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Topoisomerase poisons, such as quinolone antibiotics, are widely used as anticancer drugs and antibiotics. Quinolone antibiotics act by trapping prokaryotic type IIA topoisomerases (DNA gyrase and TOPO IV), resulting in irreversible topoisomerase cleavage complexes. However, current U.S. Food and Drug Administration (FDA) guidance reserves the use of quinolones for the most serious bacterial infections due to their associated side effects and to limit the occurrence of drug-resistant bacterial strains.

Summary: 

The National Cancer Institute (NCI) is actively seeking potential licensees and/or co-development research collaboration partners interested in advancing oxynitidine derivatives as novel inhibitors of topoisomerase IB (TOP1) and tyrosyl-DNA phosphodiesterase 1 (TDP1) for cancer treatment. These TOPI and TDP1 inhibitors, when administered together, demonstrate enhanced anti-tumor efficacy.

Description of Technology: 

Cell motility and membrane trafficking play important roles in regulating cell division, cell migration, cell death and autophagy. Impairment of these processes can result in enhanced cell proliferation and survival and increased migration and invasion leading to cancer. Several proteins involved in cell motility and membrane trafficking have been shown to be dysregulated in various cancers. There is therefore a need for development of animal models for studying the roles of these proteins in cancer and their responses to drug treatment in vivo.

Nonalcoholic fatty liver disease is caused by several factors including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an environmental contaminant. TCDD causes lipid accumulation in humans by inducing the Solute Carrier Family 46 Member 3 (SLC46A3) gene expression. To effectively study TCDD-mediated lipid accumulation, research tools such as SLC46A3 knockout cells and animal models are required.

Lung metastases are a sign of widespread cancer with poor survival rate. Lung malignancies can originate from almost any cancer type spread via the blood stream. Most common lung metastases are from melanoma, breast cancer, bladder cancer, colon cancer, prostate cancer, neuroblastoma, and sarcoma. Living more than 5 years with lung metastases is uncommon, and surgical procedures are only effective with localized lung metastases. Lung metastasis are extremely frequent and resistant to regular treatment due to immunosuppressive regulatory sulfatide-reactive type II NKT cells.

Advanced stage cancers are typically marked by metastases of the primary cancer to secondary sites such as lungs, liver, and bones. Such metastatic cancers result in strikingly low 5-year survival rates, underscoring the need for novel therapeutics. For example, bone metastasis of primary breast cancer has a 5-year survival rate of 13%, lung cancer only 1%. There is a need for targeted therapy options specific to metastases. One approach to targeting metastases is to reduce cancer cell migration and invasion.

Due to the large degree of homology among dopamine D2-like receptors, discovering ligands capable of discriminating between the D2, D3, and D4 receptor subtypes remains a significant challenge. The development of subtype-selective pharmaceutical small molecules to activate (agonists) signals regulated by D2-like receptors has been especially difficult. 

Chemotherapy resistance in a wide array of cancers is often associated with enhanced glucose uptake and dysregulation of the insulin signaling pathway.  Therapeutics capable of inhibiting insulin signaling would be valuable as a stand-alone treatment and for sensitizing resistant tumors to standard chemotherapy regiments.  Researchers at NCI’s Genitourinary Malignancies Branch have synthesized and developed a series of Englerin-A ana

The Hippo signaling pathway regulates a multitude of biological processes including cell proliferation, apoptosis, differentiation, tissue homeostasis, and stem cell functions. This axis has been recently listed as one of the top 10 signaling pathways altered in human cancer. Its role in modulating cell growth and proliferation is mediated by the activation of Yes-associated protein 1 (YAP1) and transcriptional co-activator with PDZ-binding domain (TAZ).

The Zbtb7b gene encodes the zinc finger transcription factor ThPOK (also known as cKrox) that promotes CD4 lineage differentiation in immature T cells. CD4+ T cells, also known as “helper” T cells, are critical for long-term immunity against pathogens as well as for promoting CD8+ “effector” T cell and effective B cell responses. ThPOK is needed for the development and functional fitness of CD4+ T cells as well as multiple aspects of the immune response to infection. As such, ThPOK offers a potential target for immune regulation.