piperidines and dactolisib

Human papillomavirus (HPV) infection is the major risk factor for anal dysplasia that may progress to squamous cell carcinoma of the anus. We have previously shown that systemic administration of a PI3K/mTOR inhibitor (BEZ235), an autophagic inducer, results in decreased squamous cell carcinoma of the anus in our HPV mouse model. In this study, we investigate the effect of the local, topical application of a BEZ235 on tumor-free survival, histopathology, PI3K/mTOR, and autophagy. The rationale for investigating a topical formulation is the localized nature of anal dysplasia/cancer and the goal for creating a clinically translatable formulation to decrease anal carcinogenesis. In this study, HPV transgenic mice were given no treatment, topical BEZ235, topical 7,12 dimethylbenz[a]anthracene (DMBA) (carcinogen), or both topical DMBA + BEZ235. Mice were assessed for tumor development and treatment-related toxicities. Tissue was evaluated for histology, PI3K/mTOR inhibition (pS6 and pAkt), and autophagy (LC3β and p62). DMBA-alone mice had an average of 16.9 weeks tumor-free survival, whereas mice receiving both DMBA+topical BEZ235 had 19.3 weeks (P < 0.000001). Histopathology revealed a significant decrease in dysplasia/carcinoma with the addition of topical BEZ235 to DMBA (P < 0.000001). Comparing DMBA versus DMBA + BEZ235, topical BEZ235 resulted in a significant decrease in both pS6 and pAkt (P < 0.001). Compared with no-treatment mice, both BEZ235-treated and DMBA + BEZ235-treated mice had significantly higher LC3β expression, signifying autophagic induction (P < 0.01), whereas DMBA-treated, BEZ235-treated, and DMBA+BEZ235-treated mice had a significantly lower p62 expression, signifying active autophagy (P < 0.0005). In conclusion, consistent with systemic delivery, topical application of BEZ235 shows decreased anal carcinogenesis through the activation of autophagy.

Topics: Administration, Topical; Animals; Anthracenes; Antineoplastic Agents; Anus Neoplasms; Apoptosis; Carcinogens; Cell Proliferation; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Mice; Papillomaviridae; Papillomavirus Infections; Phosphatidylinositol 3-Kinases; Piperidines; Quinolines; TOR Serine-Threonine Kinases

Ibrutinib (formerly PCI-32765) is a specific, irreversible, and potent inhibitor of Burton's tyrosine kinase (BTK) developed for the treatment of several forms of blood cancer. It is now an FDA-approved drug marketed under the name Imbruvica(TM) (Pharmacyclics, Inc.) and successfully used as an orally administered second-line drug in the treatment of mantle cell lymphoma. Since BTK is predominantly expressed in hematopoietic cells, the sensitivity of solid tumor cells to Ibrutinib has not been analyzed. In this study, we determined the effect of Ibrutinib on breast cancer cells. We demonstrate that Ibrutinib efficiently reduces the phosphorylation of the receptor tyrosine kinases ErbB1, ErbB2 and ErbB3, thereby suppressing AKT and MAPK signaling in ErbB2-positive (ErbB2+) breast cancer cell lines. Treatment with Ibrutinib significantly reduced the viability of ErbB2+ cell lines with IC50 values at nanomolar concentrations, suggesting therapeutic potential of Ibrutinib in breast cancer. Combined treatment with Ibrutinib and the dual PI3K/mTOR inhibitor BEZ235 synergistically reduces cell viability of ErbB2+ breast cancer cells. Combination indices below 0.25 at 50% inhibition of cell viability were determined by the Chou-Talalay method. Therefore, the combination of Ibrutinib and canonical PI3K pathway inhibitors could be a new and effective approach in the treatment of breast cancer with activated ErbB receptors. Ibrutinib could thus become a valuable component of targeted therapy in aggressive ErbB2+ breast cancer.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Survival; ErbB Receptors; Female; Heterocyclic Compounds, 3-Ring; Humans; Imidazoles; Mice; Mitogen-Activated Protein Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyrimidines; Quinolines; TOR Serine-Threonine Kinases