Results of TRIO-14, a phase II, multicenter, randomized, placebo-controlled trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-ganitumab in newly diagnosed epithelial ovarian cancer.

PURPOSE: Insulin-like growth factor (IGF) signaling is implicated in pathogenesis and chemotherapy resistance of epithelial ovarian cancer (EOC). We explored efficacy and safety of adding ganitumab, a monoclonal antibody targeting IGF-1R, to carboplatin/paclitaxel (CP) chemotherapy in patients with primary EOC. DESIGN: Patients were randomly assigned to receive CP/ganitumab (18 mg/kg q3w) or CP/placebo for 6 cycles followed by 6 cycles of single agent ganitumab/placebo maintenance therapy as front-line therapy. Primary endpoint was progression free survival. Secondary endpoints were time to progression and overall survival. Pretreatment samples were prospectively collected for retrospective biomarker analyses. RESULTS: 170 patients enrolled. 165 patients assessable for toxicity. Median PFS was 15.7 months with CP/ganitumab and 16.7 months with CP/placebo (HR 1.23; 95% CI 0.82-1.83, P = 0.313). All grade neutropenia (84.1% vs 71.4%), thrombocytopenia (75.3% vs 57.1%) and hyperglycemia (15.9% vs 2.6%) were more common in the ganitumab group compared to the placebo group. Ganitumab/placebo related serious adverse events were reported in 26.1% of the patients with ganitumab and in 6.5% with placebo. Non-progression related fatal events were more common with ganitumab (5 versus 2 patients). The ganitumab group experienced more dose delays which resulted in lower relative dose intensity of chemotherapy in the experimental group. In an exploratory model IGFBP2 expression was predictive of ganitumab response (treatment interaction; PFS, P = 0.03; OS, P = 0.01). CONCLUSION: Addition of ganitumab to CP chemotherapy in primary EOC did not improve PFS. Our results do not support further study of ganitumab in unselected EOC patients.

Prioritizing therapeutic targets using patient-derived xenograft models.

Effective systemic treatment of cancer relies on the delivery of agents with optimal therapeutic potential. The molecular age of medicine has provided genomic tools that can identify a large number of potential therapeutic targets in individual patients, heralding the promise of personalized treatment. However, determining which potential targets actually drive tumor growth and should be prioritized for therapy is challenging. Indeed, reliable molecular matches of target and therapeutic agent have been stringently validated in the clinic for only a small number of targets. Patient-derived xenografts (PDXs) are tumor models developed in immunocompromised mice using tumor procured directly from the patient. As patient surrogates, PDX models represent a powerful tool for addressing individualized therapy. Challenges include humanizing the immune system of PDX models and ensuring high quality molecular annotation, in order to maximize insights for the clinic. Importantly, PDX can be sampled repeatedly and in parallel, to reveal clonal evolution, which may predict mechanisms of drug resistance and inform therapeutic strategy design.

A parallel-arm phase I trial of the humanised anti-IGF-1R antibody dalotuzumab in combination with the AKT inhibitor MK-2206, the mTOR inhibitor ridaforolimus, or the NOTCH inhibitor MK-0752, in patients with advanced solid tumours.

BACKGROUND: Two strategies to interrogate the insulin growth factor 1 receptor (IGF-1R) pathway were investigated: vertical inhibition with dalotuzumab and MK-2206 or ridaforolimus to potentiate PI3K pathway targeting and horizontal cross-talk inhibition with dalotuzumab and MK-0752 to exert effects against cellular proliferation, angiogenesis, and stem cell propagation. METHODS: A phase I, multi-cohort dose escalation study was conducted in patients with advanced solid tumours. Patients received dalotuzumab (10 mg kg(-1)) and escalating doses of MK-2206 (90-200 mg) or escalating doses of dalotuzumab (7.5-10 mg kg(-1)) and MK-0752 (1800 mg) weekly. Upon maximum tolerated dose determination, patients with low-RAS signature, high-IGF1 expression ovarian cancer were randomised to dalotuzumab/MK-2206 versus dalotuzumab/ridaforolimus, whereas patients with high IGF1/low IGF2 expression colorectal cancer received dalotuzumab/MK-0752. RESULTS: A total of 47 patients were enrolled: 29 in part A (18 in the dalotuzumab/MK-2206 arm and 11 in the dalotuzumab/MK-0752 arm) and 18 in part B (6 in each arm). Dose-limiting toxicities (DLTs) for dalotuzumab/MK-2206 included grade 4 neutropenia and grade 3 serum sickness-like reaction, maculopapular rash, and gastrointestinal inflammation. For dalotuzumab/MK-0752, DLTs included grade 3 dehydration, rash, and diarrhoea. Seven patients remained on study for >4 cycles. CONCLUSIONS: Dalotuzumab/MK-2206 and dalotuzumab/MK-0752 combinations were tolerable. Further developments of prospectively validated predictive biomarkers to aid in patient selection for anti-IGF-1R therapies are needed.

Epithelial ovarian cancer experimental models.

Epithelial ovarian cancer (OvCa) is associated with high mortality and, as the majority (>75%) of women with OvCa have metastatic disease at the time of diagnosis, rates of survival have not changed appreciably over 30 years. A mechanistic understanding of OvCa initiation and progression is hindered by the complexity of genetic and/or environmental initiating events and lack of clarity regarding the cell(s) or tissue(s) of origin. Metastasis of OvCa involves direct extension or exfoliation of cells and cellular aggregates into the peritoneal cavity, survival of matrix-detached cells in a complex ascites fluid phase and subsequent adhesion to the mesothelium lining covering abdominal organs to establish secondary lesions containing host stromal and inflammatory components. Development of experimental models to recapitulate this unique mechanism of metastasis presents a remarkable scientific challenge, and many approaches used to study other solid tumors (for example, lung, colon and breast) are not transferable to OvCa research given the distinct metastasis pattern and unique tumor microenvironment (TME). This review will discuss recent progress in the development and refinement of experimental models to study OvCa. Novel cellular, three-dimensional organotypic, and ex vivo models are considered and the current in vivo models summarized. The review critically evaluates currently available genetic mouse models of OvCa, the emergence of xenopatients and the utility of the hen model to study OvCa prevention, tumorigenesis, metastasis and chemoresistance. As these new approaches more accurately recapitulate the complex TME, it is predicted that new opportunities for enhanced understanding of disease progression, metastasis and therapeutic response will emerge.

[Massive localized lymphedema: a reactive lesion simulating liposarcoma (case report]. / Masívny lokalizovaný lymfedém: reaktívna lézia simulujúca liposarkóm (Kazuistika).

The authors present a case-history of massive localized lymphedema in a 54 year old female patient (height 167 cm, weight 113 kg). The history of the lymphedema lasted about 1 year. Its growth was not accompained with subjective complaints. It was diagnosed as a pendulous tumor of soft tissues in the thigh, 70 x 65 cm large. In preoperative diagnosis it was classified as a liposarcoma. The tumor lesion was removed and sent for bioptic examinations. Both histological and immunohistochemical biopsies denied benign or malignant nature of the soft tissue tumors and confirmed the diagnosis of a massive localized lymphedema.

Farnesyl transferase inhibitors as anticancer agents.

Protein farnesylation catalysed by the enzyme farnesyl protein transferase involves the addition of a 15-carbon farnesyl group to conserved amino acid residues at the carboxyl terminus of certain proteins. Protein substrates of farnesyl transferase include several G-proteins, which are critical intermediates of cell signalling and cytoskeletal organisation such as Ras, Rho, PxF and lamins A and B. Activated Ras proteins trigger a cascade of phosphorylation events through sequential activation of the PI3 kinase/AKT pathway, which is critical for cell survival, and the Raf/Mek/Erk kinase pathway that has been implicated in cell proliferation. Ras mutations which encode for constitutively activated proteins are found in 30% of human cancers. Because farnesylation of Ras is required for its transforming and proliferative activity, the farnesyl protein transferase inhibitors were designed as anticancer agents to abrogate Ras function. However, current evidence suggests that the anticancer activity of the farnesyl transferase inhibitors may not be simply due to Ras inhibition. This review will discuss available clinical data on three of these agents that are currently undergoing clinical trials.

[Massive localized lymphedema in an extremely obese patient]. / Massives lokalisiertes Lymphödem einer extrem fettleibigen Patientin.

Soft tissue tumors are commonly encountered in all surgical departments. The authors present a case of a very rare large tumor lesion, with macroscopic signs of liposarcoma.

Receptor tyrosine kinase inhibitors.

Receptor tyrosine kinases (RTKs) are a diverse group of transmembrane proteins involved in signal transduction. Their function in many cell types is to drive a wide variety of cellular functions, including growth, differentiation and angiogenesis, by transducing growth factor signals from the external milieu to intracellular processes. In malignancies, these pathways are often exploited by tumor cells to optimize tumor growth and metastasis. Indeed, alterations in RTK pathways have been implicated in oncogenic activation, tumor angiogenesis and mitogenic stimulation. Thus, RTKs are logical targets for novel anticancer agent development. There are currently a large number of small-molecule RTK antagonists in phase I to III clinical development. These agents inhibit the intracellular tyrosine kinase activity of receptors for epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF). The biology and results of clinical trials with these agents will be discussed.

Novel pharmacological agents in clinical development for solid tumours.

For decades, cancer therapy has focused on DNA-directed mechanisms of cytotoxicity, utilising agents with limited efficacy and significant toxicity. Recent advances in tumour biology have elucidated the molecular pathways implicated in the pathogenesis and progression of cancers and have resulted in the discovery of a variety of novel molecular targets for therapeutic intervention. Promising novel agents targeting signal transduction pathways, cell cycle regulation, angiogenesis and apoptosis are in clinical testing and are discussed in this review.

Interaction between human topoisomerase I and a novel RING finger/arginine-serine protein.

The N-terminus of human topoisomerase I participates in the binding of this enzyme to helicases and other proteins. Using the N-terminal 250 amino acids of human topoisomerase I and a yeast two-hybrid/ in vitro binding screen, a novel arginine-serine-rich peptide was identified as a human topoisomerase I-binding protein. The corresponding full-length protein, named topors, contains a consensus RING zinc finger domain and nuclear localization signals in addition to the arginine-serine-rich region. The RING finger domain of topors is homologous to a similar domain in a family of viral proteins that are involved in the regulation of viral transcription. When expressed in HeLa cells as a green fluorescent protein fusion, topors localizes in the nucleus in a punctate pattern and co-immunoprecipitates with topoisomerase I. These data suggest that topors is involved in trans-cription, possibly recruiting topoisomerase I to RNA polymerase II transcriptional complexes.

Topoisomerase-I inhibitors in gynecologic tumors.

The first section of this article reviews recent studies that have clarified both the cellular role of topoisomerase I and the mechanisms of cytotoxicity of the topoisomerase inhibitors, the camptothecins. Different analogs of this new class of antitumor drug have been studied using various dose schedules in the treatment of refractory or recurrent gynecologic cancer. Response rates are between 13% and 25%. The main toxic effects are hematologic and gastrointestinal, the latter remains problematic. Radiotherapy, alkylate, platinum analogues, and topoisomerase II inhibitors are currently being studied in combination with camptothecins.

A role for the amino terminus of human topoisomerase I.

These studies indicate that SV40T antigen binds the amino terminus of human top1 both in vitro and in vivo. Additional in vitro data suggest that the interaction between these two proteins does not require DNA as an intermediary. Taken together with the finding that the amino terminus of top 1 binds the putative helicase nucleolin, these results implicate helicase binding as a general function of the amino terminus of human top1. Binding of top1 by helicases may be important in the management of structural alterations in DNA produced by helicases. The potential importance of helicase-topoisomerase interactions has been highlighted by recent data indicating that the protein defective in Bloom's syndrome is a helicase with a yeast homologue that is known to bind topoisomerases.

High-performance liquid chromatographic quantitation of total and lactone 20(S)camptothecin in patients receiving oral 20(S)camptothecin.

We have developed a sensitive high-performance liquid chromatography (HPLC) assay to quantitate total and lactone forms of 20(S)camptothecin (CPT) in human plasma. Lactone and total CPT were extracted using solid-phase extraction and liquid-liquid extraction, respectively. The extracted lactone samples could be stored without immediate HPLC analysis. The two forms of CPT were quantitated by reversed-phase HPLC with fluorescence detection. The extraction efficiencies were about 100% and 92% for the total and lactone forms, respectively. The lower limit of quantitation was 5.74 nM for the two forms. The method was reproducible with a mean interday and intraday variability of 6% for total CPT and 4% and 6%. respectively, for lactone CPT. The assay could effectively quantitate lactone and total CPT in patients receiving single dose and multiple doses of oral CPT.

Interaction between the N-terminus of human topoisomerase I and SV40 large T antigen.

We have attempted to identify human topoisomerase I-binding proteins in order to gain information regarding the cellular roles of this protein and the cytotoxic mechanisms of the anticancer drug camptothecin, which specifically targets topoisomerase I. In the course of this work we identified an interaction between the N-terminus of human topoisomerase I and the SV40 T antigen that is detectable in vitro using both affinity chromatography and co-immunoprecipitation. Additional results indicate that this interaction does not require intermediary DNA or stoichiometric quantities of other proteins. Furthermore, the interaction is detectable in vivo using a yeast two-hybrid assay. Two binding sites for T antigen are apparent on the topoisomerase I protein: one consisting of amino acids 1-139, the other present in the 383-765 region of the protein. Interestingly, nucleolin, which binds the 166-210 region of topoisomerase I, is able to bind an N-terminal fragment of topoisomerase I concurrently with T antigen. Taken together with our prior identification of nucleolin as a topoisomerase I-binding protein, the current results suggest that helicase-binding is a major role of the N-terminus of human topoisomerase I and that the resultant helicase-topoisomerase complex may function as a eukaryotic gyrase.

Involvement of amino acids 361 to 364 of human topoisomerase I in camptothecin resistance and enzyme catalysis.

Camptothecins are antineoplastic drugs that specifically target the enzyme DNA topoisomerase I. Prior work has identified a human topoisomerase I mutation, F361S, that confers resistance to camptothecin. We now demonstrate that substitutions in the 361-364 region can alter DNA cleavage/ligation by the enzyme. The defective catalysis exhibited by certain mutants likely relates to an impaired interaction with DNA, since these enzymes are more sensitive to the inhibitory effects of DNA binding ligands. Moreover, studies with peptides and fusion proteins suggest that the 361-364 region may bind DNA directly. The finding that the 361-364 region is involved in both enzyme catalysis and camptothecin resistance suggests that this region is part of the active site of human topoisomerase I and that camptothecin may interact with the enzyme at this site.