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Venetoclax and Daratumumab combination treatment demonstrates pre-clinical efficacy in mouse models of Acute Myeloid Leukemia.

ABSTRACT: Acute myeloid leukemia (AML) remains an incurable malignancy despite recent advances in treatment. Recently a number of new therapies have emerged for the treatment of AML which target BCL-2 or the membrane receptor CD38. Here, we show that treatment with Venetoclax and Daratumumab combination resulted in a slower tumor progression and a reduced leukemia growth both in vitro and in vivo. These data provide evidence for clinical evaluation of Venetoclax and Daratumumab combination in the treatment of AML.

SUBMITTER: Mistry JJ

PROVIDER: S-EPMC8117650 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Venetoclax and Daratumumab combination treatment demonstrates pre-clinical efficacy in mouse models of Acute Myeloid Leukemia.

Mistry Jayna J JJ Hellmich Charlotte C Lambert Amelia A Moore Jamie A JA Jibril Aisha A Collins Angela A Bowles Kristian M KM Rushworth Stuart A SA

Biomarker research 20210513 1

Acute myeloid leukemia (AML) remains an incurable malignancy despite recent advances in treatment. Recently a number of new therapies have emerged for the treatment of AML which target BCL-2 or the membrane receptor CD38. Here, we show that treatment with Venetoclax and Daratumumab combination resulted in a slower tumor progression and a reduced leukemia growth both in vitro and in vivo. These data provide evidence for clinical evaluation of Venetoclax and Daratumumab combination in the treatmen ...[more]

PMID: 33985565

Similar Datasets

Venetoclax efficacy on acute myeloid leukemia is enhanced by the combination with butyrate.

Project description:Venetoclax has been approved recently for treatment of Acute myeloid leukemia (AML). Venetoclax is a BH3-mimetic and induces apoptosis via Bcl-2 inhibition. However, venetoclax's effect is still restrictive and a novel strategy is needed. In the present study, we demonstrate that sodium butyrate (NaB) facilitates the venetoclax's efficacy of cell death in AML cells. As a single agent, NaB or venetoclax exerted just a weak effect on cell death induction for AML cell line KG-1. The combination with NaB and venetoclax drastically induced cell death. NaB upregulated pro-apoptotic factors, Bax and Bak, indicating the synergistic effect by the collaboration with Bcl-2 inhibition by venetoclax. The combined treatment with NaB and venetoclax strongly cleaved a caspase substrate poly (ADP-ribose) polymerase (PARP) and a potent pan-caspase inhibitor Q-VD-OPh almost completely blocked the cell death induced by the combination, meaning that the combination mainly induced apoptosis. The combination with NaB and venetoclax also strongly induced cell death in another AML cell line SKNO-1 but did not affect chronic myeloid leukemia (CML) cell line K562, indicating that the effect was specific for AML cells. Our results provide a novel strategy to strengthen the effect of venetoclax for AML treatment.

| S-EPMC10904797 | biostudies-literature

Efficacy of the combination of venetoclax and hypomethylating agents in relapsed/refractory acute myeloid leukemia.

Project description: Not available

| S-EPMC6119155 | biostudies-literature

Ceramide nanoliposomes augment the efficacy of venetoclax and cytarabine in models of acute myeloid leukemia.

Project description:Despite several new therapeutic options for acute myeloid leukemia (AML), disease relapse remains a significant challenge. We have previously demonstrated that augmenting ceramides can counter various drug-resistance mechanisms, leading to enhanced cell death in cancer cells and extended survival in animal models. Using a nanoscale delivery system for ceramide (ceramide nanoliposomes, CNL), we investigated the effect of CNL within a standard of care venetoclax/cytarabine (Ara-C) regimen. We demonstrate that CNL augmented the efficacy of venetoclax/cytarabine in in vitro, ex vivo, and in vivo models of AML. CNL treatment induced non-apoptotic cytotoxicity, and augmented cell death induced by Ara-C and venetoclax. Mechanistically, CNL reduced both venetoclax (Mcl-1) and cytarabine (Chk1) drug-resistant signaling pathways. Moreover, venetoclax and Ara-C augmented the generation of endogenous pro-death ceramide species, which was intensified with CNL. Taken together, CNL has the potential to be utilized as an adjuvant therapy to improve outcomes, potentially extending survival, in patients with AML.

| S-EPMC9544744 | biostudies-literature

Treatment of therapy-related acute myeloid leukemia and underlying multiple myeloma with decitabine/venetoclax and daratumumab.

Project description: Not available

| S-EPMC8116235 | biostudies-literature

Integrated analysis of patient samples identifies biomarkers for venetoclax efficacy and combination strategies in acute myeloid leukemia.

Project description:Deregulation of the BCL2 gene family plays an important role in the pathogenesis of acute myeloid leukemia (AML). The BCL2 inhibitor, venetoclax, has received FDA approval for the treatment of AML. However, upfront and acquired drug resistance ensues due, in part, to the clinical and genetic heterogeneity of AML, highlighting the importance of identifying biomarkers to stratify patients onto the most effective therapies. By integrating clinical characteristics, exome and RNA sequencing, and inhibitor data from primary AML patient samples, we determined that myelomonocytic leukemia, upregulation of BCL2A1 and CLEC7A, as well as mutations of PTPN11 and KRAS conferred resistance to venetoclax and multiple venetoclax combinations. Venetoclax in combination with an MCL1 inhibitor AZD5991 induced synthetic lethality and circumvented venetoclax resistance.

| S-EPMC7591155 | biostudies-literature

Valproic Acid Enhances Venetoclax Efficacy in Targeting Acute Myeloid Leukemia.

Project description:BackgroundAcute myeloid leukemia (AML) is a common and aggressive form of leukemia, yet current treatment strategies remain insufficient. Venetoclax, a BH3-mimetic approved for AML treatment, induces Bcl-2-dependent apoptosis, though its therapeutic efficacy is still limited. Therefore, new strategies to enhance the effect of venetoclax are highly sought. Valproic acid (VPA), commonly used for epilepsy, has also been studied for potential applications in AML treatment.MethodsAML cells were treated with venetoclax, with or without VPA. Cell viability was assessed using the trypan blue dye exclusion assay, while cell cycle progression was analyzed by flow cytometry. The expression of pro-apoptotic proteins Bax and Bak was measured by RT-qPCR.ResultsVenetoclax and VPA individually had only mild effects on AML cell proliferation. However, their combination significantly inhibited cell growth and triggered pronounced cell death. This combination also led to the cleavage of poly (ADP-ribose) polymerase (PARP), a substrate of caspases, indicating activation of apoptosis. VPA treatment upregulated the expression of Bax and Bak, further supporting apoptosis induction. The cell death induced by the venetoclax-VPA combination was predominantly apoptotic, as confirmed by the near-complete blockade of cell death by a pan-caspase inhibitor.ConclusionsOur study demonstrates that VPA enhances venetoclax-induced apoptosis in AML cell lines, providing a novel role for VPA and suggesting a promising combinatory strategy for AML treatment. These findings offer valuable insights into potential clinical applications of venetoclax and VPA in AML management.

| S-EPMC11764158 | biostudies-literature

AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia.

Project description:Upregulation of Pim kinases is observed in several types of leukemias and lymphomas. Pim-1, -2, and -3 promote cell proliferation and survival downstream of cytokine and growth factor signaling pathways. AZD1208 is a potent, highly selective, and orally available Pim kinase inhibitor that effectively inhibits all three isoforms at <5 nM or <150 nM in enzyme and cell assays, respectively. AZD1208 inhibited the growth of 5 of 14 acute myeloid leukemia (AML) cell lines tested, and sensitivity correlates with Pim-1 expression and STAT5 activation. AZD1208 causes cell cycle arrest and apoptosis in MOLM-16 cells, accompanied by a dose-dependent reduction in phosphorylation of Bcl-2 antagonist of cell death, 4EBP1, p70S6K, and S6, as well as increases in cleaved caspase 3 and p27. Inhibition of p4EBP1 and p-p70S6K and suppression of translation are the most representative effects of Pim inhibition in sensitive AML cell lines. AZD1208 inhibits the growth of MOLM-16 and KG-1a xenograft tumors in vivo with a clear pharmacodynamic-pharmacokinetic relationship. AZD1208 also potently inhibits colony growth and Pim signaling substrates in primary AML cells from bone marrow that are Flt3 wild-type or Flt3 internal tandem duplication mutant. These results underscore the therapeutic potential of Pim kinase inhibition for the treatment of AML.

| S-EPMC3916880 | biostudies-other

Targeting Acute Myeloid Leukemia with Venetoclax; Biomarkers for Sensitivity and Rationale for Venetoclax-Based Combination Therapies.

Project description:Venetoclax is a BCL-2 inhibitor that effectively improves clinical outcomes in newly diagnosed, relapsed and refractory acute myeloid leukemia (AML) patients, with complete response rates (with and without complete blood count recovery) ranging between 34-90% and 21-33%, respectively. Here, we aim to give an overview of the efficacy of venetoclax-based therapy for AML patients, as compared to standard chemotherapy, and on factors and mechanisms involved in venetoclax sensitivity and resistance in AML (stem) cells, with the aim to obtain a perspective of response biomarkers and combination therapies that could enhance the sensitivity of AML cells to venetoclax. The presence of molecular aberrancies can predict responses to venetoclax, with a higher response in NPM1-, IDH1/2-, TET2- and relapsed or refractory RUNX1-mutated AML. Decreased sensitivity to venetoclax was observed in patients harboring FLT3-ITD, TP53, K/NRAS or PTPN11 mutations. Moreover, resistance to venetoclax was observed in AML with a monocytic phenotype and patients pre-treated with hypomethylating agents. Resistance to venetoclax can arise due to mutations in BCL-2 or pro-apoptotic proteins, an increased dependency on MCL-1, and usage of additional/alternative sources for energy metabolism, such as glycolysis and fatty acid metabolism. Clinical studies are testing combination therapies that may circumvent resistance, including venetoclax combined with FLT3- and MCL-1 inhibitors, to enhance venetoclax-induced cell death. Other treatments that can potentially synergize with venetoclax, including MEK1/2 and mitochondrial complex inhibitors, need to be evaluated in a clinical setting.

| S-EPMC9318140 | biostudies-literature

A combination treatment based on drug repurposing demonstrates mutation agnostic efficacy in pre-clinical retinopathy models.

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-06-06 | GSE238218 | GEO

A combination treatment based on drug repurposing demonstrates mutation-agnostic efficacy in pre-clinical retinopathy models.

Project description:Inherited retinopathies are devastating diseases that in most cases lack treatment options. Disease-modifying therapies that mitigate pathophysiology regardless of the underlying genetic lesion are desirable due to the diversity of mutations found in such diseases. We tested a systems pharmacology-based strategy that suppresses intracellular cAMP and Ca2+ activity via G protein-coupled receptor (GPCR) modulation using tamsulosin, metoprolol, and bromocriptine coadministration. The treatment improves cone photoreceptor function and slows degeneration in Pde6βrd10 and RhoP23H/WT retinitis pigmentosa mice. Cone degeneration is modestly mitigated after a 7-month-long drug infusion in PDE6A-/- dogs. The treatment also improves rod pathway function in an Rpe65-/- mouse model of Leber congenital amaurosis but does not protect from cone degeneration. RNA-sequencing analyses indicate improved metabolic function in drug-treated Rpe65-/- and rd10 mice. Our data show that catecholaminergic GPCR drug combinations that modify second messenger levels via multiple receptor actions provide a potential disease-modifying therapy against retinal degeneration.

| S-EPMC11251169 | biostudies-literature

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