The presence of disseminated tumour cells (DTCs) in BM predicts poorer metastasis-free survival of breast cancer patients with localized disease. DTCs persist in distant tissues despite systemic administration of adjuvant chemotherapy. Many assume this is because the majority of DTCs are quiescent. Here, we challenge this notion and provide evidence that the microenvironment of DTCs protects them from chemotherapy, independent of cell cycle status. We show that chemoresistant DTCs occupy the perivascular niche (PVN) of distant tissues, where they are protected from therapy by vascular endothelium. Inhibiting integrin-mediated interactions between DTCs and the PVN, driven partly by endothelial-derived von Willebrand Factor and vascular cell adhesion molecule-1, sensitizes DTCs to chemotherapy. Importantly, chemosensitization is achieved without inducing DTC proliferation or exacerbating chemotherapy-associated toxicities, and ultimately results in prevention of bone metastasis. This suggests that prefacing adjuvant therapy with integrin inhibitors is a viable clinical strategy to eradicate DTCs and prevent metastasis.
Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells have shown promising clinical responses in patients with relapsed/refractory multiple myeloma. Lenalidomide, an immunomodulatory drug, potentiates T cell functionality, drives antimyeloma activity, and alters the suppressive microenvironment; these properties may effectively combine with anti-BCMA CAR T cells to enhance function. Using an anti-BCMA CAR T, we demonstrated that lenalidomide enhances CAR T cell function in a concentration-dependent manner. Lenalidomide increased CAR T effector cytokine production, particularly under low CAR stimulation or in the presence of inhibitory ligand programmed cell death 1 ligand 1. Notably, lenalidomide also enhanced CAR T cytokine production, cytolytic activity, and activation profile relative to untreated CAR T cells in chronic stimulation assays. This unique potentiation of both short-term CAR T activity and long-term functionality during chronic stimulation prompted investigation of the molecular profile of lenalidomide-treated CAR T cells. Signatures from RNA sequencing and assay for transposase-accessible chromatin using sequencing indicated that pathways associated with T-helper 1 response, cytokine production, T cell activation, cell-cycle control, and cytoskeletal remodeling were altered with lenalidomide. Finally, study of lenalidomide and anti-BCMA CAR T cells in a murine, disseminated, multiple myeloma model indicated that lenalidomide increased CAR T cell counts in blood and significantly prolonged animal survival. In summary, preclinical studies demonstrated that lenalidomide potentiated CAR T activity in vivo in low-antigen or suppressive environments and delayed onset of functional exhaustion. These results support further investigation of lenalidomide and anti-BCMA CAR T cells in the clinic.
The zebrafish (Danio rerio) was used to investigate protein expression in the liver following arsenic exposure. Several disorders have been linked to arsenic exposure, including cancer, diabetes, and cardiovascular disease. The mechanisms of arsenic toxicity are poorly understood. Prior studies have described altered gene expression, inflammation, and mitogenic signaling in acute or chronic exposure models. A proteomic approach was employed to investigate arsenic-induced alteration in the zebrafish liver proteome following a 7-day exposure to 50 ppb sodium arsenite. Over 740 unique proteins were identified, with fewer than 2% showing differential expression. Molecular pathway analysis software identified lipid metabolism and transport as potential molecular targets. Immunoblots were used to confirm protein expression changes, whereas qPCR was employed to investigate gene expression changes. Overall, 25 proteins were differentially expressed in a gender-specific manner, 11 in males and 14 in females. Of these 25, a single protein, hydroxysteroid dehydrogenase like 2, showed decreased expression in both males and females following arsenic exposure. These findings indicate that protein expression is altered following arsenic exposure. The changes presented here seem to be most prevalent in lipid transport and metabolic pathways, suggesting a potential increase in fibrosis in males and decreased lipid accumulation and uptake in females.
Small cell lung cancer comprises 15-20% of all lung cancer cases, and is more invasive and has a higher rate of proliferation with respect to non-small cell lung cancer, leading to a higher mortality rate. Most cases are responsive to chemotherapy, however there is a high rate of recurrence with treated patients and those in advanced stage of the disease often have a refractory response to treatment. As such, the need for new treatment modalities is critical. Use of patient-derived tumor xenograft (PDX) models as clinically-relevant preclinical model for novel drug development has gained widespread adoption in recent years. In previous work, we have reported using the Molecular Response tumor bank, comprising >144,000 viable tumor specimens, to establish more than 100 PDX models of various cancer types. In this work, we describe the development of 8 new SCLC PDX models established from a collection of >300 small cell lung cancer specimens, many of which come from prior-treated and metastatic patients. We report a comprehensive characterization of these models, including: histopathology, immunohistochemistry, and mutation analysis by next-generation sequencing. Additionally, we have evaluated functional response of these models with in vivo pharmacology studies. Current studies are underway to derive correlations between in vivo drug response and mutational status of these models. Our data strongly suggests the potential to use these unique PDX models to aid in efforts in drug development efforts in oncology. Citation Format: Patrick Carlson, Jill Ricono, Chelsea Mullins, Thomas Broudy, Cyrus Mirsaidi, Praveen Nair. Establishment of patient-derived xenograft (PDX) models for small cell lung cancer (SCLC) as a preclinical platform for drug development. [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 1189. doi:10.1158/1538-7445.AM2014-1189
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