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1.
Nat Commun ; 14(1): 2897, 2023 05 20.
Article in English | MEDLINE | ID: mdl-37210412

ABSTRACT

Malignant pleural mesothelioma (MPM) has relatively ineffective first/second-line therapy for advanced disease and only 18% five-year survival for early disease. Drug-induced mitochondrial priming measured by dynamic BH3 profiling identifies efficacious drugs in multiple disease settings. We use high throughput dynamic BH3 profiling (HTDBP) to identify drug combinations that prime primary MPM cells derived from patient tumors, which also prime patient derived xenograft (PDX) models. A navitoclax (BCL-xL/BCL-2/BCL-w antagonist) and AZD8055 (mTORC1/2 inhibitor) combination demonstrates efficacy in vivo in an MPM PDX model, validating HTDBP as an approach to identify efficacious drug combinations. Mechanistic investigation reveals AZD8055 treatment decreases MCL-1 protein levels, increases BIM protein levels, and increases MPM mitochondrial dependence on BCL-xL, which is exploited by navitoclax. Navitoclax treatment increases dependency on MCL-1 and increases BIM protein levels. These findings demonstrate that HTDBP can be used as a functional precision medicine tool to rationally construct combination drug regimens in MPM and other cancers.


Subject(s)
Mesothelioma, Malignant , Humans , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Bcl-2-Like Protein 11/genetics , Apoptosis , Cell Line, Tumor , Drug Combinations , bcl-X Protein/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism
3.
Nat Commun ; 13(1): 1009, 2022 02 23.
Article in English | MEDLINE | ID: mdl-35197447

ABSTRACT

The immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide are highly effective treatments for multiple myeloma. However, virtually all patients eventually relapse due to acquired drug resistance with resistance-causing genetic alterations being found only in a small subset of cases. To identify non-genetic mechanisms of drug resistance, we here perform integrated global quantitative tandem mass tag (TMT)-based proteomic and phosphoproteomic analyses and RNA sequencing in five paired pre-treatment and relapse samples from multiple myeloma patients. These analyses reveal a CDK6-governed protein resistance signature that includes myeloma high-risk factors such as TRIP13 and RRM1. Overexpression of CDK6 in multiple myeloma cell lines reduces sensitivity to IMiDs while CDK6 inhibition by palbociclib or CDK6 degradation by proteolysis targeting chimeras (PROTACs) is highly synergistic with IMiDs in vitro and in vivo. This work identifies CDK6 upregulation as a druggable target in IMiD-resistant multiple myeloma and highlights the use of proteomic studies to uncover non-genetic resistance mechanisms in cancer.


Subject(s)
Cyclin-Dependent Kinase 6 , Lenalidomide , Multiple Myeloma , ATPases Associated with Diverse Cellular Activities/metabolism , Cell Cycle Proteins/metabolism , Cyclin-Dependent Kinase 6/genetics , Cyclin-Dependent Kinase 6/metabolism , Drug Resistance, Neoplasm , Humans , Immunologic Factors/pharmacology , Lenalidomide/pharmacology , Lenalidomide/therapeutic use , Multiple Myeloma/drug therapy , Multiple Myeloma/genetics , Multiple Myeloma/metabolism , Neoplasm Recurrence, Local/drug therapy , Proteomics , Ubiquitin-Protein Ligases/metabolism , Up-Regulation
4.
Blood Adv ; 5(9): 2391-2402, 2021 05 11.
Article in English | MEDLINE | ID: mdl-33950175

ABSTRACT

The introduction of new drugs in the past years has substantially improved outcome in multiple myeloma (MM). However, the majority of patients eventually relapse and become resistant to one or multiple drugs. While the genetic landscape of relapsed/ resistant multiple myeloma has been elucidated, the causal relationship between relapse-specific gene mutations and the sensitivity to a given drug in MM has not systematically been evaluated. To determine the functional impact of gene mutations, we performed combined whole-exome sequencing (WES) of longitudinal patient samples with CRISPR-Cas9 drug resistance screens for lenalidomide, bortezomib, dexamethasone, and melphalan. WES of longitudinal samples from 16 MM patients identified a large number of mutations in each patient that were newly acquired or evolved from a small subclone (median 9, range 1-55), including recurrent mutations in TP53, DNAH5, and WSCD2. Focused CRISPR-Cas9 resistance screens against 170 relapse-specific mutations functionally linked 15 of them to drug resistance. These included cereblon E3 ligase complex members for lenalidomide, structural genes PCDHA5 and ANKMY2 for dexamethasone, RB1 and CDK2NC for bortezomib, and TP53 for melphalan. In contrast, inactivation of genes involved in the DNA damage repair pathway, including ATM, FANCA, RAD54B, and BRCC3, enhanced susceptibility to cytotoxic chemotherapy. Resistance patterns were highly drug specific with low overlap and highly correlated with the treatment-dependent clonal evolution in patients. The functional association of specific genetic alterations with drug sensitivity will help to personalize treatment of MM in the future.


Subject(s)
Multiple Myeloma , Pharmaceutical Preparations , CRISPR-Cas Systems , Humans , Lenalidomide , Multiple Myeloma/drug therapy , Multiple Myeloma/genetics , Neoplasm Recurrence, Local
5.
Cancer Cell ; 38(6): 872-890.e6, 2020 12 14.
Article in English | MEDLINE | ID: mdl-33217342

ABSTRACT

Acquired resistance to BH3 mimetic antagonists of BCL-2 and MCL-1 is an important clinical problem. Using acute myelogenous leukemia (AML) patient-derived xenograft (PDX) models of acquired resistance to BCL-2 (venetoclax) and MCL-1 (S63845) antagonists, we identify common principles of resistance and persistent vulnerabilities to overcome resistance. BH3 mimetic resistance is characterized by decreased mitochondrial apoptotic priming as measured by BH3 profiling, both in PDX models and human clinical samples, due to alterations in BCL-2 family proteins that vary among cases, but not to acquired mutations in leukemia genes. BCL-2 inhibition drives sequestered pro-apoptotic proteins to MCL-1 and vice versa, explaining why in vivo combinations of BCL-2 and MCL-1 antagonists are more effective when concurrent rather than sequential. Finally, drug-induced mitochondrial priming measured by dynamic BH3 profiling (DBP) identifies drugs that are persistently active in BH3 mimetic-resistant myeloblasts, including FLT-3 inhibitors and SMAC mimetics.


Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Drug Resistance, Neoplasm , Leukemia, Myeloid, Acute/pathology , Mitochondria/metabolism , Pyrimidines/pharmacology , Sulfonamides/pharmacology , Thiophenes/pharmacology , Animals , Apoptosis , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/metabolism , Mice , Mitochondria/drug effects , Peptide Fragments/pharmacology , Proto-Oncogene Proteins/pharmacology , Signal Transduction
7.
Int J Mol Sci ; 20(8)2019 Apr 23.
Article in English | MEDLINE | ID: mdl-31018543

ABSTRACT

The therapeutic approach for acute myeloid leukemia (AML) remains challenging, since over the last four decades a stagnation in standard cytotoxic treatment has been observed. But within recent years, remarkable advances in the understanding of the molecular heterogeneity and complexity of this disease have led to the identification of novel therapeutic targets. In the last two years, seven new targeted agents (midostaurin, gilteritinib, enasidenib, ivosidenib, glasdegib, venetoclax and gemtuzumab ozogamicin) have received US Food and Drug Administration (FDA) approval for the treatment of AML. These drugs did not just prove to have a clinical benefit as single agents but have especially improved AML patient outcomes if they are combined with conventional therapy. In this review, we will focus on currently approved and promising upcoming agents and we will discuss controversial aspects and limitations of targeted treatment strategies.


Subject(s)
Antineoplastic Agents/therapeutic use , Enzyme Inhibitors/therapeutic use , Immunoconjugates/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Molecular Targeted Therapy/methods , Animals , Drug Approval , Drug Development , Hedgehog Proteins/antagonists & inhibitors , Hedgehog Proteins/metabolism , Humans , Isocitrate Dehydrogenase/antagonists & inhibitors , Isocitrate Dehydrogenase/metabolism , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , Models, Molecular , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Proto-Oncogene Proteins c-bcl-2/metabolism , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , fms-Like Tyrosine Kinase 3/metabolism
8.
Expert Rev Hematol ; 11(5): 361-371, 2018 05.
Article in English | MEDLINE | ID: mdl-29543073

ABSTRACT

INTRODUCTION: The majority of patients with acute myeloid leukemia (AML) are older and exhibit a poor prognosis even after intensive therapy. Inducing differentiation and apoptosis of leukemic blasts by DNA-hypomethylating agents, like e.g. azacytidine (AZA) and decitabine (DAC), represent well-tolerated alternative treatment approaches. Both agents show convincing response as single agents in AML. However, there is a lack of knowledge regarding molecular mechanisms and predictive biomarkers for these agents. Areas covered: This review will (i) provide an overview of the current knowledge of molecular mechanisms underlying the action of these drugs, (ii) report promising predictive biomarkers, (iii) elude on new combined treatment options, and (iv) discuss novel approaches to improve outcomes. A literature search was performed using PubMed to find recent major publications, which provide biological and clinical research about epigenetic therapy in AML patients. Expert commentary: Numerous studies have demonstrated that HMA therapy with AZA or DAC may lead to significant response rates, even in pre-treated patients. Nevertheless, there is still an unmet need to further improve outcome in elderly AML patients. Therefore, novel treatment combinations are needed and some of them, such as AZA plus venetoclax, already show promising results.


Subject(s)
Azacitidine/therapeutic use , Decitabine/therapeutic use , Epigenesis, Genetic/drug effects , Gene Expression Regulation, Leukemic/drug effects , Leukemia, Myeloid, Acute , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , Sulfonamides/therapeutic use
9.
Biol Blood Marrow Transplant ; 23(12): 2172-2177, 2017 Dec.
Article in English | MEDLINE | ID: mdl-28860002

ABSTRACT

We report the results of a single-center analysis of a cohort of 39 patients treated between 1997 and 2016 for transplantion-associated thrombotic microangiopathy. We evaluated 2 subgroups of patients: 24 patients treated between 1997 and 2014 who received conventional therapy and 15 patients treated with the complement-inhibiting monoclonal antibody eculizumab between 2014 and 2016. The conventional therapy group was treated predominantly with defibrotide alone or in combination with plasmapheresis or rituximab. Despite an initial response rate of 61%, only 4 patients (16%) were long-term survivors, 2 of whom had a low-risk thrombotic microangiopathy without multiorgan damage. Progression of thrombotic micorangiopathy and bacterial/fungal infections contributed equally to treatment failure. The overall response rate in the eculizumab group was significantly higher, at 93%. In addition, we were able to stop eculizumab treatment in 5 patients (33%), all of whom had high-risk thrombotic microangiopathy, due to sustained recovery. Despite the very good response in the eculizumab-treated group, we did not observe a significant improved overall survival, due primarily to a high rate of infection-related mortality (70%). Therefore, further studies are needed to identify the optimal therapeutic management approach for transplantation-associated thrombotic microangiopathy to improve its dismal outcome.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Polydeoxyribonucleotides/therapeutic use , Stem Cell Transplantation/adverse effects , Thrombotic Microangiopathies/etiology , Adult , Aged , Humans , Infections/etiology , Middle Aged , Survival Analysis , Transplantation, Homologous , Treatment Outcome , Young Adult
11.
Onkologie ; 34(5): 269-74, 2011.
Article in English | MEDLINE | ID: mdl-21577035

ABSTRACT

With the cancer stem cell (CSC) hypothesis many questions regarding cancer development and drug resistance can be answered more coherently than with the traditional model based on clonal evolution. CSCs are a small subset of cancer cells within the tumour that show stem cell characteristics like self-renewal, the capability to develop into multiple lineages and the potential to proliferate extensively, and are characterised by a typical profile of different markers like CD44 and CD133. In the CSC model, the role of embryonic pathways like Wnt, Hedgehog and Notch is of special interest. This review presents current scientific knowledge on this topic and discusses the potential role of CSC in the resistance against chemotherapy or radiation and presents challenging options for therapeutic interventions.


Subject(s)
Cell Transformation, Neoplastic/metabolism , Cell Transformation, Neoplastic/pathology , Neoplasms/pathology , Neoplasms/therapy , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Animals , Humans
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