Investigational non-JAK inhibitors for chronic phase myelofibrosis

Bankar, Aniket; Gupta, Vikas

doi:10.1080/13543784.2020.1751121

Cited by 15 publications

(26 citation statements)

References 94 publications

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“…RG7112 has been tested as a single agent in relapsed refractory AML (Andreeff et al, 2016), showing modest activity, and is better suited to studies with murine AML than human-optimized RG7388 (Ding et al, 2013). CPI0610 is currently being tested in early stage human clinical trials and has been reported to be well-tolerated (Bankar and Gupta, 2020). For our experiments, we also identified well-tolerated drug doses in mice, based on a 21-day drug pilot experiment, assessing weight loss and myeloid cell counts (in bone marrow), B cells (in spleen) and T cells (in thymus) in nonleukemic normal healthy mice ( Supplementary Figure 2A, B).…”

Section: Beti and Mdm2i Cooperate To Eradicate Aml In Mouse Modelsmentioning

confidence: 99%

BRD4-mediated repression of p53 is a target for combination therapy in AML

Latif

Newcombe

et al. 2020

Preprint

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SummaryAcute Myeloid Leukemia (AML) is a typically-lethal molecularly heterogeneous disease, with few broad-spectrum therapeutic targets. Unusually, most AML retain wild-type TP53, encoding the pro-apoptotic tumor suppressor p53. MDM2 inhibitors (MDM2i), which activate wild-type p53, and BET inhibitors (BETi), targeting the BET-family co-activator BRD4, both show encouraging pre-clinical activity, but limited clinical activity as single agents. Here, we report synergistic toxicity of combined MDM2i and BETi towards AML cell lines, primary human blasts and mouse models, resulting from BETi’s ability to evict an unexpected repressive form of BRD4 from p53 target genes, and hence potentiate MDM2i-induced p53 activation. These results indicate that wild-type TP53 and a transcriptional repressor function of BRD4 together represent a potential broad-spectrum synthetic therapeutic vulnerability for AML.

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Section: Beti and Mdm2i Cooperate To Eradicate Aml In Mouse Modelsmentioning

confidence: 99%

BRD4-mediated repression of p53 is a target for combination therapy in AML

Latif

Newcombe

et al. 2020

Preprint

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“…Yet, the results were not consistent with other trials [ 79 , 83 , 85 ]. Therefore, combinations of various novel therapies with ruxolitinib emerge in the hope of eliminating MPN LSCs [ 86 ].…”

Section: Current Therapeutic Options In Mpn and Their Effects On Mmentioning

confidence: 99%

“…Telomerase is a ribonuclear protein complex comprised of human telomerase reverse transcriptase (hTERT), an RNA template (hTR), and specialized proteins (e.g., dyskerin), that extend the length of telomere [ 86 , 242 , 243 , 244 , 245 ]. It maintains replicative potential and is actively expressed in HSPC [ 86 , 242 , 243 , 244 , 245 ]. In MPN, telomerase is overexpressed and upregulated [ 86 , 242 , 243 ].…”

Section: Novel Therapies Targeting Mpn Stem Cells Via Signaling mentioning

confidence: 99%

“…It maintains replicative potential and is actively expressed in HSPC [ 86 , 242 , 243 , 244 , 245 ]. In MPN, telomerase is overexpressed and upregulated [ 86 , 242 , 243 ].…”

Section: Novel Therapies Targeting Mpn Stem Cells Via Signaling mentioning

confidence: 99%

“…Imetelstat (GRN163L) is a 13-mer oligonucleotide that inhibits hTR in telomerase [ 86 , 242 , 243 , 244 , 245 , 246 ], resulting in selective apoptosis of MPN stem cells [ 242 , 243 , 245 ]. Preclinical studies demonstrated preferential apoptosis of MF CD34 + cells irrespective of driver mutations [ 243 ], and reduced polyploidization and maturation of CD41 + /CD42b + megakaryocytes [ 242 ].…”

Section: Novel Therapies Targeting Mpn Stem Cells Via Signaling mentioning

confidence: 99%

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Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms

Yung

Lee

Chu

et al. 2021

IJMS

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Myeloproliferative neoplasms (MPNs) are unique hematopoietic stem cell disorders sharing mutations that constitutively activate the signal-transduction pathways involved in haematopoiesis. They are characterized by stem cell-derived clonal myeloproliferation. The key MPNs comprise chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). CML is defined by the presence of the Philadelphia (Ph) chromosome and BCR-ABL1 fusion gene. Despite effective cytoreductive agents and targeted therapy, complete CML/MPN stem cell eradication is rarely achieved. In this review article, we discuss the novel agents and combination therapy that can potentially abnormal hematopoietic stem cells in CML and MPNs and the CML/MPN stem cell-sustaining bone marrow microenvironment.

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Defining disease modification in myelofibrosis in the era of targeted therapy

Pemmaraju

Verstovšek

Mesa

et al. 2022

Cancer

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The development of targeted therapies for the treatment of myelofibrosis highlights a unique issue in a field that has historically relied on symptom relief, rather than survival benefit or modification of disease course, as key response criteria. There is, therefore, a need to understand what constitutes disease modification of myelofibrosis to advance appropriate drug development and therapeutic pathways. Here, the authors discuss recent clinical trial data of agents in development and dissect the potential for novel end points to act as disease modifying parameters. Using the rationale garnered from latest clinical and scientific evidence, the authors propose a definition of disease modification in myelofibrosis. With improved overall survival a critical outcome, alongside the normalization of hematopoiesis and improvement in bone marrow fibrosis, there will be an increasing need for surrogate measures of survival for use in the early stages of trials. As such, the design of future clinical trials will require re‐evaluation and updating to incorporate informative parameters and end points with standardized definitions and methodologies.

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Investigational non-JAK inhibitors for chronic phase myelofibrosis

Cited by 15 publications

References 94 publications

BRD4-mediated repression of p53 is a target for combination therapy in AML

BRD4-mediated repression of p53 is a target for combination therapy in AML

Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms

Defining disease modification in myelofibrosis in the era of targeted therapy

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