Partnering with PARP inhibitors in acute myeloid leukemia with FLT3-ITD

Dellomo, Anna J.; Rassool, Feyruz V.

doi:10.1016/j.canlet.2019.03.048

Cited by 14 publications

(10 citation statements)

References 50 publications

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“…These results are consistent with those of our previous study, in which we demonstrated that the inhibition of STAT5 downregulates DNA repair [11]. Previous studies suggested that AML with genomic instability is sensitive to PARP inhibition [10,20]. Our results showed that the combination of 7c and olaparib synergistically inhibited FLT3-ITD + AML cells, revealing that an FLT3 inhibitor and a PARP inhibitor could be a promising therapeutic approach for FLT3-ITD + AML.…”

Section: Discussionsupporting

confidence: 93%

Discovery of Oxazol-2-amine Derivatives as Potent Novel FLT3 Inhibitors

et al. 2020

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Internal tandem duplication (ITD) of FMS-like tyrosine kinase 3 (FLT3) is the most common mutation in patients with acute myeloid leukemia (AML). FLT3-ITD+ induces constitutive activation of FLT3, causing an abnormally rapid proliferation of cancer cells. In this study, we identified novel FLT3 inhibitors and investigated 5-(4-fluorophenyl)-N-phenyloxazol-2-amine (compound 7; 7c) as candidates for the treatment of AML. The results showed that 7c inhibited the activities of FLT3 and mutated FLT3 in a cell-free kinase assay and Molm-13 and MV4-11 cells, as well as the proliferation of FLT3-ITD+ AML cells, increasing apoptosis. The anti-leukemic activity of 7c was confirmed by in vivo tumor growth inhibition in MV4-11 xenograft mice. Besides, 7c suppressed the expression of DNA damage repair genes. Combination treatment with 7c and olaparib (a poly (ADP-ribose) polymerase [PARP] inhibitor) synergistically inhibited cell proliferation in Molm-13 and MV4-11 cells. Our findings demonstrated that 7c is a therapeutic candidate targeting FLT3 for AML treatment and suggested that combination treatment with 7c and a PARP inhibitor may be an effective therapy regimen for FLT3-mutated AML.

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Section: Discussionsupporting

confidence: 93%

Discovery of Oxazol-2-amine Derivatives as Potent Novel FLT3 Inhibitors

et al. 2020

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“…4D) that is a well-known prognostic marker associated with poor survival in ~25% of AML cases (Stirewalt and Radich, 2003). Our results further support the application of PARP inhibitors in FLT3 mutated AML, particularly in combination with synthetic lethal partners such as specific genetic alterations (Dellomo et al, 2019). Surprisingly, our results revealed that abnormally low expression of PARP1 in FLT3-ITD negative AML (~75% of cases) is associated with poor survival (Fig.…”

Section: Discussionsupporting

confidence: 81%

Cancer Prognosis According to Parthanatos Features

Messikommer

Maru²,

Seipel

et al. 2021

Preprint

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For nearly 50 years, translational research studies aimed at improving chemotherapy-induced killing of cancer cells have focused on the induction of apoptosis. Here we show that a PARP-1-mediated programmed cell death mechanism "parthanatos" is associated with the successful, front-line treatment of a common cancer. Peripheral blood mononuclear cells (PBMCs) from healthy human donors (10 of 10 tested), as well as primary cancer cells from approximately 50% of acute myeloid leukemia (AML) patients (n = 18 of 39 tested, French-American-British (FAB) subtypes M4 and M5) exhibited two distinctive features of parthanatos upon treatment with a front-line drug combination of cytarabine and an anthracycline. Statistically significant improvements in survival rates were observed in the parthanatos positive versus parthanatos negative AML patient groups (HR = 0.22-0.38, p = 0.002-0.05). Near-median expression of PARP1 mRNA was associated with a 50% longer survival time (HR = 0.66, p = 0.01), and the poly [ADP-ribose] polymerase (PARP) inhibitor Olaparib exhibited antagonistic activities against ara-C and idarubicin in primary blood monocytes from healthy donors as well as primary cancer isolates from ~50% of AML patients. Together these results suggest that PARP activity is a prognostic biomarker for AML subtypes M4 and M5 and support the relevance of parthanatos in curative chemotherapy of AML.

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“…Hyperactivation of PARP pathway observed in tumors can be used to selectively kill tumor cells. PARPi treatment was shown to be effective in monotherapy and in combination therapies mainly in gynecological cancers, and researchers also suspect potential of PARP inhibitors involvement in acute myeloid leukemia [9,12,13].…”

Section: Introductionmentioning

confidence: 99%

Different regulation of PARP1, PARP2, PARP3 and TRPM2 genes expression in acute myeloid leukemia cells

et al. 2020

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Background: Acute myeloid leukemia (AML) is a heterogenic lethal disorder characterized by the accumulation of abnormal myeloid progenitor cells in the bone marrow which results in hematopoietic failure. Despite various efforts in detection and treatment, many patients with AML die of this cancer. That is why it is important to develop novel therapeutic options, employing strategic target genes involved in apoptosis and tumor progression. Methods: The aim of the study was to evaluate PARP1, PARP2, PARP3, and TRPM2 gene expression at mRNA level using qPCR method in the cells of hematopoietic system of the bone marrow in patients with acute myeloid leukemia, bone marrow collected from healthy patients, peripheral blood of healthy individuals, and hematopoietic stem cells from the peripheral blood after mobilization. Results: The results found that the bone marrow cells of the patients with acute myeloid leukemia (AML) show overexpression of PARP1 and PARP2 genes and decreased TRPM2 gene expression. In the hematopoietic stem cells derived from the normal marrow and peripheral blood after mobilization, the opposite situation was observed, i.e. TRPM2 gene showed increased expression while PARP1 and PARP2 gene expression was reduced. We observed positive correlations between PARP1, PARP2, PARP3, and TRPM2 genes expression in the group of mature mononuclear cells derived from the peripheral blood and in the group of bone marrow-derived cells. In AML cells significant correlations were not observed between the expression of the examined genes. In addition, we observed that the reduced expression of TRPM2 and overexpression of PARP1 are associated with a shorter overall survival of patients, indicating the prognostic significance of these genes expression in AML. Conclusions: Our research suggests that in physiological conditions in the cells of the hematopoietic system there is mutual positive regulation of PARP1, PARP2, PARP3, and TRPM2 genes expression. PARP1, PARP2, and TRPM2 genes at mRNA level deregulate in acute myeloid leukemia cells.

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Partnering with PARP inhibitors in acute myeloid leukemia with FLT3-ITD

Cited by 14 publications

References 50 publications

Discovery of Oxazol-2-amine Derivatives as Potent Novel FLT3 Inhibitors

Discovery of Oxazol-2-amine Derivatives as Potent Novel FLT3 Inhibitors

Cancer Prognosis According to Parthanatos Features

Different regulation of PARP1, PARP2, PARP3 and TRPM2 genes expression in acute myeloid leukemia cells

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