BackgroundTumor hypoxia is relevant for tumor growth, metabolism, resistance to chemotherapy and metastasis. We have previously shown that hyperoxia, using hyperbaric oxygen treatment (HBOT), attenuates tumor growth and shifts the phenotype from mesenchymal to epithelial (MET) in the DMBA-induced mammary tumor model. This study describes the effect of HBOT on tumor growth, angiogenesis, chemotherapy efficacy and metastasis in a triple negative MDA-MB-231 breast cancer model, and evaluates tumor growth using a triple positive BT-474 breast cancer model.Materials and methods5 x 105 cancer cells were injected s.c. in the groin area of NOD/SCID female mice. The BT-474 group was supplied with Progesterone and Estradiol pellets 2-days prior to tumor cell injection. Mice were divided into controls (1 bar, pO2 = 0.2 bar) or HBOT (2.5 bar, pO2 = 2.5 bar, 90 min, every third day until termination of the experiments). Treatment effects were determined by assessment of tumor growth, proliferation (Ki67-staining), angiogenesis (CD31-staining), metastasis (immunostaining), EMT markers (western blot), stromal components collagen type I, Itgb1 and FSP1 (immunostaining) and chemotherapeutic efficacy (5FU).ResultsHBOT significantly suppressed tumor growth in both the triple positive and negative tumors, and both MDA-MB-231 and BT-474 showed a decrease in proliferation after HBOT. No differences were found in angiogenesis or 5FU efficacy between HBOT and controls. Nevertheless, HBOT significantly reduced both numbers and total area of the metastastatic lesions, as well as reduced expression of N-cadherin, Axl and collagen type I measured in the MDA-MB-231 model. No change in stromal Itgb1 and FSP1 was found in either tumor model.ConclusionDespite the fact that behavior and prognosis of the triple positive and negative subtypes of cancer are different, the HBOT had a similar suppressive effect on tumor growth, indicating that they share a common oxygen dependent anti-tumor mechanism. Furthermore, HBOT significantly reduced the number and area of metastatic lesions in the triple negative model as well as a significant reduction in the EMT markers N-cadherin, Axl and density of collagen type I.

Acute myeloid leukemia (AML) is an aggressive heterogeneous blood cancer derived from hematopoietic stem cells. Tumor-stromal interactions in AML are of importance for disease development and therapy resistance, and bone marrow stroma seem like an attractive therapeutic target. Of particular interest is colony stimulating factor 1 receptor (CSF1R, M-CSFR, c-FMS, CD115) and its role in regulating plasticity of tumor-associated macrophages. We discuss first the potential of CSF1R-targeted therapy as an attractive concept with regards to the tumor microenvironment in the bone marrow niche. A second therapy approach, supported by preclinical research, also suggests that CSF1R-targeted therapy may increase the beneficial effect of conventional and novel therapeutics. Experimental evidence positioning inhibitors of CSF1R as treatment should, together with data from preclinical and early phase clinical trials, facilitate translation and clinical development of CSF1R-targeted therapy for AML.

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day 5, followed by up to 5 consolidation cycles of decitabine plus GO, then decitabine alone (Daver et al. Leukemia 2016;30[2]:268-73). Genotyping of the following SNPs was performed and correlated with clinical outcomes: ABCB1 rs1128503, ABCB1 rs1045642, CD33 rs2455069, CD33 rs35112940, CD33 rs12459419, CD33 rs1803254, CD33 rs61736475, and CD33 rs201074739. An aggregate "6 CD33 SNP score'' was determined based on genotypes of the 6 CD33 SNPs, as previously described (Lamba J et al. ASH 2017, abstract 3826). Results: 113 pts were treated with decitabine plus GO, 104 of whom underwent CD33 and ABCB1 SNP genotyping. Baseline characteristics of the population is shown in Table 1. For the entire cohort, 36 pts (32%) achieved any response (ORR, i.e. CR + CRi + MLFS), 16 of whom (14%) achieved CR. ORR was 47% and 18%, and CR rate was 23% and 7% for the frontline and relapsed/refractory cohorts, respectively. With a median follow-up of 107 months, median RFS and OS were 4.8 and 10.0 months in the frontline, and 3.0 and 6.6 months in the relapsed/refractory cohorts, respectively. For the whole cohort, CD33 median fluorescence intensity (MFI) was not significantly associated with ORR, but was associated with CR (OR 1.02; P = 0.02). No individual CD33 or ABCB1 SNP was predictive for ORR or CR; however, among pts with 6 CD33 SNP score ≥0, there was a trend towards higher CR rate (21% vs. 8%, OR 3.08; P = 0.07), but not with ORR (P = 0.94). Neither CD33 MFI nor any individual genotype or the 6 CD33 SNP score were significantly associated with cumulative incidence of relapse (CIR), relapse-free survival (RFS) or overall survival (OS). In the subgroup of pts with AML (n = 91), CD33 MFI was not significantly associated with ORR, but was associated with CR (OR 1.02; P = 0.02). The GG genotype of CD33 rs1803254 (n = 67) was associated with lower CIR and better RFS than the CC/CG genotypes (n = 15) in the AML cohort (median RFS 5.1 versus 2.5 months, P = 0.02), although this was driven by only 3 pts with the CC/CG genotypes who responded and included in RFS analysis; there was no association with OS. No other SNP, nor the 6 CD33 SNP score, was significantly associated with CR, ORR, CIR, RFS or OS in any subgroup analyses.