Therapeutic Potential of Ralimetinib, a p38/MAPK14 Inhibitor, in Anaplastic Thyroid Cancer

View full abstracthttps://openworks.mdanderson.org/leading-edge/1028/thumbnail.jp

Characterization of Altered immunity in Anaplastic Thyroid Cancer

View full abstracthttps://openworks.mdanderson.org/leading-edge/1033/thumbnail.jp

Effects of mTOR Inhibitor Everolimus (RAD0011) On Bladder Cancer Cells

Purpose: We investigated the effect of the mTOR inhibitor everolimus (RAD001) on human bladder cancer cells in vitro and in vivo. Experimental Design: The UM-UC-3, UM-UC-6, UM-UC-9 and UM-UC-14 cell lines were treated at different concentrations of RAD001. Growth effect was assessed by crystal violet assays at different time courses, with or without RAD001 re-dosing. Flow cytometric cell cycle analyses, propidium iodide exclusion and annexin V assays were performed. Tritium radiolabeled leucine incorporation and western blot assays were also performed. In vivo experiments were performed using nude mice subcutaneously implanted with UM-UC-3, UM-UC-6, and UM-UC-9 and treated with orally RAD001 or placebo. Tumors were harvested for immunohistochemistry. Results: The RAD001 treated bladder cancer cells showed transient growth inhibition in a dosedependent manner, with growth inhibition augmented by re-treatment after 3 days. UMUC-14 was most sensitive to RAD001 therapy while UM-UC-9 was least sensitive.RAD001 showed G1 growth phase arrest only after prolonged treatment in sensitive cell lines. There was no evidence of apoptosis. Significant tumor growth inhibition compared to controls was shown in murine subcutaneous tumors from UM-UC-3, UM-UC-6, and UM-UC-9 cell lines. Protein synthesis inhibition via S6K and 4EBP1 pathway appears to be the main mechanism of bladder cancer cell growth inhibition by RAD001. However, inhibition of angiogenesis was the predominant mechanism for UM-UC-9 cells. Conclusions: The mTOR inhibitor RAD001 inhibits growth of bladder cancer cells in vitro. RAD001 is effective in treating bladder cancer in vivo, in spite of heterogeneity of tumor response in vitro

Stromal Cells Derived from Visceral and Obese Adipose Tissue Promote Growth of Ovarian Cancers

<div><p>Obesity, and in particular visceral obesity, has been associated with an increased risk of developing cancers as well as higher rates of mortality following diagnosis. The impact of obesity on adipose-derived stromal cells (ASC), which contribute to the formation of tumor stroma, is unknown. Here we hypothesized that visceral source and diet-induced obesity (DIO) changes the ASC phenotype, contributing to the tumor promoting effects of obesity. We found that ASC isolated from subcutaneous (SC-ASC) and visceral (V-ASC) white adipose tissue(WAT) of lean(Le) and obese(Ob) mice exhibited similar mesenchymal cell surface markers expression, and had comparable effects on ovarian cancer cell proliferation and migration. Obese and visceral derived ASC proliferated slower and exhibited impaired differentiation into adipocytes and osteocytes <i>in vitro</i> as compared to ASC derived from subcutaneous WAT of lean mice. Intraperitoneal co-injection of ovarian cancer cells with obese or visceral derived ASC, but not lean SC-ASC, increased growth of intraperitoneal ID8 tumors as compared to controls. Obese and V-ASC increased stromal infiltration of inflammatory cells, including CD3+ T cells and F4/80+ macrophages. Obese and visceral derived ASC, but not lean SC-ASC, increased expression of chemotactic factors IL-6, MIP-2, and MCP-1 when cultured with tumor cells. Overall, these results demonstrate that obese and V-ASC have a unique phenotype, with more limited proliferation and differentiation capacity but enhanced expression of chemotactic factors in response to malignant cells which support infiltration of inflammatory cells and support tumor growth and dissemination.</p></div