Image-guided photo-therapeutic nanoporphyrin synergized HSP90 inhibitor in patient-derived xenograft bladder cancer model.

Photodynamic therapy is a promising and effective non-invasive therapeutic approach for the treatment of bladder cancers. Therapies targeting HSP90 have the advantage of tumor cell selectivity and have shown great preclinical efficacy. In this study, we evaluated a novel multifunctional nanoporphyrin platform loaded with an HSP90 inhibitor 17AAG (NP-AAG) for use as a multi-modality therapy against bladder cancer. NP-AAG was efficiently accumulated and retained at bladder cancer patient-derived xenograft (PDX) over 7 days. PDX tumors could be synergistically eradicated with a single intravenous injection of NP-AAG followed by multiple light treatments within 7 days. NP-AAG mediated treatment could not only specifically deliver 17AAG and produce heat and reactive oxygen species, but also more effectively inhibit essential bladder cancer essential signaling molecules like Akt, Src, and Erk, as well as HIF-1α induced by photo-therapy. This multifunctional nanoplatform has high clinical relevance and could dramatically improve management for bladder cancers with minimal toxicity.

HSP90 Inhibitor Encapsulated Photo-Theranostic Nanoparticles for Synergistic Combination Cancer Therapy.

Photodynamic therapy (PDT) is a promising non-invasive therapeutic modality that has been proposed for treating prostate cancer, but the procedure is associated with limited efficacy, tumor recurrence and photo-toxicity. In the present study, we proposed to develop a novel multifunctional nano-platform for targeted delivery of heat, reactive oxygen species (ROS) and heat shock protein 90 (Hsp90) inhibitor simultaneously for combination therapy against prostate cancer. This new nano-platform combines two newly developed entities: 1) a unique organic and biocompatible nanoporphyrin-based drug delivery system that can generate efficient heat and ROS simultaneously with light activation at the tumor sites for dual-modal photothermal- and photodynamic- therapy (PTT/PDT), and 2) new nano-formulations of Hsp90 inhibitors that can decrease the levels of pro-survival and angiogenic signaling molecules induced by phototherapy, therefore, further sensitizing cancer cells to phototherapy. Furthermore, the nanoparticles have activatable near infrared (NIR) fluorescence for optical imaging to conveniently monitor the real-time drug delivery in both subcutaneous and orthotopic mouse models bearing prostate cancer xenograft. This novel multifunctional nano-platform has great potential to improve the care of prostate cancer patients through targeted combination therapy.

Prognostic Value of SETD2 Expression in Patients with Metastatic Renal Cell Carcinoma Treated with Tyrosine Kinase Inhibitors.

PURPOSE: Mutations of SETD2 occur in 3% to 16% of clear cell renal cell carcinoma cases. Previous studies identified an association between SETD2 mutation and prognosis of patients with nonmetastatic clear cell renal cell carcinoma. In this study we explored the prognostic and predictive value of SETD2 expression in patients with metastatic renal cell carcinoma treated with targeted therapy. MATERIALS AND METHODS: We retrospectively enrolled 138 patients with metastatic renal cell carcinoma treated with sunitinib or sorafenib at a single institution from 2007 to 2014. SETD2 expression was assessed by immunohistochemistry on tissue microarrays. RESULTS: After excluding those patients with loss of followup or unavailable tissue samples, 111 were included in the study. Low SETD2 expression was associated with reduced overall survival (p <0.001) and progression-free survival (p=0.001). After adjustment for histological type, Heng risk group and drugs used for targeted therapy, SETD2 was defined as an independent prognostic marker for overall survival (HR 2.535 [95% CI 1.429-4.497], p=0.001) and progression-free survival (HR 1.755 [95% CI 1.031-2.988], p=0.038). Its prognostic value for overall survival was more predominant in patients with clear cell renal cell carcinoma (p <0.001) or patients in the intermediate risk group of Heng risk criteria (p <0.001), while its predictive value for progression-free survival was more predominant in patients treated with sorafenib (p <0.001). SETD2 could also be combined with the Heng risk model for better overall survival prediction. CONCLUSIONS: SETD2 is a potential prognostic biomarker for overall survival and progression-free survival prediction in patients with metastatic renal cell carcinoma receiving targeted therapy. However, it remains to be seen whether this is generalizable to other ethnicities and prospective external validation is required.