Mortality following breast cancer diagnosis is mainly due to the development of distant metastasis. To escape from the primary site, tumor cells undergo the epithelial-to-mesenchymal transition (EMT), which helps them acquire a more motile and invasive phenotype. In our previous study, we showed that class I selective HDAC inhibitor entinostat reverses the EMT phenotype through reversal of epigenetic repression of E-cadherin. Recent evidence suggests that a subset of cells within a breast tumor may drive the metastatic outgrowth following escape from the primary site. These cells, termed tumor-initiating cells (TIC), represent a great threat to overall prognosis. They are critical in terms of drug resistance and tumor initiation at metastatic sites. Acquisition of EMT traits has also been shown to impart TIC phenotype to the cells, making EMT a "dual-threat" for prognosis. In the current study, we show that entinostat treatment can reduce the percentage of TIC cells from triple-negative breast cancer (TNBC) cells. Entinostat treatment was able to reduce the CD44 high / CD24 low cell population, ALDH-1 activity, as well as protein and mRNA expression of known TIC markers such as Bmi-1, Nanog, and Oct-4. Next, we inoculated MDA-MB-231 cells transfected with firefly luciferase (231/Luc) in mammary fat pad of NSG mice. The mice were then treated with entinostat (2.5 mg/kg/d), and tumor development and formation of metastasis were assessed by bioluminescence imaging. Treatment with entinostat significantly reduced tumor formation at the primary site as well as lung metastasis. As such, entinostat may help prevent development of distant metastasis.

Depletion of glutamine (Gln) has emerged as a potential therapeutic approach in the treatment of acute myeloid leukemia (AML), as neoplastic cells require Gln for synthesis of cellular components essential for survival. Asparaginases deplete Gln, and asparaginase derived from Erwinia chrysanthemi (Erwinaze) appears to have the greatest glutaminase activity of the available asparaginases. In this Phase I study, we sought to determine the dose of Erwinaze that safely and effectively depletes plasma Gln levels to ≤ 120 μmol/L in patients with relapsed or refractory (R/R) AML. Five patients were enrolled before the study was halted due to issues with Erwinaze manufacturing supply. All patients received Erwinaze at a dose of 25,000 IU/m intravenously three times weekly for 2 weeks. Median trough plasma Gln level at 48 h after initial Erwinaze administration was 27.6 μmol/L, and 80% (lower limit of 1-sided 95% CI 34%) of patients achieved at least one undetectable plasma Gln value (< 12.5 μmol/L), with the fold reduction (FR) in Gln level at 3 days, relative to baseline, being 0.16 (p < 0.001 for rejecting FR = 1). No dose-limiting toxicities were identified. Two patients responded, one achieved partial remission and one achieved hematologic improvement after six doses of Erwinaze monotherapy. These data suggest asparaginase-induced Gln depletion may have an important role in the management of patients with AML, and support more pharmacologic and clinical studies on the mechanistically designed asparaginase combinations in AML.

Obesity is a risk factor for breast cancer progression. Breast cancer patients who are overweight or obese or have excess abdominal fat have an increased risk of local or distant recurrence and cancer-related death. Hormone depletion therapies can also cause weight gain, exacerbating the risk for these patients. To understand the effect of obesity on hormone-dependent human breast cancer tumors, we fed ovariectomized athymic nude mice a diet containing 45% kcal fat and 17% kcal sucrose (high fat sucrose diet (HFSD)), 10% kcal fat (low fat diet (LFD)), or a standard chow diet (chow). The mice fed the HFSD developed metabolic abnormalities consistent with the development of obesity such as weight gain, high fasting blood glucose, and impaired glucose tolerance. These mice also developed hyperinsulinemia and insulin resistance. The obese mice also had a higher tumor growth rate compared to the lean mice. Furthermore, the obese mice showed a significantly reduced responsiveness to letrozole. To understand the role of obesity in this reduced responsiveness, we examined the effect of insulin on the growth of MCF-7Ca cells in response to estrogen or letrozole. The presence of insulin rendered MCF-7Ca cells less responsive to estrogen and letrozole. Exogenous insulin treatment of MCF-7Ca cells also resulted in increased p-Akt as well as ligand-independent phosphorylation of ERa. These findings suggest that diet-induced obesity may result in reduced responsiveness of tumors to letrozole due to the development of hyperinsulinemia. We conclude that obesity influences the response and resistance of breast cancer tumors to aromatase inhibitor treatment. Key Words" aromatase inhibitors " diet-induced-obesity " MCF-7Ca xenografts " breast cancer

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Background: After SARS-CoV-2 vaccines become available, they will be deployed to many countries with limited immunization systems. Methods: We conducted a cold chain capacity assessment of a simulated country in the WHO African Region. We combined region-specific data regarding immunization, population, healthcare workforce, and cold storage capacity (upper and lower range and quartile values for national and subnational levels). We used seasonal influenza vaccines as proxies for SARS-CoV-2 vaccines. We evaluated the increase in vaccine doses to be administered, doses administered per vaccinator, and cold storage volumes for SARS-CoV-2 campaigns targeting risk groups compared to routine immunization baselines. Findings: Compared to routine immunization, a SARS-CoV-2 vaccination campaign would increase monthly doses administered when targeting risk groups: ≥65 years (29.9%), chronic diseases patients (101.5%), and healthcare workers (1.2%). SARS-CoV-2 vaccination campaigns would increase doses administered per vaccinator for risk groups: ≥65 years (32.5%), chronic diseases patients (110.4%), or healthcare workers (1.4%). Routine vaccine volumes already exceed national level storage capacity for at least 75% of African Region countries, but subnational levels would have sufficient storage capacity for SARS-CoV-2 vaccines in all but the lower 25% of African Region countries. Interpretation: SARS-CoV-2 vaccination campaigns would substantially increase doses per vaccinator and cold chain capacity requirements over routine immunization baselines. Pandemic vaccination campaigns would add volume to national level stores already at their limits, but substantial capacity exists at subnational levels for SARS-CoV-2 vaccines. Immediate attention to strengthening delivery systems is essential to support pandemic vaccine responses in the African Region. Funding: None