Viral Particle-Mediated SAMHD1 Depletion Sensitizes Refractory Glioblastoma to DNA-Damaging Therapeutics by Impairing Homologous Recombination.

The current standard-of-care treatment for glioblastoma includes DNA damaging agents, γ-irradiation (IR) and temozolomide (TMZ). These treatments fail frequently and there is limited alternative strategy. Therefore, identifying a new therapeutic target is urgently needed to develop a strategy that improves the efficacy of the existing treatments. Here, we report that tumor samples from GBM patients express a high level of SAMHD1, emphasizing SAMHD1's importance. The depletion of SAMHD1 using virus-like particles containing Vpx, VLP(+Vpx), sensitized two independent GBM cell lines (LN-229 and U-87) to veliparib, a well-established PARP inhibitor, and slowed cell growth in a dose-dependent manner. In the mouse GBM xenograft model, Vpx-mediated SAMHD1 depletion reduced tumor growth and SAMHD1 knockout (KO) improved survival. In combination with IR or TMZ, SAMHD1 KO and exposure to 50% growth inhibitory dose (gID50) of VLP(+Vpx) displayed a synergistic effect, resulting in impaired HR, and improved LN-229 cells' sensitivity to TMZ and IR. In conclusion, our finding demonstrates that SAMHD1 promotes GBM resistance to treatment, and it is a plausible therapeutic target to improve the efficacy of TMZ and IR in GBM. Furthermore, we show that Vpx could be a potential therapeutic tool that can be utilized to deplete SAMHD1 in GBM.

Surgical excision of benign papillomas diagnosed with core biopsy: a community hospital approach.

Our goal was to assess the value of surgical excision of benign papillomas of the breast diagnosed on percutaneous core biopsy by determining the frequency of upgrade to malignancies and high risk lesions on a final surgical pathology. We reviewed 67 patients who had biopsies yielding benign papilloma and underwent subsequent surgical excision. Surgical pathology of the excised lesions was compared with initial core biopsy pathology results. 54 patients had concordant benign core and excisional pathology. Cancer (ductal carcinoma in situ and invasive ductal carcinoma) was diagnosed in five (7%) patients. Surgery revealed high-risk lesions in 8 (12%) patients, including atypical ductal hyperplasia, atypical lobular hyperplasia, and lobular carcinoma in situ. Cancer and high risk lesions accounted for 13 (19%) upstaging events from benign papilloma diagnosis. Our data suggests that surgical excision is warranted with core pathology of benign papilloma.