FGF401, A First-In-Class Highly Selective and Potent FGFR4 Inhibitor for the Treatment of FGF19-Driven Hepatocellular Cancer.

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and it is the third leading cause of cancer-related deaths worldwide. Recently, aberrant signaling through the FGF19/FGFR4 axis has been implicated in HCC. Here, we describe the development of FGF401, a highly potent and selective, first in class, reversible-covalent small-molecule inhibitor of the kinase activity of FGFR4. FGF401 is exquisitely selective for FGFR4 versus the other FGFR paralogues FGFR1, FGFR2, FGFR3, and all other kinases in the kinome. FGF401 has excellent drug-like properties showing a robust pharmacokinetic/pharmacodynamics/efficacy relationship, driven by a fraction of time above the phospho-FGFR4 IC90 value. FGF401 has remarkable antitumor activity in mice bearing HCC tumor xenografts and patient-derived xenograft models that are positive for FGF19, FGFR4, and KLB. FGF401 is the first FGFR4 inhibitor to enter clinical trials, and a phase I/II study is currently ongoing in HCC and other solid malignancies.

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.

Evaluation of somatostatin receptor subtype expression in human neuroendocrine tumors using two sets of new monoclonal antibodies.

INTRODUCTION: The expression and reliable detection of somatostatin receptor subtypes (SSTR1-5) is a prerequisite for the successful use of somatostatin analogs in neuroendocrine tumors (NETs). Two sets of monoclonal antibodies (mAbs) against human SSTR1, 2A, 3 and 5 have recently been developed by two independent laboratories using rabbit and mouse hybridomas. Our aim was to evaluate the usefulness of both sets of mAbs for detection of SSTRs in NET samples as they are routinely collected in clinical practice. METHODS: Mouse and rabbit mAbs were characterized in SSTR1, 2A, 3 and 5-transfected HEK293 cells and human archival samples of pancreatic tissue and NET. Comparative analysis of mAbs was also conducted by immunostaining of a tissue microarray composed of 75 cores of NET. RESULTS: Immunohistochemical analysis of HEK293 cells showed that both rabbit and mouse mAbs specifically detect their cognate receptor subtype, with mild cytoplasmic cross-reactivity observed for rabbit mAbs. Both sets of mAbs labeled normal pancreatic islets and showed similar patterns of immunoreactivity in NET controls. Direct comparison of mAb sets using a NET tissue microarray revealed strong correlation between rabbit and mouse mAbs against SSTR1 and 5, and moderate correlation for SSTR3. The rabbit mAb against SSTR2A showed higher affinity for its cognate receptor than the corresponding mouse mAb, resulting in a more reliable detection of this SSTR. CONCLUSIONS: mAbs from both sets are reliable tools for the detection of SSTR1, 3 and 5, whereas the rabbit mAb against SSTR2A is recommended for use in routine clinical testing due to its superior binding affinity.

Monoclonal antibodies against the human somatostatin receptor subtypes 1-5: development and immunohistochemical application in neuroendocrine tumors.

BACKGROUND: 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 prevents routine identification of the sstr expression profile in patients. METHODS: We generated and characterized new mouse monoclonal antibodies (mAbs) targeting the five human sstr subtypes using ELISA and immunohistochemistry, and tested their suitability in formalin-fixed and paraffin-embedded (FFPE) human tissues and archival samples of normal pancreatic tissue and NET. RESULTS: All mAbs were highly specific with no cross-reactivity. The sstr1-5 immunoreactivity in gastrointestinal NET (n=67) was correlated with clinicopathologic data. With the exception of sstr3, NET were highly positive for all receptor subtypes (42, 63, 6, 32 and 65% of tumors were positive for sstr1, sstr2a, sstr3, sstr4 and sstr5, respectively). sstr1, sstr2a and sstr5 were present at the plasma membrane and in the cytoplasm of tumor cells, whereas sstr3 and sstr4 were almost exclusively cytoplasmic. Immunoreactivity of sstr1, sstr2a and sstr4 tended to decrease as tumor aggressiveness increased. sstr5 showed an opposite pattern, with higher staining in well-differentiated carcinomas compared with well-differentiated tumors. sstr5 immunoreactivity was correlated with the presence of metastases and angioinvasion, suggesting a possible association with more aggressive behavior. CONCLUSION: Determination of the sstr1-5 by immunohistochemistry using subtype-specific mAbs is feasible in FFPE tissue and may provide a tool for routine clinical practice.