| 2. |
- Herold, Nikolas, et al.
(författare)
-
Targeting SAMHD1 with the Vpx protein to improve cytarabine therapy for hematological malignancies
- 2017
-
Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 23:2, s. 256-263
-
Tidskriftsartikel (refereegranskat)abstract
- The cytostatic deoxycytidine analog cytarabine (ara-C) is the most active agent available against acute myelogenous leukemia (AML). Together with anthracyclines, ara-C forms the backbone of AML treatment for children and adults'. In AML, both the cytotoxicity of ara-C in vitro and the clinical response to ara-C therapy are correlated with the ability of AML blasts to accumulate the active metabolite ara-C triphosphate (ara-CTP)(2-5), which causes DNA damage through perturbation of DNA synthesis(6). Differences in expression levels of known transporters or metabolic enzymes relevant to ara-C only partially account for patient-specific differential ara-CTP accumulation in AML blasts and response to ara-C treatment(7-9). Here we demonstrate that the deoxynucleoside triphosphate (dNTP) triphosphohydrolase SAM domain and HD domain 1 (SAMHD1) promotes the detoxification of intracellular ara-CTP pools. Recombinant SAMHD1 exhibited ara-CTPase activity in vitro, and cells in which SAMHD1 expression was transiently reduced by treatment with the simian immunodeficiency virus (SIV) protein Vpx were dramatically more sensitive to ara-C-induced cytotoxicity. CRISPR-Cas9-mediated disruption of the gene encoding SAMHD1 sensitized cells to ara-C, and this sensitivity could be abrogated by ectopic expression of wild-type (WT), but not dNTPase-deficient, SAMHD1. Mouse models of AML lacking SAMHD1 were hypersensitive to ara-C, and treatment ex vivo with Vpx sensitized primary patient derived AML blasts to ara-C. Finally, we identified SAMHD1 as a risk factor in cohorts of both pediatric and adult patients with de novo AML who received ara-C treatment. Thus, SAMHD1 expression levels dictate patient sensitivity to ara-C, providing proof-of-concept that the targeting of SAMHD1 by Vpx could be an attractive therapeutic strategy for potentiating ara-C efficacy in hematological malignancies.
|
|
| 3. |
- Ljungblad, Linda
(författare)
-
Omega-3 fatty acids in the treatment of childhood cancer
- 2022
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Childhood cancer is the primary cause of deaths among Swedish children. Advances in treatment regimens have improved cure rate considerably in the latest decades. Consequently, childhood cancer survivors are a growing population with a significant risk of long-term side effects such as neurocognitive decline, endocrine dysfunction, risk of relapse or a second malignancy. The embryonal tumors neuroblastoma and medulloblastoma are heterogenous childhood tumors arising in the peripheral nervous system and cerebellum, respectively. While low-risk subsets of neuroblastoma and medulloblastoma have a good prognosis with survival rates above 90%, high-risk subsets have poor prognosis with survival rates below 50% despite intensified treatment. The polyunsaturated omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) exhibit anti-tumor and anti-inflammatory properties in various cancers including neuroblastoma. In contrast, the pro-inflammatory metabolite prostaglandin E2 (PGE2), derived from the omega-6 fatty acid arachidonic acid (AA) is known to induce inflammation and immune suppression in the tumor microenvironment. Inhibition of PGE2 formation has been identified as an attractive therapeutic approach in malignancies including medulloblastoma and neuroblastoma. This thesis is based on preclinical and clinical studies aiming to promote better treatment for children with cancer using the omega-3 fatty acids EPA and DHA and in particular investigate effects on medulloblastoma and neuroblastoma. The investigations in paper I revealed that omega-3 supplementation reduced tumor growth, PGE2 production, and CRYAB expression in preclinical models of medulloblastoma. Omega-3 supplementation modulated neuroblastoma tumor microenvironment by increasing the chemoattractant CCL3 and reducing AA-derived metabolites, including PGE2. Additionally, the AA-derived metabolites correlated with the infiltration of regulatory T cells in the tumors. Available gene expression data sets indicate that low CCL3 expression is associated with high-risk subgroups, metastatic disease, and poor overall survival in neuroblastoma (paper II). Several studies of omega-3 supplementation have been performed in adults and children of various ages and size but without reaching consensus regarding appropriate dosing so far. To pave way for future clinical studies and elucidate a dosing strategy, a dose-finding study of EPA and DHA supplementation was performed (paper III). Children aged 3-16 years in clinical remission after concluded cancer therapy received EPA and DHA supplementation based on the body surface area for 90 days. No severe adverse events were observed and the participants exhibited high adherence to the supplementation regardless of dose. Our findings suggest an EPA +DHA dose of about 1500 mg/m2 body surface area for further studies based on a sufficient incorporation of EPA and DHA in erythrocytes, a decrease of the omega- 6:omega-3 ratios, and the observed unpredictability of fatty acid incorporation at the highest doses. While the main aim of this study was to guide dosing for future clinical trials, immunomonitoring of the patients during the supplementation was included as a secondary aim revealing an increase in activated NK cells (paper IV). In summary, this thesis provides insight into the inhibitory effect of omega-3 fatty acids on the AA-derived metabolites in medulloblastoma and neuroblastoma tumor tissue and, additionally, proposes a dosing strategy for omega-3 fatty acid supplementation for comparative studies in pediatric oncology.
|
|
