Targeting the Microenvironment in MDS: The Final Frontier

Teodorescu, Patric; Pașca, Sergiu; Dima, Delia; Tomuleasa, Ciprian; Ghiaur, Gabriel

doi:10.3389/fphar.2020.01044

Cited by 17 publications

(12 citation statements)

References 96 publications

(120 reference statements)

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“…Both treatment-na€ ıve and treated CLL patients were at increased risk of MDS and, theoretically, these observations could be driven by effects of CLL on the bone marrow microenvironment. 15 As more treatment options become available for patients with CLL, further characterization of their individual sets of late effects becomes increasingly important for informed choice of therapy. For MDS, our analyses suggested that the risk was particularly increased for patients receiving fludarabine containing regimens.…”

Section: Discussionmentioning

confidence: 99%

Risk of new malignancies among patients with CLL treated with chemotherapy: results of a Danish population‐based study

Cunha‐Bang

Rostgaard²,

Andersen

et al. 2021

Br J Haematol

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Patients with chronic lymphocytic leukaemia (CLL) have an increased risk of new malignancies. However, limited data have been published about the impact of CLL treatment on this risk. Here we followed a Danish population-based cohort of CLL patients for risks of new malignancies. Patients in the Danish CLL registry (2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015)(2016)(2017) were included. Up to 50 CLL-free matched comparators were identified. First-line treatment was categorized into four groups; bendamustine, chlorambucil, fludarabine or other. Patients were followed from CLL diagnosis for individual types of malignancy. Adjusted hazard ratios (HR) for new malignancies and 95% confidence intervals (95% CI) were calculated. Overall, 4286 CLL patients and 214 150 controls developed 594 and 20 565 new malignancies respectively. Risk of new malignancies was increased for CLL patients. Chemotherapy treatment was registered for 1064 (25%) patients with CLL. Chemotherapy was associated with increased HR (1Á51, 95% CI: 1Á3-1Á8) of any new malignancy. Specifically, fludarabine was associated with an increased risk of myelodysplastic syndrome (MDS) (HR 4Á93, 95% CI: 1Á2-19Á8). Patients with CLL are at increased risk of other haematological and solid malignancies compared to the general population. Chemotherapy exposure is associated with increased risk of second malignancies and fludarabine is associated with increased risk of MDS.

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Section: Discussionmentioning

confidence: 99%

Risk of new malignancies among patients with CLL treated with chemotherapy: results of a Danish population‐based study

Cunha‐Bang

Rostgaard²,

Andersen

et al. 2021

Br J Haematol

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“…In addition, it has been hypothesized that the interaction of MDS blasts and the BM microenvironment might play an important role for disease homeostasis. More precisely, a bidirectional crosstalk between MDS clone and BM microenvironment seems to maintain the malignant clone, but also shape the BM environment [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Altered Spatial Composition of the Immune Cell Repertoire in Association to CD34+ Blasts in Myelodysplastic Syndromes and Secondary Acute Myeloid Leukemia

Bauer

Vaxevanis

Al-Ali

et al. 2021

Cancers

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Background: Myelodysplastic syndromes (MDS) are caused by a stem cell failure and often include a dysfunction of the immune system. However, the relationship between spatial immune cell distribution within the bone marrow (BM), in relation to genetic features and the course of disease has not been analyzed in detail. Methods: Histotopography of immune cell subpopulations and their spatial distribution to CD34+ hematopoietic cells was determined by multispectral imaging (MSI) in 147 BM biopsies (BMB) from patients with MDS, secondary acute myeloid leukemia (sAML), and controls. Results: In MDS and sAML samples, a high inter-tumoral immune cell heterogeneity in spatial proximity to CD34+ blasts was found that was independent of genetic alterations, but correlated to blast counts. In controls, no CD8+ and FOXP3+ T cells and only single MUM1p+ B/plasma cells were detected in an area of ≤10 μm to CD34+ HSPC. Conclusions: CD8+ and FOXP3+ T cells are regularly seen in the 10 μm area around CD34+ blasts in MDS/sAML regardless of the course of the disease but lack in the surrounding of CD34+ HSPC in control samples. In addition, the frequencies of immune cell subsets in MDS and sAML BMB differ when compared to control BMB providing novel insights in immune deregulation.

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“…In addition to TAMs, the influence of niche stem cells on tumor development and drug resistant is also relevant. Interestingly, many studies have shown that STAT activity is essential to localize, maintain, and renew Hematopoietic Stem/Progenitors cells (HSPC) into tumoral niche and that STAT hyperactivation is associated with uncontrolled proliferation of HSPC (151)(152)(153)(154)(155). Thereby, dual strategies targeting both tumor cell proliferation and tumor niche and/or regulation of TIM represent a promising therapeutic strategy (156,157).…”

Section: Signal Transducers and Activators Of Transcription (Stat)mentioning

confidence: 99%

The Mevalonate Pathway, a Metabolic Target in Cancer Therapy

et al. 2021

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A hallmark of cancer cells includes a metabolic reprograming that provides energy, the essential building blocks, and signaling required to maintain survival, rapid growth, metastasis, and drug resistance of many cancers. The influence of tumor microenviroment on cancer cells also results an essential driving force for cancer progression and drug resistance. Lipid-related enzymes, lipid-derived metabolites and/or signaling pathways linked to critical regulators of lipid metabolism can influence gene expression and chromatin remodeling, cellular differentiation, stress response pathways, or tumor microenviroment, and, collectively, drive tumor development. Reprograming of lipid metabolism includes a deregulated activity of mevalonate (MVA)/cholesterol biosynthetic pathway in specific cancer cells which, in comparison with normal cell counterparts, are dependent of the continuous availability of MVA/cholesterol-derived metabolites (i.e., sterols and non-sterol intermediates) for tumor development. Accordingly, there are increasing amount of data, from preclinical and epidemiological studies, that support an inverse association between the use of statins, potent inhibitors of MVA biosynthetic pathway, and mortality rate in specific cancers (e.g., colon, prostate, liver, breast, hematological malignances). In contrast, despite the tolerance and therapeutic efficacy shown by statins in cardiovascular disease, cancer treatment demands the use of relatively high doses of single statins for a prolonged period, thereby limiting this therapeutic strategy due to adverse effects. Clinically relevant, synergistic effects of tolerable doses of statins with conventional chemotherapy might enhance efficacy with lower doses of each drug and, probably, reduce adverse effects and resistance. In spite of that, clinical trials to identify combinatory therapies that improve therapeutic window are still a challenge. In the present review, we revisit molecular evidences showing that deregulated activity of MVA biosynthetic pathway has an essential role in oncogenesis and drug resistance, and the potential use of MVA pathway inhibitors to improve therapeutic window in cancer.

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Targeting the Microenvironment in MDS: The Final Frontier

Cited by 17 publications

References 96 publications

Risk of new malignancies among patients with CLL treated with chemotherapy: results of a Danish population‐based study

Risk of new malignancies among patients with CLL treated with chemotherapy: results of a Danish population‐based study

Altered Spatial Composition of the Immune Cell Repertoire in Association to CD34+ Blasts in Myelodysplastic Syndromes and Secondary Acute Myeloid Leukemia

The Mevalonate Pathway, a Metabolic Target in Cancer Therapy

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