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TGFβ-Directed Therapeutics: 2020.

ABSTRACT: The transforming growth factor-beta (TGFβ) pathway is essential during embryo development and in maintaining normal homeostasis. During malignancy, the TGFβ pathway is co-opted by the tumor to increase fibrotic stroma, to promote epithelial to mesenchymal transition increasing metastasis and producing an immune-suppressed microenvironment which protects the tumor from recognition by the immune system. Compelling preclinical data demonstrate the therapeutic potential of blocking TGFβ function in cancer. However, the TGFβ pathway cannot be described as a driver of malignant disease. Two small molecule kinase inhibitors which block the serine-threonine kinase activity of TGFβRI on TGFβRII, a pan-TGFβ neutralizing antibody, a TGFβ trap, a TGFβ antisense agent, an antibody which stabilizes the latent complex of TGFβ and a fusion protein which neutralizes TGFβ and binds PD-L1 are in clinical development. The challenge is how to most effectively incorporate blocking TGFβ activity alone and in combination with other therapeutics to improve treatment outcome.

SUBMITTER: Teicher BA

PROVIDER: S-EPMC7770020 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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TGFβ-Directed Therapeutics: 2020.

Teicher Beverly A BA

Pharmacology & therapeutics 20200821

The transforming growth factor-beta (TGFβ) pathway is essential during embryo development and in maintaining normal homeostasis. During malignancy, the TGFβ pathway is co-opted by the tumor to increase fibrotic stroma, to promote epithelial to mesenchymal transition increasing metastasis and producing an immune-suppressed microenvironment which protects the tumor from recognition by the immune system. Compelling preclinical data demonstrate the therapeutic potential of blocking TGFβ function in ...[more]

PMID: 32835827

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Project description:Earlier, we reported that three Food and Drug Administration-approved drugs, trifluoperazine (TFP; an antipsychotic), amoxapine (AXPN; an antidepressant), and doxapram (DXP; a breathing stimulant), identified from an in vitro murine macrophage cytotoxicity screen, provided mice with 40 to 60% protection against pneumonic plague when administered at the time of infection for 1 to 3 days. In the present study, the therapeutic potential of these drugs against pneumonic plague in mice was further evaluated when they were administered at up to 48 h postinfection. While the efficacy of TFP was somewhat diminished as treatment was delayed to 24 h, the protection of mice with AXPN and DXP increased as treatment was progressively delayed to 24 h. At 48 h postinfection, these drugs provided the animals with significant protection (up to 100%) against challenge with the agent of pneumonic or bubonic plague when they were administered in combination with levofloxacin. Likewise, when they were used in combination with vancomycin, all three drugs provided mice with 80 to 100% protection from fatal oral Clostridium difficile infection when they were administered at 24 h postinfection. Furthermore, AXPN provided 40 to 60% protection against respiratory infection with Klebsiella pneumoniae when it was administered at the time of infection or at 24 h postinfection. Using the same in vitro cytotoxicity assay, we identified an additional 76/780 nonantibiotic drugs effective against K. pneumoniae For Acinetobacter baumannii, 121 nonantibiotic drugs were identified to inhibit bacterium-induced cytotoxicity in murine macrophages. Of these 121 drugs, 13 inhibited the macrophage cytotoxicity induced by two additional multiple-antibiotic-resistant strains. Six of these drugs decreased the intracellular survival of all three A. baumannii strains in macrophages. These results provided further evidence of the broad applicability and utilization of drug repurposing screening to identify new therapeutics to combat multidrug-resistant pathogens of public health concern.

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Dataset Information

TGFβ-Directed Therapeutics: 2020.

Publications

TGFβ-Directed Therapeutics: 2020.

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