GPNMB is expressed in osteosarcoma and targeting GPNMB with the antibody-drug conjugate glembatumumab vedotin demonstrates osteosarcoma cytotoxic activity. Clinical trials are indicated to assess the efficacy of targeting GPNMB in patients with osteosarcoma.
Background Leukopenia is a frequent complication following kidney transplantation. Granulocyte colony‐stimulating factor (G‐CSF) has been used to accelerate white blood cell (WBC) count recovery; however, published experience in kidney transplantation is limited. Methods We retrospectively reviewed our kidney transplant recipients from January 2012 to September 2016 with a G‐CSF order to evaluate leukopenia management (defined as WBC <3000 cells/μL). Results Thirty‐six recipients were included. On average, G‐CSF treatment began at 98 ± 38 days. At G‐CSF initiation, mean WBC count was 1240 ± 420 cells/μL and absolute neutrophil count (ANC) was 653 ± 368 cells/μL. Mean G‐CSF dose was 4.6 ± 1.2 mcg/kg/dose (total 11.8 ± 9.0 mcg/kg), 77.8% of recipients were prescribed G‐CSF as outpatients, and overall, median time to WBC count recovery was 9 (IQR 4‐14) days. Changes in immunosuppression and prophylaxis regimens for leukopenia were also common. Within 1 month following leukopenia onset, no patients experienced acute rejection and 5 (14%) developed infection requiring hospitalization or opportunistic infection. Conclusion In kidney recipients with leukopenia, G‐CSF may be helpful to achieve WBC count recovery in addition to changes in immunosuppression and prophylaxis medications. Prospective, randomized data are still needed to determine optimal G‐CSF dosing in this population.
Primary hyperoxaluria type 1 is a rare genetic condition characterized by oxalate deposition in the kidneys. We report findings of an 8-month old female presenting with failure to thrive, poor oral intake, and kidney stones resulting in the diagnosis of primary hyperoxaluria type 1. The patient exhibits a unique presentation without renal failure at the time of diagnosis suggesting a previously unreported comorbidity in early stages of disease.
Despite numerous clinical trials to improve outcomes for osteosarcoma treatment, there has been no significant improvement in cure rates over the last three decades. Glycoprotein NMB (GPNMB), also known as osteoactivin, is a transmembrane glycoprotein that is expressed in various normal cell types including osteoclasts and osteoblasts, and plays a role in development and differentiation, respectively. Studies have also shown that GPNMB is highly expressed in cancers including breast cancers and melanomas. CDX-011 is an antibody-drug conjugate that targets the GPNMB protein. A human monoclonal antibody glembatumumab is linked to monomethyl auristatin E, an antimitotic agent. Recent studies have shown the drug is effective in treating patients with metastatic triple- negative GPNMB-expressing breast cancer, and melanoma. The pediatric preclinical testing program (PPTP) has recently shown the drug is efficacious in xenograft models of osteosarcoma. In this study, we explore the feasibility of GPNMB as a target for antibody-mediated therapy in osteosarcoma and assess the anti-tumor effects of CDX-011. Since CDX-011 activity appears to correlate with GPNMB protein expression, a cohort of osteosarcoma tissue sections from patients at the time of initial biopsy, definitive surgery, and recurrence was stained immunohistochemically to determine the presence or absence of GPNMB protein. The majority of samples show positive staining suggesting further that osteosarcoma might be a candidate for CDX-011 treatment. Flow cytometry was performed on human osteosarcoma xenografts and cell lines to determine the surface expression level of GPNMB prior to treatment with CDX-011. Of the 9 cell lines studied, 5 lines showed high surface expression of GPNMB protein. Cytotoxicity assays were performed on the same 9 cell lines representing both high and low GPNMB surface expression patterns to determine the in vitro effectiveness of CDX-011 in osteosarcoma cell lines and its correlation with GPNMB expression. IC50 on those cell lines ranged from 3.5- 56 µM. Three out of 5 cell lines, which showed high GPNMB surface expression pattern, demonstrated lower IC50 (3- 14 µM) compared to the others. These findings suggest that CDX-011 may be a potential targeted treatment in osteosarcoma patients with elevated GPNMB expression patterns. In addition, further studies are ongoing, including quantitative PCR for GPNMB gene expression, and ELISA to further validate expression of GPNMB protein to better understand the mechanism of CDX-011 in osteosarcoma. Citation Format: Sajida Piperdi, Vicky Kuo, Amy Park, Michael Roth, Richard Gorlick. Elucidating expression patterns of GPNMB and potential anti-tumor effects of the antibody-drug conjugate, glembatumumab vedotin (CDX-011) in human osteosarcoma primary samples and cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3984. doi:10.1158/1538-7445.AM2014-3984
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