Genome-wide study of genetic polymorphisms predictive for outcome from first-line oxaliplatin-based chemotherapy in colorectal cancer patients.

We conducted the first large genome-wide association study to identify novel genetic variants that predict better (or poorer) prognosis in colorectal cancer patients receiving standard first-line oxaliplatin-based chemotherapy vs chemotherapy without oxaliplatin. We used data from two phase III trials, NCCTG N0147 and NCCTG N9741 and a population-based patient cohort, DACHS. Multivariable Cox proportional hazards models were employed, including an interaction term between each SNP and type of treatment for overall survival (OS) and progression-free survival. The analysis was performed for studies individually, and the results were combined using fixed-effect meta-analyses separately for resected stage III colon cancer (3098 patients from NCCTG N0147 and 549 patients from DACHS) and mCRC (505 patients from NCCTG N9741 and 437 patients from DACHS). We further performed gene-based analysis as well as in silico bioinformatics analysis for CRC-relevant functional genomic annotation of identified loci. In stage III colon cancer patients, a locus on chr22 (rs11912167) was associated with significantly poorer OS after oxaliplatin-based chemotherapy vs chemotherapy without oxaliplatin (Pinteraction < 5 × 10-8 ). For mCRC patients, three loci on chr1 (rs1234556), chr12 (rs11052270) and chr15 (rs11858406) were found to be associated with differential OS (P < 5 × 10-7 ). The locus on chr1 located in the intronic region of RCSD1 was replicated in an independent cohort of 586 mCRC patients from ALGB/SWOG 80405 (Pinteraction = .04). The GWA gene-based analysis yielded for RCSD1 the most significant association with differential OS in mCRC (P = 6.6 × 10-6 ). With further investigation into its biological mechanisms, this finding could potentially be used to individualize first-line treatment and improve clinical outcomes.

Extensive Peritonectomy is an Independent Risk Factor for Cisplatin HIPEC-Induced Acute Kidney Injury.

BACKGROUND: Cisplatin (CDDP)-containing hyperthermic intraperitoneal chemotherapy (HIPEC) is frequently applied in selected patients with peritoneal malignancies derived from ovarian cancer, gastric cancer, and primary peritoneal mesothelioma. HIPEC with CDDP increases perioperative morbidity, in particular by inducing acute kidney injury (AKI). Factors contributing to occurrence of AKI after intraperitoneal perfusion with CDDP have not been sufficiently evaluated. PATIENTS AND METHODS: Data from 63 patients treated with a CDDP-containing HIPEC regimen were retrospectively analyzed concerning demographics, underlying disease, surgery, and HIPEC details to evaluate risk factors of AKI. A preclinical rat perfusion model was applied to assess the influence of temperature, concentration, perfusate volume, perfusion flow rate, and extent of peritonectomy on drug absorption upon intraperitoneal CDDP perfusion. RESULTS: AKI occurred in 66.1% of patients undergoing CDDP-containing HIPEC, with total intraoperative fluid influx being a negative and the extent of parietal peritonectomy being a positive independent predictor of postoperative AKI. In a preclinical model, bilateral anterior parietal peritonectomy significantly increased systemic CDDP absorption by 1.6 to 2-fold. CDDP plasma levels in animals were significantly higher after both perfusion with increased CDDP perfusate concentrations and bilateral anterior parietal peritonectomy. CONCLUSION: CDDP-containing HIPEC is associated with relevant morbidity owing to its systemic toxicity. Extent of parietal peritonectomy is an independent predictor of AKI. CDDP dose reduction should be considered in case of extensive parietal peritonectomy. Cytostatic drug concentrations in HIPEC perfusate should be paid more attention to than total dose per body surface area. Further clinical studies are needed to confirm the presented preclinical findings.

Circulating B-vitamin biomarkers and B-vitamin supplement use in relation to quality of life in patients with colorectal cancer: results from the FOCUS consortium.

BACKGROUND: B vitamins have been associated with the risk and progression of colorectal cancer (CRC), given their central roles in nucleotide synthesis and methylation, yet their association with quality of life in established CRC is unclear. OBJECTIVES: To investigate whether quality of life 6 months postdiagnosis is associated with: 1) circulating concentrations of B vitamins and related biomarkers 6 months postdiagnosis; 2) changes in these concentrations between diagnosis and 6 months postdiagnosis; 3) B-vitamin supplement use 6 months postdiagnosis; and 4) changes in B-vitamin supplement use between diagnosis and 6 months postdiagnosis. METHODS: We included 1676 newly diagnosed stage I-III CRC patients from 3 prospective European cohorts. Circulating concentrations of 9 biomarkers related to the B vitamins folate, riboflavin, vitamin B6, and cobalamin were measured at diagnosis and 6 months postdiagnosis. Information on dietary supplement use was collected at both time points. Health-related quality of life (global quality of life, functioning scales, and fatigue) was assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 6 months postdiagnosis. Confounder-adjusted linear regression analyses were performed, adjusted for multiple testing. RESULTS: Higher pyridoxal 5'-phosphate (PLP) was cross-sectionally associated with better physical, role, and social functioning, as well as reduced fatigue, 6 months postdiagnosis. Associations were observed for a doubling in the hydroxykynurenine ratio [3-hydroxykynurenine: (kynurenic acid + xanthurenic acid + 3-hydroxyanthranilic acid + anthranilic acid); an inverse marker of vitamin B6] and both reduced global quality of life (ß = -3.62; 95% CI: -5.88, -1.36) and worse physical functioning (ß = -5.01; 95% CI: -7.09, -2.94). Dose-response relations were observed for PLP and quality of life. No associations were observed for changes in biomarker concentrations between diagnosis and 6 months. Participants who stopped using B-vitamin supplements after diagnosis reported higher fatigue than nonusers. CONCLUSIONS: Higher vitamin B6 status was associated with better quality of life, yet limited associations were observed for the use of B-vitamin supplements. Vitamin B6 needs further study to clarify its role in relation to quality of life.

Impact of Perfusate Concentration on Hyperthermic Intraperitoneal Chemotherapy Efficacy and Toxicity in a Rodent Model.

BACKGROUND: Cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC) has been shown to be beneficial in treating limited peritoneal carcinomatosis (PC) from colorectal cancer (CRC). Perfusate volume directly affects treatment concentration and therefore is a key parameter defining HIPEC; yet little is known about the impact of perfusate concentration on systemic toxicity and treatment morbidity. MATERIALS AND METHODS: PC was induced through intraperitoneal injection of human CRC cell lines. A novel perfusion model was developed to treat athymic nude mice with continuous circulation of adequately miniaturized volumes of heated perfusate. Oxaliplatin HIPEC was performed applying different volumes of perfusate with fixed doses or fixed concentrations. Early postoperative mortality and morbidity were assessed as well as long-term survival. In addition, antiproliferative and proapoptotic effects of HIPEC were determined in vitro and in vivo. RESULTS: Perfusate concentration crucially affected the toxicity of fixed-dose oxaliplatin HIPEC as indicated by postoperative weight loss and early postoperative mortality. Applying different perfusate volumes at a fixed concentration did not influence toxicity. Adequately miniaturized HIPEC with oxaliplatin did not exert relevant cytotoxic effects toward PC arising from human CRC cells in vivo. CONCLUSIONS: We describe a novel murine model that adequately miniaturizes all physical parameters of HIPEC as applied in humans. HIPEC drug concentration is a crucial parameter determining excess toxicity and should be better standardized. HIPEC with oxaliplatin fails to induce relevant antitumor activity or to improve survival in this murine model of PC from CRC.

Green tea component EGCG, insulin and IGF-1 promote nuclear efflux of atrophy-associated transcription factor Foxo1 in skeletal muscle fibers.

Prevention and slowing of skeletal muscle atrophy with nutritional approaches offers the potential to provide far-reaching improvements in the quality of life for our increasingly aging population. Here we show that polyphenol flavonoid epigallocatechin 3-gallate (EGCG), found in the popular beverage green tea (Camellia sinensis), demonstrates similar effects to the endogenous hormones insulin-like growth factor 1 (IGF-1) and insulin in the ability to suppress action of the atrophy-promoting transcription factor Foxo1 through a net translocation of Foxo1 out of the nucleus as monitored by nucleo-cytoplasmic movement of Foxo1-green fluorescent protein (GFP) in live skeletal muscle fibers. Foxo1-GFP nuclear efflux is rapid in IGF-1 or insulin, but delayed by an additional 30 min for EGCG. Once activated, kinetic analysis with a simple mathematical model shows EGCG, IGF-1 and insulin all produce similar apparent rate constants for Foxo1-GFP unidirectional nuclear influx and efflux. Interestingly, EGCG appears to have its effect at least partially via parallel signaling pathways that are independent of IGF-1's (and insulin's) downstream PI3K/Akt/Foxo1 signaling axis. Using the live fiber model system, we also determine the dose-response curve for both IGF-1 and insulin on Foxo1 nucleo-cytoplasmic distribution. The continued understanding of the activation mechanisms of EGCG could allow for nutritional promotion of green tea's antiatrophy skeletal muscle benefits and have implications in the development of a clinically significant parallel pathway for new drugs to target muscle wasting and the reduced insulin receptor sensitivity which causes type II diabetes mellitus.

Grants4Targets - an innovative approach to translate ideas from basic research into novel drugs.

Collaborations between industry and academia are steadily gaining importance. To combine expertises Bayer Healthcare has set up a novel open innovation approach called Grants4Targets. Ideas on novel drug targets can easily be submitted to http://www.grants4targets.com. After a review process, grants are provided to perform focused experiments to further validate the proposed targets. In addition to financial support specific know-how on target validation and drug discovery is provided. Experienced scientists are nominated as project partners and, depending on the project, tools or specific models are provided. Around 280 applications have been received and 41 projects granted. According to our experience, this type of bridging fund combined with joint efforts provides a valuable tool to foster drug discovery collaborations.

The target discovery process.

In order to minimise attrition rates in drug development projects, a target discovery process is implemented to select and characterise the most suitable candidate kinase targets, before lead identification and lead optimisation are embarked upon. The process consists of 1) target selection, 2) target assessment, and 3) target validation. This rational approach to target discovery, as a prerequisite for lead discovery, ensures that new therapeutic targets fulfil a set of general criteria, as well as indication-specific, descriptive and functional ones. The approach should ultimately maximise the likelihood of achieving target-selective inhibition by small-molecule inhibitors with minimal in vivo side effects and a therapeutic effect based on a sound biological hypothesis.