Lessons from Tarceva in pancreatic cancer: where are we now, and how should future trials be designed in pancreatic cancer?

PURPOSE OF REVIEW: The recent advances in the use of targeted therapy in pancreatic cancer are based on the knowledge of genetic alterations that occur during pancreatic carcinogenesis. We describe the repository of frequent alterations targeting tumour suppressor genes and oncogenes. We focus our attention on the epidermal growth factor receptor signalling pathway, which can be activated through different alterations and seems to play a central role in the cell transformation. Multiple targeted drugs have been developed against different partners of this network trying to improve the treatment of pancreatic cancer patients. RECENT FINDINGS: Tarceva has obtained approval in the USA and Europe for metastatic pancreatic cancer with a modest increase of median survival and a 6% increase in 1-year survival rates, suggesting that only a small fraction of patients truly benefit from it. The comparison with lung and colon cancer suggests that Kras mutations could be a predictive marker of resistance. Other promising drugs targeting different partners of the epidermal growth factor receptor signalling pathway could play a synergistic role with Tarceva as inhibitors of mTOR, mitogen-activated protein kinase kinase 1, and nuclear factor-kappaB or can directly turn down Ras. SUMMARY: The biology of the epidermal growth factor receptor, mitogen-activated protein kinase, PI3K/mTOR network suggests that a combination of drugs targeting simultaneously different partners should improve survival

EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies), 2013 . Scientific Opinion on Rooster Combs Extract

Following a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to carry out the additional assessment for ‘Rooster Combs Extract’ (RCE) as a food ingredient in the context of Regulation (EC) No 258/97, taking into account the comments and objections of a scientific nature raised by Member States. Rooster combs extract results from a production process involving enzymatic hydrolysis of rooster combs and subsequent filtration, concentration and precipitation steps. The principle constituents of RCE are the glycosaminoglycans hyaluronic acid, chondroitin sulphate A and dermatan sulphate. The applicant intends to add RCE to a number of dairy products with a recommended maximum intake of 80 mg RCE per portion and per day. The target population is the general population, with the exception of pregnant women, children and people with adverse reactions to sodium hyaluronate and/or avian protein. In the high intake scenario for “consumers only”, the highest daily intake would occur in adults in Belgium (0.788 g). The highest intake scenario for “all subjects” was estimated for adolescents in Denmark (0.427 g/day). The Panel notes that no adverse effects were observed at the highest tested dose of 600 mg/kg bw per day in a 90-day oral toxicity study in rats. Considering the nature, the natural occurrence and previous consumption of RCE constituents, the Panel is of the opinion that the margin between the intended as well as the estimated maximum possible intake of RCE in relation to the highest dose administered to rats without adverse effects in a subchronic oral toxicity study is sufficient. The Panel concludes that the novel food ingredient, Rooster Comb Extract, is safe under the proposed uses and use levels

Is the gene encoding Chibby implicated as a tumour suppressor in colorectal cancer ?

BACKGROUND: A novel member of the Wnt signalling pathway, Chibby, was recently identified. This protein inhibits Wnt/β-catenin mediated transcriptional activation by competing with Lef-1 (the transcription factor and target of β-catenin) to bind to β-catenin. This suggests that Chibby could be a tumour suppressor protein. The C22orf2 gene coding Chibby is located on chromosome 22, a region recurrently lost in colorectal cancer. Activation of the Wnt pathway is a major feature of colorectal cancer and occurs through inactivation of APC or activation of β-catenin. All of this led us to analyse the possible implication of Chibby in colorectal carcinogenesis. METHODS: First, 36 tumour and matched normal colonic mucosa DNA were genotyped with five microsatellite markers located on chromosome 22 to search for loss of heterozygosity. Then, mutation screening of the C22orf2 coding sequence and splice sites was performed in the 36 tumour DNA. Finally, expression of Chibby was analysed by quantitative RT-PCR on 10 patients, 4 with loss of heterozygosity (LOH) on chromosome 22. RESULTS: Loss of heterozygosity involving the C22orf2 region was detected in 11 out of 36 patients (30%). Sequencing analysis revealed a known variant, rs3747174, in exon 5: T321C leading to a silent amino acid polymorphism A107A. Allelic frequencies were 0.69 and 0.31 for T and C variants respectively. No other mutation was detected. Among the 10 patients studied, expression analysis revealed that Chibby is overexpressed in 2 tumours and underexpressed in 1. No correlations were found with 22q LOH status. CONCLUSION: As no somatic mutation was detected in C22orf2 in 36 colorectal tumour DNA, our results do not support the implication of Chibby as a tumour suppressor in colorectal carcinogenesis. This was supported by the absence of underexpression of Chibby among the tumour samples with 22q LOH. The implication of other Wnt pathway members remains to be identified to explain the part of colorectal tumours without mutation in APC and β-catenin

Sensitivity to CPT-11 of xenografted human colorectal cancers as a function of microsatellite instability and p53 status

Biological parameters influencing the response of human colorectal cancers (CRCs) to CPT-11, a topoisomerase 1 (top1) inhibitor, were investigated using a panel of nine CRCs xenografted into nude mice. CRC xenografts differed in their p53 status (wt or mut) and in their microsatellite instability phenotype (MSI+when altered). Five CRC xenografts were established from clinical samples. All five had a functional p53, two were MSI+and three were MSI–. Tumour-bearing nude mice were treated intraperitonealy (i.p.) with CPT-11. At 10 mg kg–1of CPT-11, four injections at 4-day intervals, four of the five xenografts responded to CPT-11 (growth delay of up to 10 days); the non-responder tumour was MSI−. At 40 mg kg−1of CPT-11, six injections at 4-day intervals, the five CRCs displayed variable but marked responses with complete regressions. In order to assess the role of p53 status in CPT-11 response, four CRC lines were used. HT29 cell line was MSI−/ Ala273-mutp53, its subclone HT29A3 being transfected by wtp53. LoVo cell line was MSI+/ wtp53, its subclone X17LoVo dominantly expressed Ala273-mutp53 after transfection. LoVo tumours (MSI+/ mutp53) were more sensitive than X17LoVo (MSI+/ mutp53. HT 29 tumours (MSI−Imutp53), were refractory to CPT-11 while HT29A3 tumours (MSI−/ wtp53) were sensitive, showing that wtp53 improves the drug-response in these MSI−tumours. Levels of mRNA expression of top1, fasR, TP53 and mdr1 were semi-quantified by reverse transcription polymerase chain reaction. None of these parameters correlated with CPT-11 response. Taken together, these observations indicate that MSI and p53 alterations could be associated with different CPT-11 sensitivities; MSI phenotype moderately influences the CPT-11 sensitivity, MSI+being more sensitive than MSI−CRC freshly obtained from patients, mutp53 status being associated with a poor response to CPT-11. © 2000 Cancer Research Campaig

Review of the current status of RAS mutation testing in patients with metastatic colorectal cancer (mCRC): Flash-RAS study

Présentation PosterInternational audienceOBJECTIVES: In 2013, it was shown that mutations in KRAS exons 3 and 4, or NRAS exons 2 to 4 had a similar effect. The primary objective was to assess the practices in conducting RAS testing in 2014. The secondary objectives were to describe the evolution of the RAS testing prescription rates from 2011, the process and time required to obtain the results, and to analyze their impact on the therapeutic strategy. METHODS: FLASH-RAS is an observational retrospective French multicenter study. RESULTS: 375 mCRC patients diagnosed and initiating a 1st line treatment (L1) between March and June 2014 were analyzed. For 90.1% of the patients (IC95%= [87.1%; 93.2%]), a genotyping request for RAS biomarkers was made in L1, i.e. a significantly increased rate compared to 2011 (81.1% in 2011, p<0.001). For 75% of the patients, the request was made before or at least one month after the diagnosis of the first metastases (1st M). No increase was observed in the median and mean times to obtain the test results between 2011 and 2014 despite the increased number of exons tested. CONCLUSIONS: In 2014, the rate of RAS genotyping requests has been increasing since 2011. For a majority of patients, the request is made before or at the latest one month after 1st M diagnosis. Nevertheless, for 24.5% of the patients, the request is made more than one month after 1st M diagnosis, which is not compatible with an informed treatment decision in L1

Point mutations of the P53 gene, human hepatocellular carcinoma and aflatoxins

The tumor suppressor p53 exerts important protective functions towards DNA-damaging agents. Its inactivation by allelic deletions or point mutations within the P53 gene as well as complex formation of wildtype p53 with cellular or viral proteins is a common and crucial event in carcinogenesis. Mutations increase the half-life of the p53 protein allowing the immunohistochemical detection and anti-p53 antibody formation. Distinct G to T point mutations in codon 249 leading to a substitution of the basic amino acid arginine by the neutral amino acid serin are responsible for the altered functionality of the mutant gene product and were originally identified in 8 of 16 Chinese and 5 of 10 African HCC patients. Both groups are frequently exposed to mycotoxin contaminations of their food. Today an average P53 gene mutation rate of 25% is assumed for high-aflatoxin B1-exposure regions. This is double the rate observed in low-aflatoxin B1-exposure countries. Although many HCC patients displaying P53 mutations also suffer from HBV infection, which itself can lead to rearrangements of P53 coding regions or induce the synthesis of viral proteins possibly interacting with p53, the specific G to T transversion within codon 249 of the P53 gene seems to directly reflect the extent of aflatoxin B1 exposure

Complex interplay between β-catenin signalling and Notch effectors in intestinal tumorigenesis

International audienceAims The activation of β-catenin signalling is a key step in intestinal tumorigenesis. Interplay between the β-catenin and Notch pathways during tumorigenesis has been reported, but the mechanisms involved and the role of Notch remain unclear. Methods Notch status was analysed by studying expression of the Notch effector Hes1 and Notch ligands/receptors in human colorectal cancer (CRC) and mouse models of Apc mutation. A genetic approach was used, deleting the Apc and RBP-J or Atoh1 genes in murine intestine. CRC cell lines were used to analyse the control of Hes1 and Atoh1 by β-catenin signalling. Results Notch signalling was found to be activated downstream from β-catenin. It was rapidly induced and maintained throughout tumorigenesis. Hes1 induction was mediated by β-catenin and resulted from both the induction of the Notch ligand/receptor and Notch-independent control of the Hes1 promoter by β-catenin. Surprisingly, the strong phenotype of unrestricted proliferation and impaired differentiation induced by acute Apc deletion in the intestine was not rescued by conditional Notch inactivation. Hyperactivation of β-catenin signalling overrode the forced differention induced by Notch inhibition, through the downregulation of Atoh1, a key secretory determinant factor downstream of Notch. This process involves glycogen synthase kinase 3 β (GSK3β) and proteasome-mediated degradation. The restoration of Atoh1 expression in CRC cell lines displaying β-catenin activation was sufficient to increase goblet cell differentiation, whereas genetic ablation of Atoh1 greatly increased tumour formation in Apc mutant mice. Conclusion Notch signalling is a downstream target of β-catenin hyperactivation in intestinal tumorigenesis. However, its inhibition had no tumour suppressor effect in the context of acute β-catenin activation probably due to the downregulation of Atoh1. This finding calls into question the use of γ-secretase inhibitors for the treatment of CRC and suggests that the restoration of Atoh1 expression in CRC should be considered as a therapeutic approach

STRATEGIC-1: A multiple-lines, randomized, open-label GERCOR phase III study in patients with unresectable wild-type RAS metastatic colorectal cancer

International audienceBackground: The management of unresectable metastatic colorectal cancer (mCRC) is a comprehensive treatment strategy involving several lines of therapy, maintenance, salvage surgery, and treatment-free intervals. Besides chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), molecular-targeted agents such as anti-angiogenic agents (bevacizumab, aflibercept, regorafenib) and anti-epidermal growth factor receptor agents (cetuximab, panitumumab) have become available. Ultimately, given the increasing cost of new active compounds, new strategy trials are needed to define the optimal use and the best sequencing of these agents. Such new clinical trials require alternative endpoints that can capture the effect of several treatment lines and be measured earlier than overall survival to help shorten the duration and reduce the size and cost of trials. Methods/Design: STRATEGIC-1 is an international, open-label, randomized, multicenter phase III trial designed to determine an optimally personalized treatment sequence of the available treatment modalities in patients with unresectable RAS wild-type mCRC. Two standard treatment strategies are compared: first-line FOLFIRI-cetuximab, followed by oxaliplatin-based second-line chemotherapy with bevacizumab (Arm A) vs. first-line OPTIMOX-bevacizumab, followed by irinotecan-based second-line chemotherapy with bevacizumab, and by an anti-epidermal growth factor receptor monoclonal antibody with or without irinotecan as third-line treatment (Arm B). The primary endpoint is duration of disease control. A total of 500 patients will be randomized in a 1:1 ratio to one of the two treatment strategies.Discussion: The STRATEGIC-1 trial is designed to give global information on the therapeutic sequences in patients with unresectable RAS wild-type mCRC that in turn is likely to have a significant impact on the management of this patient population. The trial is open for inclusion since August 2013. Trial registration: STRATEGIC-1 is registered a

STRATEGIC-1: A multiple-lines, randomized, open-label GERCOR phase III study in patients with unresectable wild-type RAS metastatic colorectal cancer.

BACKGROUND: The management of unresectable metastatic colorectal cancer (mCRC) is a comprehensive treatment strategy involving several lines of therapy, maintenance, salvage surgery, and treatment-free intervals. Besides chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), molecular-targeted agents such as anti-angiogenic agents (bevacizumab, aflibercept, regorafenib) and anti-epidermal growth factor receptor agents (cetuximab, panitumumab) have become available. Ultimately, given the increasing cost of new active compounds, new strategy trials are needed to define the optimal use and the best sequencing of these agents. Such new clinical trials require alternative endpoints that can capture the effect of several treatment lines and be measured earlier than overall survival to help shorten the duration and reduce the size and cost of trials. METHODS/DESIGN: STRATEGIC-1 is an international, open-label, randomized, multicenter phase III trial designed to determine an optimally personalized treatment sequence of the available treatment modalities in patients with unresectable RAS wild-type mCRC. Two standard treatment strategies are compared: first-line FOLFIRI-cetuximab, followed by oxaliplatin-based second-line chemotherapy with bevacizumab (Arm A) vs. first-line OPTIMOX-bevacizumab, followed by irinotecan-based second-line chemotherapy with bevacizumab, and by an anti-epidermal growth factor receptor monoclonal antibody with or without irinotecan as third-line treatment (Arm B). The primary endpoint is duration of disease control. A total of 500 patients will be randomized in a 1:1 ratio to one of the two treatment strategies. DISCUSSION: The STRATEGIC-1 trial is designed to give global information on the therapeutic sequences in patients with unresectable RAS wild-type mCRC that in turn is likely to have a significant impact on the management of this patient population. The trial is open for inclusion since August 2013. TRIAL REGISTRATION: STRATEGIC-1 is registered at Clinicaltrials.gov: NCT01910610, 23 July, 2013. STRATEGIC-1 is registered at EudraCT-No.: 2013-001928-19, 25 April, 2013