Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Toll-like receptors (TLR) are pattern recognition receptors that play a pivotal role in the initiation of immune responses. Here we report that the murine mammary carcinoma 4T1 constitutively expressed genes encoding TLR2, 3, 4 and 5. Moreover, treatment of the 4T1 cell line with peptidoglycan (PGN), polyinosinic-polycytidylic acid (Poly(I:C)) or lipopolysaccharide (LPS), agonists for TLR2, 3 or 4 respectively, induced nuclear translocation of NFkappaB and secretion of CCL2, CCL5 and CXCL1 in a dose dependent manner. Although treating the tumor cells with the TLR agonists did not modulate growth or viability of the tumor cells in vitro, 4T1 exhibited a decreased growth rate in vivo following treatment with LPS that was dependent upon the presence of CD8(+) T cells. Analysis of 3 additional murine mammary carcinomas revealed that they also secreted CCL2, CCL5 and CXCL1 in response to TLR agonist treatment, and LPS treated 168 and SM1 tumors exhibited decreased growth rates in vivo, but not in vitro. These data indicated that 4 out of 4 murine mammary carcinomas secreted proinflammatory chemokines following treatment with TLR agonists, and 3 out of 4 of the mammary carcinomas responded to LPS treatment in a manner that decreased tumor growth in vivo.
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PMID:Lipopolysacchride-treated mammary carcinomas secrete proinflammatory chemokines and exhibit reduced growth rates in vivo, but not in vitro. 1986 May 85

The BRAF mutant, BRAF(V600E), is expressed in nearly half of melanomas, and oral BRAF inhibitors induce substantial tumor regression in patients with BRAF(V600E) metastatic melanoma. The inhibitors are believed to work primarily by inhibiting BRAF(V600E)-induced oncogenic MAPK signaling; however, some patients treated with BRAF inhibitors exhibit increased tumor immune infiltration, suggesting that a combination of BRAF inhibitors and immunotherapy may be beneficial. We used two relatively resistant variants of Braf(V600E)-driven mouse melanoma (SM1 and SM1WT1) and melanoma-prone mice to determine the role of host immunity in type I BRAF inhibitor PLX4720 antitumor activity. We found that PLX4720 treatment downregulated tumor Ccl2 gene expression and decreased tumor CCL2 expression in both Braf(V600E) mouse melanoma transplants and in de novo melanomas in a manner that was coincident with reduced tumor growth. While PLX4720 did not directly increase tumor immunogenicity, analysis of SM1 tumor-infiltrating leukocytes in PLX4720-treated mice demonstrated a robust increase in CD8(+) T/FoxP3(+)CD4(+) T cell ratio and NK cells. Combination therapy with PLX4720 and anti-CCL2 or agonistic anti-CD137 antibodies demonstrated significant antitumor activity in mouse transplant and de novo tumorigenesis models. These data elucidate a role for host CCR2 in the mechanism of action of type I BRAF inhibitors and support the therapeutic potential of combining BRAF inhibitors with immunotherapy.
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PMID:Host immunity contributes to the anti-melanoma activity of BRAF inhibitors. 2659 10

Isoxazole is a five-membered heterocycle that is widely used in drug discovery endeavors. Here, we report the design, synthesis, and structural and biological characterization of SS-208, a novel HDAC6-selective inhibitor containing the isoxazole-3-hydroxamate moiety as a zinc-binding group as well as a hydrophobic linker. A crystal structure of the Danio rerio HDAC6/SS-208 complex reveals a bidentate coordination of the active-site zinc ion that differs from the preferred monodentate coordination observed for HDAC6 complexes with phenylhydroxamate-based inhibitors. While SS-208 has minimal effects on the viability of murine SM1 melanoma cells in vitro, it significantly reduced in vivo tumor growth in a murine SM1 syngeneic melanoma mouse model. These findings suggest that the antitumor activity of SS-208 is mainly mediated by immune-related antitumor activity as evidenced by the increased infiltration of CD8+ and NK+ T cells and the enhanced ratio of M1 and M2 macrophages in the tumor microenvironment.
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PMID:Discovery of a New Isoxazole-3-hydroxamate-Based Histone Deacetylase 6 Inhibitor SS-208 with Antitumor Activity in Syngeneic Melanoma Mouse Models. 3141 1