PARP inhibitors in acute myeloid leukaemia therapy: How a synthetic lethality approach can be a valid therapeutic alternative

Gafencu, Grigore; Tomuleasa, Ciprian; Ghiaur, Gabriel

doi:10.1016/j.mehy.2017.05.015

Cited by 15 publications

(9 citation statements)

References 31 publications

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“…Therapy for acute leukemias, both myeloid and lymphoblastic, has become increasingly effective in the past decade (1)(2)(3)(4)(5)(6)(7). This is explained by the increasing efforts of personalizing chemotherapy treatment and supportive care that continuously adapts to initial diagnostic and progression of the disease, and which has resulted in better quality of life and higher overall survival (OS) rate in leukemic patients (8)(9)(10)(11).…”

Section: Background On the Central Nervous Systems (Cns) Involvement In Acute Leukemiasmentioning

confidence: 99%

A narrative review of central nervous system involvement in acute leukemias

Deak¹,

Gorcea-Andronic²,

Sas³

et al. 2021

Ann Transl Med

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Acute leukemias (both myeloid and lymphoblastic) are a group of diseases for which each year more successful therapies are implemented. However, in a subset of cases the overall survival (OS) is still exceptionally low due to the infiltration of leukemic cells in the central nervous system (CNS) and the subsequent formation of brain tumors. The CNS involvement is more common in acute lymphocytic leukemia (ALL), than in adult acute myeloid leukemia (AML), although the rates for the second case might be underestimated. The main reasons for CNS invasion are related to the expression of specific adhesion molecules (VLA-4, ICAM-1, VCAM, L-selectin, PECAM-1, CD18, LFA-1, CD58, CD44, CXCL12) by a subpopulation of leukemic cells, called "sticky cells" which have the ability to interact and adhere to endothelial cells. Moreover, the microenvironment becomes hypoxic and together with secretion of VEGF-A by ALL or AML cells the permeability of vasculature in the bone marrow increases, coupled with the disruption of blood brain barrier. There is a single subpopulation of leukemia cells, called leukemia stem cells (LSCs) that is able to resist in the new microenvironment due to its high adaptability. The LCSs enter into the arachnoid, migrate, and intensively proliferate in cerebrospinal fluid (CSF) and consequently infiltrate perivascular spaces and brain parenchyma. Moreover, the CNS is an immune privileged site that also protects leukemic cells from chemotherapy. CD56/NCAM is the most important surface molecule often overexpressed by leukemic stem cells that offers them the ability to infiltrate in the CNS. Although

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Section: Background On the Central Nervous Systems (Cns) Involvement In Acute Leukemiasmentioning

confidence: 99%

A narrative review of central nervous system involvement in acute leukemias

Deak¹,

Gorcea-Andronic²,

Sas³

et al. 2021

Ann Transl Med

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“…This concept of synthetic lethality using PARP inhibitors has been effectively examined in BRCA1-defective solid tumors, but was also exploited for the treatment hematological malignancies like AML [315][316][317]. Indeed, several in vitro studies in AML reported that PARP inhibitors induced cell cycle arrest and apoptosis, and combination with chemotherapy may induce synthetic lethality [133,318,319].…”

Section: Pi3k/akt/mtor Inhibitors In Combination With Dna Repair Inhimentioning

confidence: 99%

Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence

Darici

Alkhaldi

Horne

et al. 2020

JCM

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Acute myeloid leukemia (AML) is a highly heterogeneous hematopoietic malignancy characterized by excessive proliferation and accumulation of immature myeloid blasts in the bone marrow. AML has a very poor 5-year survival rate of just 16% in the UK; hence, more efficacious, tolerable, and targeted therapy is required. Persistent leukemia stem cell (LSC) populations underlie patient relapse and development of resistance to therapy. Identification of critical oncogenic signaling pathways in AML LSC may provide new avenues for novel therapeutic strategies. The phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling pathway, is often hyperactivated in AML, required to sustain the oncogenic potential of LSCs. Growing evidence suggests that targeting key components of this pathway may represent an effective treatment to kill AML LSCs. Despite this, accruing significant body of scientific knowledge, PI3K/Akt/mTOR inhibitors have not translated into clinical practice. In this article, we review the laboratory-based evidence of the critical role of PI3K/Akt/mTOR pathway in AML, and outcomes from current clinical studies using PI3K/Akt/mTOR inhibitors. Based on these results, we discuss the putative mechanisms of resistance to PI3K/Akt/mTOR inhibition, offering rationale for potential candidate combination therapies incorporating PI3K/Akt/mTOR inhibitors for precision medicine in AML.

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“…(iv) Since the elderly samples were genetically and epigenetically correlated to DNA instability perhaps treatment of elderly AML should be adapted accordingly. The possibilities of obtaining synthetic lethality by targeting DNA damage response pathways that are underway should be applied to elderly AML (PARP, ATR, ATM, CHK or DNA-PK inhibitors) 177 . The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib has already shown therapeutic benefits in BRCA-mutant ovarian and breast cancer 178 and induction of apoptosis of AML in vitro 179 .…”

Section: Specific Targets In Elderly Amlmentioning

confidence: 99%