An expert overview of emerging therapies for acute myeloid leukemia: novel small molecules targeting apoptosis, p53, transcriptional regulation and metabolism

MANIFEST, a Phase 2 Study of CPI-0610, a Bromodomain and Extraterminal Domain Inhibitor (BETi), As Monotherapy or "Add-on" to Ruxolitinib, in Patients with Refractory or Intolerant Advanced Myelofibrosis

(2020) John Mascarenhas et al.   BLOOD

Phase 2 Results of APR-246 and Azacitidine (AZA) in Patients with TP53 mutant Myelodysplastic Syndromes (MDS) and Oligoblastic Acute Myeloid Leukemia (AML)

(2020) David A Sallman et al.   BLOOD

Interim Analysis of a Phase II Study of the Glutaminase Inhibitor Telaglenastat (CB-839) in Combination with Azacitidine in Advanced Myelodysplastic Syndrome (MDS)

(2020) Veronica A Guerra et al.   BLOOD

Updated Results from the Venetoclax (Ven) in Combination with Idasanutlin (Idasa) Arm of a Phase 1b Trial in Elderly Patients (Pts) with Relapsed or Refractory (R/R) AML Ineligible for Cytotoxic Chemotherapy

(2020) Naval G. Daver et al.   BLOOD

Cancer statistics, 2020

(2020) Rebecca L. Siegel et al.   CA-A CANCER JOURNAL FOR CLINICIANS

Current and Future Molecular Targets for Acute Myeloid Leukemia Therapy

(2020) Shaheedul A. Sami et al.   CURRENT TREATMENT OPTIONS IN ONCOLOGY

Therapeutic targeting of preleukemia cells in a mouse model of NPM1 mutant acute myeloid leukemia

(2020) Hannah J. Uckelmann et al.   SCIENCE

Patterns of care and clinical outcomes with cytarabine-anthracycline induction chemotherapy for AML patients in the United States

(2020) Amer M. Zeidan et al.   Blood Advances

Glasdegib: First Global Approval

(2019) Sheridan M. Hoy   DRUGS

The Role of Inhibition of Apoptosis in Acute Leukemias and Myelodysplastic Syndrome

(2019) Amanda McBride et al.   Frontiers in Oncology

BRD4 Inhibition Enhances Azacitidine Efficacy in Acute Myeloid Leukemia and Myelodysplastic Syndromes

(2019) Fernando Vieira Pericole et al.   Frontiers in Oncology

Recent advances in the development of Mcl-1 inhibitors for cancer therapy

(2019) Alexander W. Hird et al.   PHARMACOLOGY & THERAPEUTICS

Current Outlook on Autophagy in Human Leukemia: Foe in Cancer Stem Cells and Drug Resistance, Friend in New Therapeutic Interventions

(2019) Katharina Rothe et al.   INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES

Targeting Glutamine Metabolism and Redox State for Leukemia Therapy

(2019) Mark A. Gregory et al.   CLINICAL CANCER RESEARCH

The novel dihydroorotate dehydrogenase (DHODH) inhibitor BAY 2402234 triggers differentiation and is effective in the treatment of myeloid malignancies

(2019) Sven Christian et al.   LEUKEMIA

MDM2 antagonists as a novel treatment option for acute myeloid leukemia: perspectives on the therapeutic potential of idasanutlin (RG7388)

(2019) Arushi Khurana et al.   OncoTargets and Therapy

The TP53 Apoptotic Network is a Primary Mediator of Resistance to BCL2 inhibition in AML Cells

(2019) Tamilla Nechiporuk et al.   Cancer Discovery

The novel autophagy inhibitor ROC-325 augments the antileukemic activity of azacitidine

(2019) Steffan T. Nawrocki et al.   LEUKEMIA

T cell receptor gene therapy targeting WT1 prevents acute myeloid leukemia relapse post-transplant

(2019) Aude G. Chapuis et al.   NATURE MEDICINE

Rewiring the Epigenetic Networks in MLL-Rearranged Leukemias: Epigenetic Dysregulation and Pharmacological Interventions

(2019) Anthony K. N. Chan et al.   Frontiers in Cell and Developmental Biology

Death after hematopoietic stem cell transplantation: changes over calendar year time, infections and associated factors

(2019) Jan Styczyński et al.   BONE MARROW TRANSPLANTATION

MCL-1 inhibitors – where are we now (2019)?

(2019) Steven Fletcher   EXPERT OPINION ON THERAPEUTIC PATENTS

Synergistic effects of PRIMA-1Met (APR-246) and Azacitidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia

(2019) Nabih Maslah et al.   HAEMATOLOGICA

Recent drug approvals for acute myeloid leukemia

(2019) Catherine Lai et al.   Journal of Hematology & Oncology

Assessing Metabolic Intervention with a Glutaminase Inhibitor in Real-time by Hyperpolarized Magnetic Resonance in Acute Myeloid Leukemia

(2019) Niki M. Zacharias et al.   MOLECULAR CANCER THERAPEUTICS

Epigenetic therapies in acute myeloid leukemia: where to from here?

(2019) Katie A. Fennell et al.   BLOOD

How I treat acute myeloid leukemia in the era of new drugs

(2019) Courtney D. DiNardo et al.   BLOOD

The QUAZAR AML-001 Maintenance Trial: Results of a Phase III International, Randomized, Double-Blind, Placebo-Controlled Study of CC-486 (Oral Formulation of Azacitidine) in Patients with Acute Myeloid Leukemia (AML) in First Remission

(2019) Andrew H. Wei et al.   BLOOD

ASLAN003, a potent dihydroorotate dehydrogenase inhibitor for differentiation of acute myeloid leukemia

(2019) Jianbiao Zhou et al.   HAEMATOLOGICA

Inhibition of mitochondrial translation overcomes venetoclax resistance in AML through activation of the integrated stress response

(2019) David Sharon et al.   Science Translational Medicine

A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia

(2019) Andrei V. Krivtsov et al.   CANCER CELL

Menin inhibitor MI-3454 induces remission in MLL1-rearranged and NPM1-mutated models of leukemia

(2019) Szymon Klossowski et al.   JOURNAL OF CLINICAL INVESTIGATION

Targeting Glutamine Metabolism for Cancer Treatment

(2018) Yeon-Kyung Choi et al.   Biomolecules & Therapeutics

Oncogene-induced senescence and tumour control in complex biological systems

(2018) Lorenzo Galluzzi et al.   CELL DEATH AND DIFFERENTIATION

A Phase I Study of CPI-613 in Combination with High-Dose Cytarabine and Mitoxantrone for Relapsed or Refractory Acute Myeloid Leukemia

(2018) Timothy S. Pardee et al.   CLINICAL CANCER RESEARCH

Targeting Myeloid Differentiation Using Potent 2-Hydroxypyrazolo[1,5-a]pyridine Scaffold-Based Human Dihydroorotate Dehydrogenase Inhibitors

(2018) Stefano Sainas et al.   JOURNAL OF MEDICINAL CHEMISTRY

Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia

(2018) Luis A. Carvajal et al.   Science Translational Medicine

APR-246 reactivates mutant p53 by targeting cysteines 124 and 277

(2018) Qiang Zhang et al.   Cell Death & Disease

BRD4 Profiling Identifies Critical Chronic Lymphocytic Leukemia Oncogenic Circuits and Reveals Sensitivity to PLX51107, a Novel Structurally Distinct BET Inhibitor

(2018) Hatice Gulcin Ozer et al.   Cancer Discovery

BCL-2 inhibition in AML: an unexpected bonus?

(2018) Marina Konopleva et al.   BLOOD

Phase ib/2a study of PLX51107, a small molecule BET inhibitor, in subjects with advanced hematological malignancies and solid tumors.

(2018) Amita Patnaik et al.   JOURNAL OF CLINICAL ONCOLOGY

Acute myeloid leukaemia

(2018) Nicholas J Short et al.   LANCET

The Mutant p53-Targeting Compound APR-246 Induces ROS-Modulating Genes in Breast Cancer Cells

(2018) Naoise C. Synnott et al.   Translational Oncology

A Novel MCL-1 Inhibitor Combined with Venetoclax Rescues Venetoclax Resistant Acute Myelogenous Leukemia

(2018) Haley E. Ramsey et al.   Cancer Discovery

Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia

(2018) Courtney D. DiNardo et al.   BLOOD

The emergence of dihydroorotate dehydrogenase (DHODH) as a therapeutic target in acute myeloid leukemia

(2018) David B. Sykes   EXPERT OPINION ON THERAPEUTIC TARGETS

Targeting of Hematologic Malignancies with PTC299, A Novel Potent Inhibitor of Dihydroorotate Dehydrogenase with Favorable Pharmaceutical Properties

(2018) Liangxian Cao et al.   MOLECULAR CANCER THERAPEUTICS

Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia

(2018) Daniel A. Pollyea et al.   NATURE MEDICINE

Revisiting the role of dihydroorotate dehydrogenase as a therapeutic target for cancer

(2018) Joseph T. Madak et al.   PHARMACOLOGY & THERAPEUTICS

Efficacy, Safety, and Biomarkers of Response to Azacitidine and Nivolumab in Relapsed/Refractory Acute Myeloid Leukemia: A Non-randomized, Open-label, Phase 2 Study

(2018) Naval Daver et al.   Cancer Discovery

Glutamine: Metabolism and Immune Function, Supplementation and Clinical Translation

(2018) Vinicius Cruzat et al.   Nutrients

Functions of bromodomain-containing proteins and their roles in homeostasis and cancer

(2017) Takao Fujisawa et al.   NATURE REVIEWS MOLECULAR CELL BIOLOGY

Inhibition of autophagy as a treatment strategy for p53 wild-type acute myeloid leukemia

(2017) Hendrik Folkerts et al.   Cell Death & Disease

Chemotherapy-Resistant Human Acute Myeloid Leukemia Cells Are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism

(2017) Thomas Farge et al.   Cancer Discovery

Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel

(2016) Hartmut Döhner et al.   BLOOD

Anti-leukaemic effects induced by APR-246 are dependent on induction of oxidative stress and the NFE2L2/HMOX1 axis that can be targeted by PI3K and mTOR inhibitors in acute myeloid leukaemia cells

(2016) Dina Ali et al.   BRITISH JOURNAL OF HAEMATOLOGY

TP53mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes

(2016) Tapan M. Kadia et al.   CANCER

Binding of Released Bim to Mcl-1 is a Mechanism of Intrinsic Resistance to ABT-199 which can be Overcome by Combination with Daunorubicin or Cytarabine in AML Cells

(2016) X. Niu et al.   CLINICAL CANCER RESEARCH

Amino Acids Rather than Glucose Account for the Majority of Cell Mass in Proliferating Mammalian Cells

(2016) Aaron M. Hosios et al.   DEVELOPMENTAL CELL

Genomic Classification and Prognosis in Acute Myeloid Leukemia

(2016) Elli Papaemmanuil et al.   NEW ENGLAND JOURNAL OF MEDICINE

The Warburg Effect: How Does it Benefit Cancer Cells?

(2016) Maria V. Liberti et al.   TRENDS IN BIOCHEMICAL SCIENCES

An open-label phase I dose-finding study of APR-246 in hematological malignancies

(2016) S Deneberg et al.   Blood Cancer Journal

Efficacy and Biological Correlates of Response in a Phase II Study of Venetoclax Monotherapy in Patients with Acute Myelogenous Leukemia

(2016) M. Konopleva et al.   Cancer Discovery

Inhibiting glutaminase in acute myeloid leukemia: metabolic dependency of selected AML subtypes

(2016) Polina Matre et al.   Oncotarget

Targeting MCL-1/BCL-XL Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia

(2016) Kevin H. Lin et al.   Scientific Reports

Bromodomain inhibitor OTX015 in patients with acute leukaemia: a dose-escalation, phase 1 study

(2016) Céline Berthon et al.   Lancet Haematology

Acute myeloid leukemia-Major progress over four decades and glimpses into the future

(2015) Hagop Kantarjian   AMERICAN JOURNAL OF HEMATOLOGY

International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts

(2015) H. Dombret et al.   BLOOD

Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition

(2015) N. Jacque et al.   BLOOD

The BCL-2 protein family, BH3-mimetics and cancer therapy

(2015) A R D Delbridge et al.   CELL DEATH AND DIFFERENTIATION

Results of the Phase I Trial of RG7112, a Small-Molecule MDM2 Antagonist in Leukemia

(2015) M. Andreeff et al.   CLINICAL CANCER RESEARCH

Cell Death and Cancer Therapy: Don't Forget to Kill the Cancer Cell!

(2015) A. Letai   CLINICAL CANCER RESEARCH

BET bromodomain inhibitors in leukemia

(2015) Faisal Basheer et al.   EXPERIMENTAL HEMATOLOGY

The fate of patients with acute myeloid leukemia not undergoing induction chemotherapy

(2015) Masamitsu Yanada et al.   INTERNATIONAL JOURNAL OF HEMATOLOGY

Acute Myeloid Leukemia

(2015) Hartmut Döhner et al.   NEW ENGLAND JOURNAL OF MEDICINE

APR-246 overcomes resistance to cisplatin and doxorubicin in ovarian cancer cells

(2015) N Mohell et al.   Cell Death & Disease

BET inhibitor OTX015 targets BRD2 and BRD4 and decreases c-MYC in acute leukemia cells

(2015) Marie-Magdelaine Coudé et al.   Oncotarget

Small-molecule inhibition of BRD4 as a new potent approach to eliminate leukemic stem- and progenitor cells in acute myeloid leukemia (AML)

(2015) Harald Herrmann et al.   Oncotarget

PRIMA-1Met induces myeloma cell death independent of p53 by impairing the GSH/ROS balance

(2014) B. Tessoulin et al.   BLOOD

Highly Active Combination of BRD4 Antagonist and Histone Deacetylase Inhibitor against Human Acute Myelogenous Leukemia Cells

(2014) W. Fiskus et al.   MOLECULAR CANCER THERAPEUTICS

BET Protein Antagonist JQ1 Is Synergistically Lethal with FLT3 Tyrosine Kinase Inhibitor (TKI) and Overcomes Resistance to FLT3-TKI in AML Cells Expressing FLT-ITD

(2014) W. Fiskus et al.   MOLECULAR CANCER THERAPEUTICS

The Mechanisms behind the Therapeutic Activity of BET Bromodomain Inhibition

(2014) Junwei Shi et al.   MOLECULAR CELL

BCL-2 Inhibition Targets Oxidative Phosphorylation and Selectively Eradicates Quiescent Human Leukemia Stem Cells

(2013) Eleni D. Lagadinou et al.   Cell Stem Cell

Loss of MCL-1 leads to impaired autophagy and rapid development of heart failure

(2013) R. L. Thomas et al.   GENES & DEVELOPMENT

Deletion of MCL-1 causes lethal cardiac failure and mitochondrial dysfunction

(2013) X. Wang et al.   GENES & DEVELOPMENT

On Dihydroorotate Dehydrogenases and Their Inhibitors and Uses

(2013) Hélène Munier-Lehmann et al.   JOURNAL OF MEDICINAL CHEMISTRY

Recurrent mutations, including NPM1c, activate a BRD4-dependent core transcriptional program in acute myeloid leukemia

(2013) M A Dawson et al.   LEUKEMIA

Selective BCL-2 Inhibition by ABT-199 Causes On-Target Cell Death in Acute Myeloid Leukemia

(2013) R. Pan et al.   Cancer Discovery

The p53 pathway in hematopoiesis: lessons from mouse models, implications for humans

(2012) V. Pant et al.   BLOOD

Selectively targeting Mcl-1 for the treatment of acute myelogenous leukemia and solid tumors

(2012) G. J. Gores et al.   GENES & DEVELOPMENT

Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemia

(2012) S. P. Glaser et al.   GENES & DEVELOPMENT

Targeting p53 in Vivo: A First-in-Human Study With p53-Targeting Compound APR-246 in Refractory Hematologic Malignancies and Prostate Cancer

(2012) Sören Lehmann et al.   JOURNAL OF CLINICAL ONCOLOGY

Raise standards for preclinical cancer research

(2012) C. Glenn Begley et al.   NATURE

BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc

(2011) Jake E. Delmore et al.   CELL

Hallmarks of Cancer: The Next Generation

(2011) Douglas Hanahan et al.   CELL

Bromodomains as therapeutic targets

(2011) Susanne Muller et al.   EXPERT REVIEWS IN MOLECULAR MEDICINE

Long-Term Survival and Late Deaths After Allogeneic Hematopoietic Cell Transplantation

(2011) John R. Wingard et al.   JOURNAL OF CLINICAL ONCOLOGY

RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia

(2011) Johannes Zuber et al.   NATURE

High drug attrition rates—where are we going wrong?

(2011) Lisa Hutchinson et al.   Nature Reviews Clinical Oncology

Analysis of the p53 and MDM-2 gene in acute myeloid leukemia

(2010) Barbara Seliger et al.   EUROPEAN JOURNAL OF HAEMATOLOGY

APR-246 exhibits anti-leukemic activity and synergism with conventional chemotherapeutic drugs in acute myeloid leukemia cells

(2010) Dina Ali et al.   EUROPEAN JOURNAL OF HAEMATOLOGY

Mcl1 haploinsufficiency protects mice from Myc-induced acute myeloid leukemia

(2010) Zhifu Xiang et al.   JOURNAL OF CLINICAL INVESTIGATION

Selective inhibition of BET bromodomains

(2010) Panagis Filippakopoulos et al.   NATURE

The Tumor Suppressor p53: From Structures to Drug Discovery

(2010) A. C. Joerger et al.   Cold Spring Harbor Perspectives in Biology

PRIMA-1 Reactivates Mutant p53 by Covalent Binding to the Core Domain

(2009) Jeremy M.R. Lambert et al.   CANCER CELL

The prognostic impact of 17p (p53) deletion in 2272 adults with acute myeloid leukemia

(2009) H Seifert et al.   LEUKEMIA

TP53 Mutations in Human Cancers: Origins, Consequences, and Clinical Use

(2009) M. Olivier et al.   Cold Spring Harbor Perspectives in Biology

5-Fluorouracil: Mechanisms of Resistance and Reversal Strategies

(2008) Ning Zhang et al.   MOLECULES