Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Phase I dose-escalation study of SCB01A, a microtubule inhibitor with vascular disrupting activity, in patients with advanced solid tumors

[[abstract]]LESSONS LEARNED: SCB01A is a novel microtubule inhibitor with vascular disrupting activity. This first-in-human study demonstrated SCB01A safety, pharmacokinetics, and preliminary antitumor activity. SCB01A is safe and well-tolerated in patients with advanced solid malignancies with manageable neurotoxicity. BACKGROUND: SCB01A, a novel microtubule inhibitor, has vascular disrupting activity (VDA). METHODS: In this phase I dose-escalation and extension study, patients with advanced solid tumors were administered intravenous SCB01A infusions for 3 hours once every 21 days. Rapid titration and a 3+3 design escalated the dose from 2 mg/m(2) to the maximum tolerated dose (MTD) based on dose-limiting toxicity (DLT). SCB01A-induced cellular neurotoxicity was evaluated in dorsal root ganglion cells. The primary endpoint was MTD. Safety, pharmacokinetics (PK), and tumor response were secondary endpoints. RESULTS: Treatment-related adverse events included anemia, nausea, vomiting, fatigue, fever, and peripheral sensorimotor neuropathy. DLTs included grade (G)4 elevated creatine phosphokinase (CPK) in the 4 mg/m(2) cohort; G3 gastric hemorrhage in the 6.5 mg/m(2) cohort; G2 thromboembolic event in the 24 mg/m(2) cohort; G3 peripheral sensorimotor neuropathy, G3 elevated aspartate aminotransferase, and G3 hypertension in the 32 mg/m(2) cohort. The MTD was 24 mg/m(2) , and average half-life was ~2.5 hours. The area under the curve-dose response relationship was linear. Nineteen subjects were stable after two cycles. The longest treatment lasted 24 cycles. SCB01A-induced neurotoxicity was reversible in vitro. CONCLUSION: The MTD of SCB01A was 24 mg/m(2) every 21 days; it is safe and tolerable in patients with solid tumors

Randomised clinical trial: Comparison of two everolimus dosing schedules in patients with advanced hepatocellular carcinoma

[[abstract]]Background: Deregulation of mammalian target of rapamycin (mTOR) signalling is common in human hepatocellular carcinoma (HCC). Aim: To determine the maximum tolerated dose (MTD) of the oral mTOR inhibitor everolimus in advanced HCC patients. Methods: Patients with locally advanced or metastatic HCC (Child-Pugh class A or B) were enrolled in an open-label phase 1 study and randomly assigned to daily (2.5–10 mg) or weekly (20–70 mg) everolimus in a standard 3 + 3 dose-escalation design. MTD was based on the rate of dose-limiting toxicities (DLTs). Secondary endpoints included safety, pharmacokinetics and tumour response. In a post hoc analysis, serum hepatitis B virus (HBV) DNA levels were quantified. Results: Thirty-nine patients were enrolled. DLTs occurred in five of 21 patients in the daily and two of 19 patients in the weekly cohort. Daily and weekly MTDs were 7.5 mg and 70 mg respectively. Grade 3/4 adverse events with a ≥10% incidence were thrombocytopenia, hypophosphataemia and alanine transaminase (ALT) elevation. In four hepatitis B surface antigen (HBsAg)-seropositive patients, grade 3/4 ALT elevations were accompanied by significant (>1 log) increases in serum HBV levels. The incidence of hepatitis flare (defined as ALT increase >100 IU/mL from baseline) in HBsAg-seropositive patients with and without detectable serum HBV DNA before treatment was 46.2% and 7.1% respectively (P < 0.01, Fisher exact test). Disease control rates in the daily and weekly cohorts were 71.4% and 44.4% respectively. Conclusions: The recommended everolimus dosing schedule for future hepatocellular carcinoma studies is 7.5 mg daily. Prophylactic anti-viral therapy should be mandatory for HBsAg-seropositive patients

Pulmonary embolism after transcatheter arterial chemoembolization

[[abstract]]Metastatic hepatic tumours can be treated with hepatic transcatheter arterial chemoembolization (TACE). Common complications associated with TACE include hepatic insufficiency, fever, and pain. However, pulmonary embolism is rarely documented as a fatal adverse effect. We report a case of pulmonary embolism following TACE in a renal cell carcinoma patient with liver metastases. Total recovery is noted after the effective treatment

Inhibition of cell growth and nuclear factor-kappa B activity in pancreatic cancer cell lines by a tylophorine analogue, DCB-3503

[[abstract]]A tylophorine analogue, DCB-3503, has been shown to have potent activity against tumor growth in vitro and in vivo, as well as activity in an autoimmune disease model in vivo. This study focuses on investigating the mechanisms responsible for antitumor activity of DCB-3503. The concentrations for inhibiting 50% growth/colony formation ability are 50/162 and 40/149 nmol/L for PANC-1 and HPAC cells, respectively. The growth inhibition effects are associated with DCB-3503-induced reprogramming of tumor cells. DCB-3503 could interfere with cell cycle progression. Several cell cycle regulatory proteins, including cyclin D-1, are down-regulated by DCB-3503. Using several different transcription elements coupled with a reporter gene, it was found that the nuclear factor-kappa B (NF-kappa B) signaling pathway is the most sensitive pathway mediator affected by DCB-3503. The inhibition of NF-kappa B activity is dependent on the down-regulation of nuclear phosphorylated p65, a component of the active form of the NF-kappa B complex. Such a decrease in nuclear phosphorylated p65 can be reversed by a proteosome inhibitor. Furthermore, the activity and protein expression of nuclear I kappa B kinase alpha, which is responsible for p65 phosphorylation, is suppressed and down-regulated in cells treated with DCB-3503. In summary, DCB-3503 could affect cell cycle regulatory proteins and is a potent modulator of NF-kappa B function. It is a potentially useful compound in the management of cancers in which cyclin D1 overexpression and high NF-kappa B activity play a pivotal role

Phase I and pharmacokinetic study of oral thalidomide in patients with advanced hepatocellular carcinoma

[[abstract]]Purpose: To evaluate the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics of thalidomide in patients with advanced hepatocellular carcinoma (HCC). Methods: Patients with advanced HCC who were not feasible for definitive local therapy were eligible. Patients were enrolled in a cohort of three to receive thalidomide twice daily for 1 week to determine the MTD. Intra-patient dose escalation was permitted. Pharmacokinetic studies were performed at the first dose level and repeated at the second dose level of each patient. Results: Fifteen patients were accrued at four dose levels with the starting dose range 100-400 mg/day. Two patients at 400 mg/day experienced DLT (grade 3 angioedema and dyspnea, respectively). The MTD of twice-daily schedule was determined as 300 mg/day. The mean steady-state maximal blood concentration and mean steady-state area under the curve had a trend toward positive correlation, but non-linear proportionate, to the daily dose of thalidomide. Pharmacokinetic parameters are comparable for patients of Child-Pugh's A and B. Apparent mild, transient drug-induced transaminitis was early onset, self-limited, which occurred in 30.7% of patients. Serum hepatitis B or C viral titers was largely not affected. Conclusion: The absorption and elimination of thalidomide are not significantly different in HCC patients with compensated or decompensated hepatic dysfunction

Phase I-II trial of weekly gemcitabine plus high-dose 5-fluorouracil and leucovorin in advanced pancreatic cancer

[[abstract]]Background: Pancreatic cancer is a dismal disease. Few drugs, including gemcitabine and 5-fluorouracil (5-FU), have notable antitumor effects against advanced pancreatic cancer. The purpose of the present study was to determine the maximum tolerated dose (MTD) of 5-FU and the efficacy and toxicity profile of weekly gemcitabine plus infusional 5-FU/leucovorin in advanced pancreatic cancer. Methods: Patients with histo-/cytologically confirmed, advanced pancreatic cancer were eligible. Treatment consisted of a 30-min infusion of gemcitabine (800 mg/m(2)), followed by a 24-h infusion of 5-FU and leucovorin (300 mg/m(2)) at day 1, day 8 and day 15 every 28 days, and was termed the GemFL(24) regimen. The dose of 5-FU was escalated from 1600, 2000, to 2600 mg/m(2) in the phase I study, and fixed MTD for subsequent enrolled patients. Results: Eighteen patients were enrolled in the phase I study, and 24 in phase II. The MTD of 5-FU was 2000 mg/m(2), with major dose-limiting toxicities being febrile neutropenia and delayed recovery from neutropenia. The dose intensity of gemcitabine of the 35 patients with 5-FU dosage set at MTD was 593 mg/m(2) per week. In the entire series of 42 patients, myelosuppression was the main toxicity, with grade 3 neutropenia in eight patients, and grade 3/4 thrombocytopenia in six. On an intention-to-treat analysis, the overall and clinical benefit response rates were 22% and 46%, respectively; with median progression-free and overall survival of 4.1 and 6.9 months, respectively. Conclusions: The GemFL(24) regimen is a feasible and moderately active treatment with manageable toxicities for advanced pancreatic cancer, and could be a basis for further combination with other anticancer drugs. (C) 2005 Blackwell Publishing Asia Pty Ltd