Browsing by Subject "Cancer."
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Item Reprogramming T cell specific immune responses to Cyclin B1 in breast cancer patients using a TLR 8/7 agonist.(2012-08-08) Smith, Jennifer L.; Palucka, Karolina, 1959-; Biomedical Studies.; Baylor University. Institute of Biomedical Studies.Cyclin B1 is a cell cycle regulatory protein aberrantly overexpressed in a number of cancers, including breast cancer. While the current standards of care for breast cancer are sometimes curative, many patients suffer relapse. This necessitates novel therapeutic approaches. Therapeutic vaccination has become an increasingly attractive option because of the ability to expand and possibly correct the function of cancer antigen-specific T cells, expand memory T cells, and effectively control tumor antigen delivery. Therefore, we analyzed the immune repertoire to Cyclin B1 in patients with breast cancer in order to achieve these goals. Healthy donor CD4+ and CD8+ T cells can express IFNγ in response to Cyclin B1 long peptides, thus confirming prior findings. Cyclin B1 long peptides were also able to stimulate antigen-specific cytokine secretion from breast cancer patients PBMCs (22 out of 25 patients studied). However, PBMCs from breast cancer patients secrete high amounts of type 2 cytokines (IL-4, IL-5, IL-13, TNFα) and low amounts of IFNγ when compared to healthy donors. These results suggest a Type 2 bias in breast cancer patients PBMCs, similar to our earlier findings showing a pro-tumor, inflammatory Th2 microenvironment in tumor infiltrates. We next analyzed whether this response could be modified, resulting in a block of Th2 cytokines, or increase in Th1 cytokines. Our earlier studies suggested that CL-075, a TLR8/7 agonist, generates Type I cytokine secretion and drives antigen-specific CD8+ T cell responses. In healthy donor PBMCs, we found this led to a significant increase in the amount of antigen-specific IFNγ expressed by both CD4+ and CD8+ T cells. In breast cancer patient PBMCs, 21 out of 22 patients showed a modified cytokine secretion signature that was antigen-specific with CL-075. Those patients were also able to either increase IFNγ-specific response or block Th2 cytokine response, while 6 out of 22 patients were able to do both. Therefore, the inflammatory Th2 immune response to Cyclin B1 in breast cancer patients can be modified using a TLR8/7 agonist, thereby providing a rationale for a combination of Cyclin B1 long peptides and TLR8/7 agonists as a therapeutic possibility.Item Targeting cancer through inhibition of cathepsin B by non-peptidic small molecule thiosemicarbazones and disruption of pre-existing vasculature by colchicine-like benzosuberene analogues.(2014-01-28) Sevcik, Amanda K.; Trawick, Mary Lynn.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.Cancer is a leading cause of death in men and women under in the United States and is characterized by uncontrolled cellular proliferation and migration (metastasis) which can impinge on surrounding organs, modify ordinary biological functions, and lead to death. This study focuses on two strategies for cancer therapy: targeting cathepsin B, an enzyme linked to tumor metastasis and progression, and the disruption of pre-existing tumor vasculature as a means to starve tumors of oxygen and nutrients. Cathepsin B is a cysteine protease involved in intra- and extracellular degradation of proteins. Increased expression of cathepsin B has been documented in a number of different cancers and is associated with a poor disease prognosis, and increased tumor vascularization, degradation of the extracellular matrix, invasion, and metastasis. Inhibition of cathepsin B has the potential to arrest cancer cell invasion and metastasis. In a collaborative project between the Trawick and Pinney laboratories at Baylor University, a focused synthetic library of non-peptidic, small molecule thiosemicarbazone derivatives was screened for their ability to inhibit cathepsin B activity as monitored by a fluorogenic enzyme assay. Five compounds were found to be effective inhibitors of cathepsin B in the low micromolar range, and the best four were characterized for their mode of inhibition. Kinetic analysis revealed that two of the active thiosemicarbazone compounds were time dependent, competitive, tight binding, slowly reversible inhibitors of cathepsin B. The other compounds analyzed were rapidly reversible, competitive inhibitors with KI values in the low micromolar range. Vascular disrupting agents (VDAs) are a promising class of anticancer drugs that selectively disrupt tumor vasculature. Tubulin-binding VDAs disrupt microtubule dynamics of endothelial cells lining tumor vasculature. A lead benzosuberene analogue exhibited extreme cytotoxicity against a panel of human cancer cell lines. The lead compound and several of its analogues were investigated for their ability to inhibit tubulin polymerization, bind to the colchicine binding site of tubulin as determined by a competitive radiometric binding assay and arrest human breast cancer cells in the G2/M phase of the cell cycle as indicated by flow cytometry. The results support the mechanism of action of the lead benzosuberene analogues as VDAs.