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The family of human angiopoietins comprises factors with important roles in vascular development and angiogenesis. All angiopoietins bind with similar affinity to the endothelial cell-specific receptor, Tie2. The mechanism by which they contribute to angiogenesis is thought to involve regulation of endothelial cell interactions with supporting perivascular cells. In this study the genomic structures of all three human angiopoietins were characterised by direct sequencing of human genomic DNA from the appropriate P1 artificial chromosome (PAC) clones. The exact positions at the intron/exon boundaries and the lengths of all eight introns were determined. As would be expected from the homology of these three proteins, the positions of the introns in the three genes are highly conserved. The putative RNA transcription start site for each angiopoietin gene was also determined. Intron-specific primers were used to amplify each exon of angiopoietin-1 and angiopoietin-2 from individual genomic DNAs. Although no polymorphism has been detected in the coding region of angiopoietin-1, three independent polymorphisms have been identified for angiopoietin-2. Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The recently discovered Angiopoietin family is comprised of four growth factors thought to be very important for vascular development. All four angiopoetins bind to the endothelial cell-specific receptor Tie-2 with similar affinity. The mechanism by which these proteins contribute to angiogenesis is thought to involve regulation of endothelial cell interactions with supporting perivascular cells. Angiopoietin 3 and angiopoietin 4 appear to represent rapidly diverging orthologs in mouse and man, with disparate expression profiles and differing abilities to activate the Tie-2 receptor.

Introduction: The undiminished need for more effective cancer treatments stimulates the development of novel cancer immunotherapy candidates. The archetypical cancer immunotherapy would induce robust, targeted and long-lasting immune responses while simultaneously circumventing immunosuppression in the tumour microenvironment. For this purpose, we developed a novel immunomodulatory nanomedicine: PRECIOUS-01. As a PLGA-based nanocarrier, PRECIOUS-01 encapsulates a tumour antigen (NY-ESO-1) and an invariant natural killer T cell activator to target and augment specific antitumour immune responses in patients with NY-ESO-1-expressing advanced cancers., Methods and Analysis: This open-label, first-in-human, phase I dose-escalation trial investigates the safety, tolerability and immune-modulatory activity of increasing doses of PRECIOUS-01 administered intravenously in subjects with advanced NY-ESO-1-expressing solid tumours. A total of 15 subjects will receive three intravenous infusions of PRECIOUS-01 at a 3-weekly interval in three dose-finding cohorts. The trial follows a 3+3 design for the dose-escalation steps to establish a maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D). Depending on the toxicity, the two highest dosing cohorts will be extended to delineate the immune-related parameters as a readout for pharmacodynamics. Subjects will be monitored for safety and the occurrence of dose-limiting toxicities. If the MTD is not reached in the planned dose-escalation cohorts, the RP2D will be based on the observed safety and immune-modulatory activity as a pharmacodynamic parameter supporting the RP2D. The preliminary efficacy will be evaluated as an exploratory endpoint using the best overall response rate, according to Response Evaluation Criteria in Solid Tumors V.1.1., Ethics and Dissemination: The Dutch competent authority (CCMO) reviewed the trial application and the medical research ethics committee (CMO Arnhem-Nijmegen) approved the trial under registration number NL72876.000.20. The results will be disseminated via (inter)national conferences and submitted for publication to a peer-reviewed journal., Trial Registration Number: NCT04751786., Competing Interests: Competing interests: IW is an employee of iOx Therapeutics and has stock ownership., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

There has been great interest over the past two decades in developing gene therapies (GTs) to treat a variety of diseases; however, translating research findings into clinical treatments have proved to be a challenge. A major milestone in the development of GT has been achieved with the approval of alipogene tiparvovec (Glybera(®)) in Europe for the treatment of familial lipoprotein lipase deficiency. At this important stage with the evolution of GT into the clinic, this review will examine the safety aspects GT with adeno-associated virus (AAV) vectors. The topics that will be covered include acute reactions, immunological reactions to the AAV capsid and expressed transgene, viral biodistribution and shedding, DNA integration and carcinogenicity. These safety aspects of GT will be discussed with a focus on alipogene tiparvovec, in addition to other AAV vector GT products currently in clinical development.

The National Health System in the UK has evolved to become one of the largest healthcare systems in the world. At the time of writing of this review (August 2010) the UK government in its 2010 White Paper "Equity and excellence: Liberating the NHS" has announced a strategy on how it will "create a more responsive, patient-centred NHS which achieves outcomes that are among the best in the world". This review article presents an overview of the UK healthcare system as it currently stands, with emphasis on Predictive, Preventive and Personalised Medicine elements. It aims to serve as the basis for future EPMA articles to expand on and present the changes that will be implemented within the NHS in the forthcoming months.

Purpose: To test the hypothesis that simultaneous, equipotent inhibition of epidermal growth factor receptor (EGFR; erbB1), erbB2 (human epidermal growth factor receptor 2), and erbB3 receptor signaling, using the novel small-molecule inhibitor AZD8931, will deliver broad antitumor activity in vitro and in vivo., Experimental Design: A range of assays was used to model erbB family receptor signaling in homodimers and heterodimers, including in vitro evaluation of erbB kinase activity, erbB receptor phosphorylation, proliferation in cells, and in vivo testing in a human tumor xenograft panel, with ex vivo evaluation of erbB phosphorylation and downstream biomarkers. Gefitinib and lapatinib were used to compare the pharmacological profile of AZD8931 with other erbB family inhibitors., Results: In vitro, AZD8931 showed equipotent, reversible inhibition of EGFR (IC(50), 4 nmol/L), erbB2 (IC(50), 3 nmol/L), and erbB3 (IC(50), 4 nmol/L) phosphorylation in cells. In proliferation assays, AZD8931 was significantly more potent than gefitinib or lapatinib in specific squamous cell carcinoma of the head and neck and non-small cell lung carcinoma cell lines. In vivo, AZD8931 inhibited xenograft growth in a range of models while significantly affecting EGFR, erbB2, and erbB3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation., Conclusions: AZD8931 has a unique pharmacologic profile providing equipotent inhibition of EGFR, erbB2, and erbB3 signaling and showing greater antitumor activity than agents with a narrower spectrum of erbB receptor inhibition in specific preclinical models. AZD8931 provides the opportunity to investigate whether simultaneous inhibition of erbB receptor signaling could be of utility in the clinic, particularly in the majority of solid tumors that do not overexpress erbB2.

The RET kinase has emerged as a promising target for the therapy of medullary thyroid cancers (MTC) and of a subset of papillary thyroid cancers. NVP-AST487, a N,N'-diphenyl urea with an IC(50) of 0.88 mumol/L on RET kinase, inhibited RET autophosphorylation and activation of downstream effectors, and potently inhibited the growth of human thyroid cancer cell lines with activating mutations of RET but not of lines without RET mutations. NVP-AST487 induced a dose-dependent growth inhibition of xenografts of NIH3T3 cells expressing oncogenic RET, and of the MTC cell line TT in nude mice. MTCs secrete calcitonin, a useful indicator of tumor burden. Human plasma calcitonin levels derived from the TT cell xenografts were inhibited shortly after treatment, when tumor volume was still unchanged, indicating that the effects of RET kinase inhibition on calcitonin secretion were temporally dissociated from its tumor-inhibitory properties. Accordingly, NVP-AST487 inhibited calcitonin gene expression in vitro in TT cells, in part, through decreased gene transcription. These data point to a previously unknown physiologic role of RET signaling on calcitonin gene expression. Indeed, the RET ligands persephin and GDNF robustly stimulated calcitonin mRNA, which was blocked by pretreatment with NVP-AST487. Antagonists of RET kinase activity in patients with MTC may result in effects on plasma calcitonin that are either disproportionate or dissociated from the effects on tumor burden, because RET kinase mediates a physiologic pathway controlling calcitonin secretion. The role of traditional tumor biomarkers may need to be reassessed as targeted therapies designed against oncoproteins with key roles in pathogenesis are implemented.

Characterization of trabecular bone structures requires necropsy of animals followed by a labor-intense histomorphometric or ex vivo micro-CT analysis. We tested the novel vivaCT40 from Scanco Medical AG (Bassersdorf, Switzerland), which allows monitoring such changes repeatedly in anesthetized rats and mice. Postmenopausal osteoporosis: in 8-month-old ovariectomized (OVX) rats, the vivaCT40 was capable of picking up the decrease in trabecular bone volume and trabecular thinning as well as the decrease in the number of trabecular elements as a function of time. The bone anabolic effects of parathyroid hormone [hPTH(1-34)], which resulted in an increase in trabecular thickness but not their number, as well as the bone protective effect of the two antiresorptive agents zoledronic acid (ZA) and 17-alpha ethinylestradiol (aEE), were detected correctly with the vivaCT40. Adjuvans arthritis: the vivaCT40 allowed measuring trabecular bone loss caused by periarticular inflammation in a rat model of adjuvans arthritis and demonstrated the bone protective effect of dexamethasone (DM). In addition, it was possible to image the subtle erosive lesions in subchondral bone caused by the inflammatory processes. Tumor osteolysis: the vivaCT40 allowed monitoring of the progressive osteolytic response following the local administration of 4T1luc2000 tumor cells into the tibia metaphysis of nude mice. The potent protective effect of ZA on tumor osteolysis was demonstrated. In summary, the new vivaCT40 can monitor the effects of known agents and diseases such as osteoporosis, inflammatory arthritis, and tumor invasion on 3-D trabecular microarchitecture accurately, repeatedly, reliably, and quickly in anesthetized rats and mice. The scanner represents a breakthrough for noninvasive imaging and structural measurements in small rodents.

Aberrant epidermal growth factor receptor (EGFR) and ErbB2 expression are associated with advanced disease and poor patient prognosis in many tumor types (breast, lung, ovarian, prostate, glioma, gastric, and squamous carcinoma of head and neck). In addition, a constitutively active EGFR type III deletion mutant has been identified in non-small cell lung cancer, glioblastomas, and breast tumors. Hence, members of the EGFR family are viewed as promising therapeutic targets in the fight against cancer. In a similar vein, vascular endothelial growth factor (VEGF) receptor kinases are also promising targets in terms of an antiangiogenic treatment strategy. AEE788, obtained by optimization of the 7H-pyrrolo[2,3-d]pyrimidine lead scaffold, is a potent combined inhibitor of both epidermal growth factor (EGF) and VEGF receptor tyrosine kinase family members on the isolated enzyme level and in cellular systems. At the enzyme level, AEE788 inhibited EGFR and VEGF receptor tyrosine kinases in the nm range (IC(50)s: EGFR 2 nm, ErbB2 6 nm, KDR 77 nm, and Flt-1 59 nm). In cells, growth factor-induced EGFR and ErbB2 phosphorylation was also efficiently inhibited (IC(50)s: 11 and 220 nm, respectively). AEE788 demonstrated antiproliferative activity against a range of EGFR and ErbB2-overexpressing cell lines (including EGFRvIII-dependent lines) and inhibited the proliferation of epidermal growth factor- and VEGF-stimulated human umbilical vein endothelial cells. These properties, combined with a favorable pharmacokinetic profile, were associated with a potent antitumor activity in a number of animal models of cancer, including tumors that overexpress EGFR and or ErbB2. Oral administration of AEE788 to tumor-bearing mice resulted in high and persistent compound levels in tumor tissue. Moreover, AEE788 efficiently inhibited growth factor-induced EGFR and ErbB2 phosphorylation in tumors for >72 h, a phenomenon correlating with the antitumor efficacy of intermittent treatment schedules. Strikingly, AEE788 also inhibited VEGF-induced angiogenesis in a murine implant model. Antiangiogenic activity was also apparent by measurement of tumor vascular permeability and interstitial leakage space using dynamic contrast enhanced magnetic resonance imaging methodology. Taken together, these data indicate that AEE788 has potential as an anticancer agent targeting deregulated tumor cell proliferation as well as angiogenic parameters. Consequently, AEE788 is currently in Phase I clinical trials in oncology.

SuperGen Inc is developing a cyclodextrin-based reformulation of mitomycin C (MitoExtra) for the potential treatment of gastic, pancreatic, breast lung and colorectal cancers. In April 2002, the NDA was pending approval from the US FDA after a March 2002 filing of a final response including data from a phase II trial [447618]. MitoExtra is a proprietary reformulation of the approved anticancer drug mitomycin C. SuperGen's reformulation is based on technology designed to improve the handling characteristics and safety profile of mitomycin C and other anticancer drugs by enhancing the drug's stability in solution form and 'shielding' it at the injection site [205482]. In a phase II study in patients with advanced solid tumors, MitoExtra showed no evidence of diminished efficacy or unexpected toxicity [447618]. In April 2000, SuperGen' was issued US-06048845, protecting the company's proprietary Extra technology platform [363494].

In view of the clinical potential of a number of natural products, Combretastatin A-1 phosphate was developed as a water-soluble derivative of combretastatin A-1. This study examined the anti-tumour activity of this compound against an experimental colon tumour (MAC29) in mice. A comparison was made with the clinically active combretastatin A-4 phosphate. The new compound was well-tolerated up to a dose of 250 mg/kg and was more effective at producing tumour growth delays than the A-4 analogue. Significant growth delays were seen at a dose of 50 mg/kg whereas the A-4 phosphate produced no measurable growth delay until a dose of 150 mg/kg was administered. Histological examination of treated tumours indicated that combretastatin A-1 phosphate caused very severe haemorrhagic necrosis in the tumour tissue and analysis of the sections indicated that almost 94 percent of the tumour was dead within 24 hours of treatment. The mechanism of action of combretastatin A-1 phosphate appears to be similar to the A-4 phosphate in that tumour vascular shutdown occurs within 4 hours of treatment. In summary combretastatin A-1 phosphate, the water-soluble analogue of combretastatin A-1, is more potent against a well-vascularised murine colon tumour than its predecessor, combretastatin A-4 phosphate. These data suggest this compound may have potential for clinical development.

Kyowa Hakko Kogyo is developing UCN-01, a selective but non-specific inhibitor of kinases with good activity against protein kinase C (PKC) and the cyclin-dependent kinases (CDKs). This hydroxylated derivative of staurosporine has potential for the treatmentfor cancer [154087], [311028], and may be useful in the treatment of chronic lymphocytic leukemia [312089]. It is in phase I clinical trials [321641], [326004], [326256]. At the 11th NCI-EORTC-AACR Symposium (Amsterdam, November 2000), a presentation was made on UCN-01. In the initial clinical trial, in which UCN-01 was administered by continuous infusion for 72 h, a prolonged half-life of 600 h was observed. The MTD was 42.5 mg/m2/day x 3. One patient with refractory melanoma achieved a partial response, another patient with refractory anaplastic large cell lymphoma had no evaluable diseasefor more than three years [391376].

EntreMed has licensed the worldwide rights to the angiogenesis inhibitor Endostatin, a 20 kDa C-terminal fragment of collagen XVIII, from the Children's Hospital of Boston, a teaching affiliate of Harvard Medical School. It is being developed as a potential cancer treatment and may also be useful in certain types of blindness and arthritis [227427]. EntreMed filed an IND for Endostatin in June 1999 [334125] and as of September 1999, phase I trials were underway [341462]. As of April 2000, the company had initiated plans for testing low doses of Endostatin in cancer patients using continuous infusion and sc administration in a further phase I study to be conducted in Europe [361594]. A phase I trial of Endostatin which will evaluate the safety and efficacy of Endostatin at a range of doses in no more than 100 cancer patients has been initiated. The trial will take place at the University of Texas MD Anderson Medical Center and the University of Wisconsin Cancer Center in Madison. The National Cancer Center will be sponsoring the trial, which is expected to be completed in late 2000. As of March 2000, there had been no serious adverse events attributable to Endostatin administration. The first report from this trial is expected in autumn 2000 [341462], [366312]. The mechanism of action for Endostatin remains unclear, although reports from the 91st AACR Meeting in April 2000 showed that recombinant human endostatin bound to a number of tropomyosin cDNAs in a library screen [362039]. In preclinical studies, repeated administration of Endostatin consistently shrank primary tumors and did not produce any drug resistance. In mice, a variety of tumors which had progressed to 1 to 2% of total body weight, regressed to microscopic, dormant lesions following Endostatin treatment [231418], [231470], [270673]. Types of cancers which respond to Endostatin include lung, skin, vascular and fibrosarcomas. Toxicology studies in cynomolgus monkeys showed that bolus injections of human endostatin at doses up to 300 mg/kg produced no toxic effects [317916]. Research presented at the 91st Annual Meeting of the AACR (San Francisco, April 2000), demonstrated that peritumoral administration of Endostatin, at concentrations 2000-fold less than that required to inhibit tumor progression in previously published reports using systemic dosing, significantly deters the development of a variety of tumors in mice [361584]. Other research presented at the meeting demonstrated a role for tropomysin as a molecular target for Endostatin [361680]. In August 1997, EntreMed and the NCI signed letters of intent to commence research collaborations for developing anti-angiogenic therapies, including Endostatin, in preclinical and clinical studies [258354], while in August 1998, EntreMed entered into an agreement with Covance Biotechnology Services for the production of Endostatin [304919]. In August 1999, Entremed and Cell Genesys entered a collaboration to combine Entremed's Endostatin genes with Cell Genesys's gene delivery system as a possible treatment for cancer [336909]. In December 1999, EntreMed signed an agreement with Chiron for the production of bulk Endostatin for phase II clinical trials [350397]. In April 1999, analysts at First Security Van Kasper predicted a US launch for Endostatin in 2004, with first-year revenues of US 320 million dollars, including 70 million dollars in royalties to EntreMed. European launch was predicted for 2005, with total revenues from Europe and the US for that year of US 760 milion dollars (160 million dollars royalties to EntreMed), rising to 1600 million dollars (335 million dollars royalties to EntreMed) in 2007 [370813].