25 research outputs found
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
Investigation of serotonin type 4 receptor expression in human and non-human primate gastrointestinal samples.
BACKGROUND: The serotonin type 4 (5-HT4) receptor has been associated with functions of the gastrointestinal tract such as modulation of the peristaltic reflex, smooth muscle tone, intestinal secretion and visceral sensitivity. The activation of peripheral 5-HT4 receptors with agonists such as tegaserod has been shown to accelerate gastric emptying and improve symptoms of constipation in animals and humans. However, detailed data on the expression profile and on the localization of this receptor subtype are lacking so far. OBJECTIVE: To study the pattern and expression levels of 5-HT4 receptor messenger RNA expression in the gut. METHOD: Normal tissue samples were collected from the whole gastrointestinal tract of patients undergoing abdominal surgery and, in addition, of monkeys. We performed a comprehensive analysis of 5-HT4 receptor expression by quantitative reverse transcription-polymerase chain reaction, using human and non-human primate tissues from the oesophagus to the rectum. In addition, the brain and heart of non-human primates were analysed. RESULTS: Significantly higher levels of 5-HT4 receptor mRNA were measured in the human stomach, duodenum, jejunum, ileum and caecum and also in the corresponding non-human primate gut segments, ranging from 2- to 12-fold compared with the liver. No differences were found between females and males of both human and non-human primates. CONCLUSIONS: These results show 5-HT4 receptor mRNA expression throughout the gastrointestinal tract in humans and primates, and also support the preclinical and clinical findings of 5-HT4 receptors ligands exhibiting multiple effects throughout the gastrointestinal tract
Comprehensive Mapping of p53 Pathway Alterations Reveals an Apparent Role for Both SNP309 and MDM2 Amplification in Sarcomagenesis
Comprehensive mapping of p53 pathway alterations in sarcomas reveals an apparent role for MDM2 SNP309 in sarcomagenesis
Re-activation of p53 tumour suppressor activity in diseases such as soft tissue sarcomas is considered an attractive means of targeted therapy. To assess the pattern of mutations affecting the p53 pathway, we have comprehensively mapped mutational events in a panel of 192 bone and soft-tissue sarcomas. These include TP53 and CDKN2A mutational and SNP status, MDM2 and MDM4 amplification and MDM2 SNP309 status. Overall, we found an inverse relationship between MDM2 amplification and TP53 mutations in our samples. Although CDKN2A exon and gene deletions were observed, ARF was found to be predominantly wild-type. Alternatively, a high rate of point mutations in TP53 was observed in leiomyosarcoma and osteosarcoma. Our data show the expected high level of MDM2 amplification in well- and de-differentiated liposarcomas, as well subtype specific patterns. Similarly, MDM4 was amplified in a subtype specific manner. Notably, MDM2 and MDM4 amplification events were found to be frequently associated. We have also analysed the risk allele frequencies for MDM2 SNP309, and show that homozygosity for the G SNP was strongly associated with both liposarcomas and MDM2 amplification. Moreover, our data on a set of tumour-matched normal controls indicates a clear directional progression of the MDM2 SNP309 G allele in tumour samples. In summary, our data suggest that at least 70% of sarcomas sustain some type of genetic alterations in the p53 pathway, of which most impinge on either MDM2 or MDM4. We propose, therefore, that these tumour types should be suitable candidates for trials of MDM2 antagonists
Inhibition of wild-type p53-expressing AML by novel small molecule HDM2 inhibitor, CGM097
The tumor suppressor, p53, is a key regulator of apoptosis and functions upstream in the apoptotic cascade by both indirectly and directly regulating Bcl-2 family proteins. In cells expressing wild-type (wt) p53, the Human Double Minute 2 (HDM2) protein binds to p53 and blocks its activity. Inhibition of HDM2:p53 interaction activates p53 and causes apoptosis or cell cycle arrest. We have characterized the novel HDM2 inhibitor, CGM097, as having significant activity against wt p53-expressing acute myeloid leukemia (AML). Specifically, CGM097 potently and selectively inhibited the proliferation of human AML cell lines and primary AML cells expressing wt p53, but not mutant p53, in a target-specific manner. Several patient samples that harbored mutant p53 were comparatively unresponsive to CGM097. Synergy was observed when CGM097 was combined with FLT3 inhibition against mutant FLT3-expressing cells, as well as when combined with MEK inhibition in cells with activated MAPK signaling. Finally, CGM097 was effective in reducing leukemia burden in vivo. Taken together, these data suggest that CGM097 might be a promising treatment for AML characterized as harboring wt p53 as a single agent, as well as possibly in combination with another targeted therapy using tyrosine kinase inhibitors (TKIs) against oncogenes that drive AML
Fibroblast growth factor receptors as novel therapeutic targets in malignant rhabdoid tumors
Malignant rhabdoid tumors (MRTs) are highly aggressive pediatric cancers arising in brain, kidney and soft tissues, which are characterized by loss of the tumor suppressor SNF5. MRTs are poorly responsive to chemotherapy and thus a high unmet clinical need exists for novel therapies for MRT patients. SNF5 is a core subunit of the SWI/SNF chromatin remodeling complex which affects gene expression by nucleosome remodeling. In this study, we report that loss of SNF5 function correlates with increased expression of fibroblast growth factor receptors (FGFRs) in MRT cell lines and primary tumor samples and that re-expression of SNF5 in MRT cell lines causes a striking repression of FGFR expression. Conversely, siRNA-mediated impairment of SWI/SNF function leads to elevated levels of FGFR2 in human fibroblast. In vivo, treatment with NVP-BGJ398, a novel selective, pan-specific FGFR inhibitor, blocks progression of a MRT allograft derived from a SNF5-deficient mouse model. Hence, we identify FGFR signaling as an aberrantly activated oncogenic pathway in MRTs and propose pharmacological inhibition of FGFRs as a potential novel clinical therapy for MRTs
Comprehensive Mapping of p53 Pathway Alterations Reveals an Apparent Role for Both SNP309 and MDM2
A conditional inducible JAK2V617F transgenic mouse model reveals myeloproliferative disease that is reversible upon switching off transgene expression
Aberrant activation of the JAK/STAT pathway is thought to be the critical event in the pathogenesis of the chronic myeloproliferative neoplasms (MPNs) polycythemia vera, essential thrombocythemia and primary myelofibrosis. The most frequent genetic alteration in these pathologies is the activating JAK2V617F mutation, and expression of the mutant gene in mouse models was shown to cause a phenotype resembling the human diseases. Given the body of genetic evidence, it has come as a sobering finding that JAK inhibitor therapy only modestly suppresses the JAK2V617F allele burden, despite showing clear benefits in terms of reducing splenomegaly and constitutional symptoms in patients. To gain a better understanding if JAK2V617F is required for maintenance of myeloproliferative disease once it has evolved, we generated a conditional inducible transgenic JAK2V617F mouse model using the SCL-tTA-2S tet-off system. Our model corroborates that expression of JAK2V617F in hematopoietic stem and progenitor cells recapitulates key hallmarks of human MPNs, and exhibits gender differences in disease manifestation. The disease was found to be transplantable, and importantly, reversible when transgenic JAK2V617F expression was switched off. Our results indicate that mutant JAK2V617F-specific inhibitors should result in profound disease modification by disabling the MPN clone bearing mutant JAK2
FGFR genetic alterations predict for response to NVP-BGJ398, a selective pan-FGFR inhibitor in Phase I clinical trials
Patient stratification biomarkers that enable the translation of cancer genetic knowledge into clinical utility are essential for the successful and rapid development of emerging targeted anti-cancer therapeutics. Here we describe the identification of patient stratification biomarkers for NVP-BGJ398, a novel and selective FGFR inhibitor. By intersecting genome-wide gene expression and genomic alteration data with cell line sensitivity data across an annotated collection of cancer cell lines termed the “Cancer Cell Line Encyclopedia”, we show that genetic alterations for FGFR family members predict for sensitivity to NVP-BGJ398 in specific cancer types, thus providing the rationale for clinical trials in well defined subpopulations of cancer patients with tumors harboring these molecular abnormalities