Since its first identification in prostate cancers and prostate tissues, transient receptor potential melastatin-subfamily member 8 (TRPM8) is subsequently found to be overexpressed in a wide range of cancers and is shown to be implicated in tumorigenesis and tumor progression. Here, we used N-(3-aminopropyl)-2-[(3-methylphenyl) methoxy] -N-(2-thienylmethyl) benzamide hydrochloride (AMTB), a specific TRPM8 antagonist, to explore its antitumoral effect on osteosarcoma. We find that AMTB suppresses osteosarcoma cell proliferation, metastasis and induces cellular apoptosis. Xenograft model in nude mice experiments also define that AMTB can increase the sensitivity of tumor cells to cisplatin, the cytotoxic chemotherapeutic regimens in treating osteosarcoma. Molecularly, AMTB specifically antagonizes TRPM8 which is upregulated in osteosarcoma and its expression level in osteosarcoma tissues is negatively related to patients’ prognosis. Finally, RNA sequencing analysis was performed to explore the mechanism underlying the antitumoral effect of AMTB on osteosarcoma cells and the results prove that AMTB suppresses the Transforming Growth Factor β (TGFβ) signaling pathway. Our study provides evidence that TRPM8 could be a potential therapeutic target and AMTB can suppress growth and metastasis of osteosarcoma cells through repressing the TGFβ signaling pathway and increase the sensitivity of tumor cells to cisplatin.

Study Design.: A retrospective study of 84 patients with spinal metastasis from prostate cancer (SMPCa) was performed. Objective.: The aim of this study was to predict the survival of patients with SMPCa by establishing an effective prognostic nomogram model, associating with the affecting factors and compare its efficacy with the existing scoring models. Summary of Background Data.: Prostate cancer (PCa) is the second most frequently malignant cancer causing death in men, and the spine is the most common site of bone metastatic burden. The aim of this study was to establish a prognostic nomogram for survival prediction of patients with SMPCa, explore associated factors, and compare the effectiveness of the new nomogram prediction model with the existing scoring systems. Methods.: Included in this study were 84 SMPCa patients who were admitted in our spinal tumor center between 2006 and 2018. Their clinical data were retrospectively analyzed by univariate and multivariate analyses to identify independent variables that enabled to predict prognosis. A nomogram, named Changzheng Nomogram for Survival Prediction (CNSP), was established on the basis of preoperative independent variables, and then subjected to bootstrap re-samples for internal validation. The predictive accuracy and discriminative ability were measured by concordance index (C-index). Receiver-operating characteristic (ROC) analysis with the corresponding area under the ROC was used to estimate the prediction efficacy of CNSP and compare it with the four existing prognostic models Tomita, Tokuhashi, Bauer, and Crnalic. Results.: A total of seven independent variables including Gleason score (P = 0.001), hormone refractory (P < 0.001), visceral metastasis (P < 0.001), lymphocyte to monocyte ratio (P = 0.009), prostate-specific antigen (P = 0.018), fPSA/tPSA (P = 0.029), Karnofsky Performance Status (P = 0.039) were identified after accurate analysis, and then entered the nomogram with the C-index of 0.87 (95% confidence interval, 0.84–0.90). The calibration curves for probability of 12-, 24-, and 36-month overall survival (OS) showed good consistency between the predictive risk and the actual risk. Compared with the previous prognostic models, the CNSP model was significantly more effective than the four existing prognostic models in predicting OS of the SMPCa patients (p < 0.05). Conclusion.: The overall performance of the CNSP model was satisfactory and could be used to estimate the survival outcome of individual patients more precisely and thus help clinicians design more specific and individualized therapeutic regimens. Level of Evidence: 4

Osteosarcoma (OS) is the most prevalent type of primary malignant bone cancer and currently lacks effective targeted treatments. Increasing evidence indicates that SOX2 overexpression is a primary driver of OS. By screening a small-molecule kinase inhibitor library, we identified AKT as a kinase essential for robust SOX2 expression in OS cells. AKT was found to be frequently overexpressed in OS and positively correlated with SOX2 protein levels. We demonstrated that AKT has no effect on SOX2 transcription but promotes SOX2 protein stability. Mechanistically, AKT binds to and phosphorylates SOX2 at T116, preventing SOX2 ubiquitination and proteasome-dependent degradation by ubiquitin E3 ligases UBR5 and STUB1. Moreover, we found that AKT-SOX2 axis is a significant modulator of cancer stemness and chemoresistance and that the combination of AKT inhibitor MK2206 and cisplatin resulted in a synergistic and potent inhibition of OS tumor growth in the PDX model. In conclusion, we identified a critical role for AKT in promoting SOX2 overexpression, tumor stemness, and chemoresistance in OS, and provided evidence that targeting AKT combined with chemotherapy may hold promise for treating refractory OS.

Bone tumors occur in bone or its accessory tissues. Benign bone tumors are easy to cure and have good prognosis, while malignant bone tumors develop rapidly and have poor and high mortality. So far, there is no satisfactory treatment method. Here, we designed a universal template vector for bone tumor therapy that simultaneously meets the needs of bone targeting, tumor killing, osteoclast suppression, and tumor imaging. The template is composed of a polydopamine (PDA) core and a multifunctional surface. PDA has excellent biosafety and photothermal performance. In this study, alendronate sodium (ALN) is grafted to enable its general bone targeting function. PDA core can carry a variety of chemotherapy drugs, and the rich ALN group can carry a variety of metal ions with an imaging function. Therefore, more personalized treatment plans can be designed for different bone tumor patients. In addition, the PDA core enables photothermal therapy and enhanced chemotherapy. Through template drug Doxorubicin (DOX) and template imaging ion Fe (Ⅱ), we systematically verified the therapeutic effect, imaging effect, and inhibition of bone dissolution of the agent on Osteosarcoma (OS), a primary malignant bone tumor, in vivo. In conclusion, our work provides a more general template carrier for the clinical treatment of bone tumors, through which personalized treatment of bone tumors can be achieved.