The Identification Of Novel Therapies For The Treatment Of Follicular Dendritic Cell Sarcoma
BLOOD(2015)
摘要
Introduction Follicular dendritic cell sarcoma (FDCS) is a rare malignant neoplasm arising from dendritic cells of the lymphoid follicles. The inciting event that leads to the development of malignancy remains unknown. The prevalent therapeutic approach involves surgical excision with the possibility of radiation therapy. However, most initial responders develop eventual recurrence. Furthermore, due to the rarity of the malignancy, there are no official recommendations for optimal FDCS therapy. To further elucidate possible therapies for FDCS, we assessed the effects of multiple agents in vitro on the cell viability of patient primary cells and employed our patient-derived xenograft (PDX) model to validate the efficacy of these agents in an in vivo model system. Methods A 53-year-old female with highly metastatic FDCS, who had been refractory to multiple treatments, presented at the hospital with hypotension, weakness, and anorexia. FDCS samples were isolated from the patient9s pleural fluid, and an in vitro primary patient cell culture was established and a subset of the patient cells were engrafted into SCID mice implanted with a human fetal bone chip to create the PDX model. A series of in vitro drug screens conducted with MTS cell viability and Annexin V apoptosis assays identified the therapies that decreased the cell viability of these cells. After passaging the cells for 3 generations, and based on the in vitro results, the mice were administered intravenous treatment with DMSO control (1%, n=2), bortezomib (0.5 mg/kg, n=3), carfilzomib (1 mg/kg, n=3), or combination bortezomib with CTX (0.5 mg/kg and 10 mg/kg, respectively, n=3) twice a week for 3 weeks. The average days of survival, tumor volume, and tumor mass were determined in vivo . Results The clinical pathology report showed that the FDCS case was rare, with the immunophenotypes CD21 - CD23 - and weakly positive CD35, which was also confirmed in our PDX model. The MTS assay demonstrated that the proteasome inhibitors carfilzomib and bortezomib as well as Bruton9s tyrosine kinase inhibitor ibrutinib and the SINE XP01 antagonist KPT-330 inhibited the growth of the freshly isolated FDCS cells derived from either the patient or the PDX mice. The Annexin V-binding assay demonstrated carfilzomib, bortezomib, and KPT-330 significantly induced apoptosis of both the patient and PDX-derived FDCS cells. CTX is the primary chemotherapy drug administered to FDCS patients; therefore, we combined CTX with bortezomib, the most effective anti-tumor drug observed in our in vitro studies, to investigate the therapeutic effects of this novel combination in our PDX model. Our in vivo results validated the in vitro data and demonstrated that the bortezomib and CTX combination therapy significantly inhibited tumor growth in PDX mice compared with the proteasome inhibitors bortezomib or carfilzomib alone. Conclusion The data presented here suggest the potential of utilizing parallel in vitro drug screening and in vivo PDX tumor studies to determine possible therapies for rare malignancies. The combination therapy of bortezomib and CTX is a promising modality to treat relapsed FDCS. However, the patient died of hypotension and weakness after receiving bortezomib plus CHOP. Disclosures Pham: Amgen, Onyx, Millennium: Research Funding. Wang: Janssen: Honoraria; Pharmacyclics, Janssen, Celgene, Oncopep, Kite, Juno: Research Funding.
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sarcoma,novel therapies
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