Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer. Pathologic activation of... more Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer. Pathologic activation of PI3K/mTOR pathway and elevated expression of c-Myc are frequently detected in MCC. Yet, there is no targeted therapy presently available for this lethal disease. Recently, MLN0128, a second-generation dual TORC1/2 inhibitor is shown to have therapeutic efficacy in preclinical studies. MLN0128 is currently in clinical trials as a potential therapy for advanced cancers. Here we characterize the therapeutic efficacy of MLN0128 in the preclinical setting of MCC and delineate downstream targets of mTORC1/2 in MCC cellular systems. MLN0128 significantly attenuates xenograft MCC tumor growth independent of Merkel cell polyomavirus. Moreover, MLN0128 markedly diminishes MCC cell proliferation and induces apoptosis. Further investigations indicate that senescence does not contribute to MLN0128-mediated repression of xenograft MCC tumor growth. Finally, we also observe robust antitumor effects of MLN0128 when administered as a dual therapy with JQ1, a bromodomain protein BRD4 inhibitor. These results suggest dual blockade of PI3K/ mTOR pathway and c-Myc axis is effective in the control of MCC tumor growth. Our results demonstrate that MLN0128 is potent as monotherapy or as a member of combination therapy with JQ1 for advanced MCC.
Background: Cisplatin-induced ototoxicity affects a high percentage of new cancer patients worldw... more Background: Cisplatin-induced ototoxicity affects a high percentage of new cancer patients worldwide. The detailed mechanism of cisplatin-induced ototoxicity is not completely understood. We investigated whether rapamycin could protect rats from cisplatin-induced ototoxicity. Methods: Forty-eight male Wistar rats were randomly divided into six groups. Three groups were intra-peritoneally (IP) infused with cisplatin at a dose of 16 mg/kg and immediately injected with either dimethylsulfoxide (DMSO), rapamycin, or chloroquine (CQ). The remaining three groups were treated with rapamycin, CQ, or saline alone. The auditory brainstem response (ABR) test was performed to detect the rats' hearing status. Serum was isolated to measure the level of the oxidative marker malondialde-hyde (MDA), the basilar membrane was prepared to count the outer hair cell loss, and soft tissue samples extracted from the cochleae were lysed to analyze the microtubule-associated protein light chain 3 (LC3) and Beclin-1. Results: The rapamycin treatment significantly attenuated cisplatin-induced hearing loss, decreased oxidative stress, and alleviated the hair cell damage that was associated with the upregulation of the LC3-II/GAPDH ratio and increased Beclin-1 expression. Conclusion: Our results demonstrated that rapamycin has an otoprotective effect; it attenuates cisplatin-induced ototoxicity, probably by attenuating oxidative damage and inducing autophagy.
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer. Pathologic activation of... more Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer. Pathologic activation of PI3K/mTOR pathway and elevated expression of c-Myc are frequently detected in MCC. Yet, there is no targeted therapy presently available for this lethal disease. Recently, MLN0128, a second-generation dual TORC1/2 inhibitor is shown to have therapeutic efficacy in preclinical studies. MLN0128 is currently in clinical trials as a potential therapy for advanced cancers. Here we characterize the therapeutic efficacy of MLN0128 in the preclinical setting of MCC and delineate downstream targets of mTORC1/2 in MCC cellular systems. MLN0128 significantly attenuates xenograft MCC tumor growth independent of Merkel cell polyomavirus. Moreover, MLN0128 markedly diminishes MCC cell proliferation and induces apoptosis. Further investigations indicate that senescence does not contribute to MLN0128-mediated repression of xenograft MCC tumor growth. Finally, we also observe robust antitumor effects of MLN0128 when administered as a dual therapy with JQ1, a bromodomain protein BRD4 inhibitor. These results suggest dual blockade of PI3K/ mTOR pathway and c-Myc axis is effective in the control of MCC tumor growth. Our results demonstrate that MLN0128 is potent as monotherapy or as a member of combination therapy with JQ1 for advanced MCC.
Background: Cisplatin-induced ototoxicity affects a high percentage of new cancer patients worldw... more Background: Cisplatin-induced ototoxicity affects a high percentage of new cancer patients worldwide. The detailed mechanism of cisplatin-induced ototoxicity is not completely understood. We investigated whether rapamycin could protect rats from cisplatin-induced ototoxicity. Methods: Forty-eight male Wistar rats were randomly divided into six groups. Three groups were intra-peritoneally (IP) infused with cisplatin at a dose of 16 mg/kg and immediately injected with either dimethylsulfoxide (DMSO), rapamycin, or chloroquine (CQ). The remaining three groups were treated with rapamycin, CQ, or saline alone. The auditory brainstem response (ABR) test was performed to detect the rats' hearing status. Serum was isolated to measure the level of the oxidative marker malondialde-hyde (MDA), the basilar membrane was prepared to count the outer hair cell loss, and soft tissue samples extracted from the cochleae were lysed to analyze the microtubule-associated protein light chain 3 (LC3) and Beclin-1. Results: The rapamycin treatment significantly attenuated cisplatin-induced hearing loss, decreased oxidative stress, and alleviated the hair cell damage that was associated with the upregulation of the LC3-II/GAPDH ratio and increased Beclin-1 expression. Conclusion: Our results demonstrated that rapamycin has an otoprotective effect; it attenuates cisplatin-induced ototoxicity, probably by attenuating oxidative damage and inducing autophagy.
Uploads
Papers by BIN FANG