occupies the hydrophobic groove of BCL-2. Its selectivity profile demonstrates no significant binding to MCL-1, BFL-1 (BCL2A1/A1) and poor affinity for BCL-XL. Accordingly, S55746 has no cytotoxic activity on BCL-XL-dependent cells, such as platelets. In a panel of hematological cell lines, S55746 induces hallmarks of apoptosis including externalization of phosphatidylserine, caspase-3 activation and PARP cleavage. , S55746 induces apoptosis in the low nanomolar range in primary Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma patient samples. Finally, S55746 administered by oral route daily in mice demonstrated robust anti-tumor efficacy in two hematological xenograft models with no weight lost and no change in behavior. Taken together, these data demonstrate that S55746 is a novel, well-tolerated BH3-mimetic targeting selectively and potently the BCL-2 protein.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.24744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929447PMC
April 2018

Responses to the Selective Bruton's Tyrosine Kinase (BTK) Inhibitor Tirabrutinib (ONO/GS-4059) in Diffuse Large B-cell Lymphoma Cell Lines.

Cancers (Basel) 2018 Apr 23;10(4). Epub 2018 Apr 23.

Ono Pharmaceutical Co. Ltd., Osaka 618-8585, Japan.

Bruton's tyrosine kinase (BTK) is a key regulator of the B-cell receptor signaling pathway, and aberrant B-cell receptor (BCR) signaling has been implicated in the survival of malignant B-cells. However, responses of the diffuse large B-cell lymphoma (DLBCL) to inhibitors of BTK (BTKi) are infrequent, highlighting the need to identify mechanisms of resistance to BTKi as well as predictive biomarkers. We investigated the response to the selective BTKi, tirabrutinib, in a panel of 64 hematopoietic cell lines. Notably, only six cell lines were found to be sensitive. Although activated B-cell type DLBCL cells were most sensitive amongst all cell types studied, sensitivity to BTKi did not correlate with the presence of activating mutations in the BCR pathway. To improve efficacy of tirabrutinib, we investigated combination strategies with 43 drugs inhibiting 34 targets in six DLBCL cell lines. Based on the results, an activated B-cell-like (ABC)-DLBCL cell line, TMD8, was the most sensitive cell line to those combinations, as well as tirabrutinib monotherapy. Furthermore, tirabrutinib in combination with idelalisib, palbociclib, or trametinib was more effective in TMD8 with acquired resistance to tirabrutinib than in the parental cells. These targeted agents might be usefully combined with tirabrutinib in the treatment of ABC-DLBCL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers10040127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5923382PMC
April 2018

Differential activation of pro-survival pathways in response to CD40LG/IL4 stimulation in chronic lymphocytic leukaemia cells.

Br J Haematol 2019 03 20;184(5):867-869. Epub 2018 Apr 20.

Mechanisms of Cancer and Ageing Laboratory, Department of Molecular and Cell Biology, University of Leicester, Leicester, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.15197DOI Listing
March 2019

Paradoxical activation of alternative pro-survival pathways determines resistance to MEK inhibitors in chronic lymphocytic leukaemia.

Br J Haematol 2018 09 2;182(6):921-924. Epub 2017 Aug 2.

Mechanisms of Cancer and Ageing Laboratory, Department of Molecular and Cell Biology, University of Leicester, Leicester, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.14880DOI Listing
September 2018

Hsp72 and Nek6 Cooperate to Cluster Amplified Centrosomes in Cancer Cells.

Cancer Res 2017 09 18;77(18):4785-4796. Epub 2017 Jul 18.

Department of Molecular and Cell Biology, University of Leicester, Leicester, United Kingdom.

Cancer cells frequently possess extra amplified centrosomes clustered into two poles whose pseudo-bipolar spindles exhibit reduced fidelity of chromosome segregation and promote genetic instability. Inhibition of centrosome clustering triggers multipolar spindle formation and mitotic catastrophe, offering an attractive therapeutic approach to selectively kill cells with amplified centrosomes. However, mechanisms of centrosome clustering remain poorly understood. Here, we identify a new pathway that acts through NIMA-related kinase 6 (Nek6) and Hsp72 to promote centrosome clustering. Nek6, as well as its upstream activators polo-like kinase 1 and Aurora-A, targeted Hsp72 to the poles of cells with amplified centrosomes. Unlike some centrosome declustering agents, blocking Hsp72 or Nek6 function did not induce formation of acentrosomal poles, meaning that multipolar spindles were observable only in cells with amplified centrosomes. Inhibition of Hsp72 in acute lymphoblastic leukemia cells resulted in increased multipolar spindle frequency that correlated with centrosome amplification, while loss of Hsp72 or Nek6 function in noncancer-derived cells disturbs neither spindle formation nor mitotic progression. Hence, the Nek6-Hsp72 module represents a novel actionable pathway for selective targeting of cancer cells with amplified centrosomes. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-16-3233DOI Listing
September 2017

Targeting anti-apoptotic BCL2 family proteins in haematological malignancies - from pathogenesis to treatment.

Br J Haematol 2017 08 27;178(3):364-379. Epub 2017 Apr 27.

Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, UK.

The B-cell lymphoma 2 (BCL2) family of proteins comprise key regulators of apoptosis and are implicated in the pathogenesis of many malignancies, including lymphomas and leukaemias. Targeting of BCL2 proteins can be directly toxic to tumour cells or render them more sensitive to chemotherapy. Inhibition of the anti-apoptotic functions of BCL2 proteins using structure-based design to produce specific inhibitors of protein-protein interactions has been achieved for BCL2, MCL1 and BCL-X (also termed BCL2L1), providing an armamentarium of new targeted therapies called BH3-mimetics. The first BCL2-specific inhibitor, venetoclax, has shown extraordinary single agent activity in chronic lymphocytic leukaemia (CLL), with surprisingly little toxicity given the expression of BCL2 in normal tissues. Despite success in CLL, where sensitivity to BCL2 inhibition is seen in nearly all cases, key questions have not yet been addressed. For example, responses to venetoclax in other B-cell and myeloid malignancies are heterogeneous, highlighting the need to identify biomarkers that correlate with response and, secondly, to identify/develop other specific compounds that synergise with BCL2 inhibition. In this review, we summarise the biology of BCL2 proteins, the mechanism of action of BH3-mimetics and the status of their clinical development in haematological malignancies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.14684DOI Listing
August 2017
-->