The Public Repository of Xenografts enables discovery and randomized phase II-like trials in mice

More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment, called the Public Repository of Xenografts (PRoXe). PRoXe includes all de-identified information relevant to the primary specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease

Monoclonal antibodies against the human somatostatin receptor subtypes 1–5: Development and immunohistochemical application in neuroendocrine tumors

Activation of somatostatin receptors (sstr1–5) by somatostatin and its analogues exerts an inhibitory effect on hormone secretion and provides the basis for the treatment of a range of endocrine diseases, such as acromegaly, Cushing’s disease and neuroendocrine tumors (NET). The lack of well characterized commercially available sstr subtype-specific antibodies, however, has prevented a routine expression profile of sstrs in patients. To address this need, we generated and characterized new mouse monoclonal antibodies (mAbs) targeting the five human sstr subtypes. All mAbs were tested intensively by ELISA and immunohistochemistry for specificity and were found to selectively recognize their cognate receptor subtype with no cross-reactivity. The suitability of the mAbs to investigate sstrs expression in formalin-fixed and paraffin-embedded (FFPE) human tissues was then demonstrated by staining archival samples of normal pancreatic tissue and NET. The expression profile of sstr1–5 using these mAbs was analyzed using tissue microarray technology in a series of gastrointestinal neuroendocrine tumors (NET) (n=67) and correlated with clinicopathologic data. With the exception of sstr3, all receptor subtypes were expressed in NET (54%, 83%, 0%, 54% and 63% of tumors were positive for sstr1, sstr2a, sstr3, sstr4 and sstr5, respectively), with sstr1, sstr2a and sstr5 being present both at the plasma membrane and in the cytoplasm of tumor cells. Protein levels of sstr1, sstr2a and sstr4 tended to decrease as tumor aggressiveness increased, while sstr5 showed an opposite pattern, with higher expression in well differentiated carcinomas compared with well differentiated tumors. Similarly, a correlation between sstr5 expression and the presence of metastases and angioinvasion was demonstrated, suggesting the possible involvement of this specific receptor subtype in more aggressive behavior in NET. Further data are required to confirm this hypothesis. We conclude that determination of the sstr1–5 expression profile by immunohistochemistry using subtype-specific mAbs is feasible in FFPE tissue. This finding suggests new opportunities to explore the significance of sstr expression in the development and progression of NET providing a tool for routine clinical practice

The Public Repository of Xenografts enables discovery and randomized phase II-like trials in mice

More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment, called the Public Repository of Xenografts (PRoXe). PRoXe includes all de-identified information relevant to the primary specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease