Annette T. Byrne

Porphyrin and Nonporphyrin Photosensitizers in Oncology: Preclinical and Clinical Advances in Photodynamic Therapy

Photodynamic therapy (PDT) is now a well‐recognized modality for the treatment of cancer. While PDT has developed progressively over the last century, great advances have been observed in the field in recent years. The concept of dual selectivity of PDT agents is now widely accepted due to the relative specificity and selectivity of PDT along with the absence of harmful side effects often encountered with chemotherapy or radiotherapy. Traditionally, porphyrin‐based photosensitizers have dominated the PDT field but these first generation photosensitizers have several disadvantages, with poor light absorption and cutaneous photosensitivity being the predominant side effects. As a result, the requirement for new photosensitizers, including second generation porphyrins and porphyrin derivatives as well as third generation photosensitizers has arisen, with the aim of alleviating the problems encountered with first generation porphyrins and improving the efficacy of PDT. The investigation of nonporphyrin photosensitizers for the development of novel PDT agents has been considerably less extensive than porphyrin‐based compounds; however, structural modification of nonporphyrin photosensitizers has allowed for manipulation of the photochemotherapeutic properties. The aim of this review is to provide an insight into PDT photosensitizers clinically approved for application in oncology, as well as those which show significant potential in ongoing preclinical studies.

Patient-Derived Xenograft Models: An Emerging Platform for Translational Cancer Research

UNLABELLED Recently, there has been an increasing interest in the development and characterization of patient-derived tumor xenograft (PDX) models for cancer research. PDX models mostly retain the principal histologic and genetic characteristics of their donor tumor and remain stable across passages. These models have been shown to be predictive of clinical outcomes and are being used for preclinical drug evaluation, biomarker identification, biologic studies, and personalized medicine strategies. This article summarizes the current state of the art in this field, including methodologic issues, available collections, practical applications, challenges and shortcomings, and future directions, and introduces a European consortium of PDX models. SIGNIFICANCE PDX models are increasingly used in translational cancer research. These models are useful for drug screening, biomarker development, and the preclinical evaluation of personalized medicine strategies. This review provides a timely overview of the key characteristics of PDX models and a detailed discussion of future directions in the field.

Bioluminescent imaging: a critical tool in pre-clinical oncology research†

Bioluminescent imaging (BLI) is a non‐invasive imaging modality widely used in the field of pre‐clinical oncology research. Imaging of small animal tumour models using BLI involves the generation of light by luciferase‐expressing cells in the animal following administration of substrate. This light may be imaged using an external detector. The technique allows a variety of tumour‐associated properties to be visualized dynamically in living models. The increasing use of BLI as a small‐animal imaging modality has led to advances in the development of xenogeneic, orthotopic, and genetically engineered animal models expressing luciferase genes. This review aims to provide insight into the principles of BLI and its applications in cancer research. Many studies to assess tumour growth and development, as well as efficacy of candidate therapeutics, have been performed using BLI. More recently, advances have also been made using bioluminescent imaging in studies of protein‐protein interactions, genetic screening, cell‐cycle regulators, and spontaneous cancer development. Such novel studies highlight the versatility and potential of bioluminescent imaging in future oncological research. Copyright

Interrogating open issues in cancer precision medicine with patient-derived xenografts

Patient-derived xenografts (PDXs) have emerged as an important platform to elucidate new treatments and biomarkers in oncology. PDX models are used to address clinically relevant questions, including the contribution of tumour heterogeneity to therapeutic responsiveness, the patterns of cancer evolutionary dynamics during tumour progression and under drug pressure, and the mechanisms of resistance to treatment. The ability of PDX models to predict clinical outcomes is being improved through mouse humanization strategies and the implementation of co-clinical trials, within which patients and PDXs reciprocally inform therapeutic decisions. This Opinion article discusses aspects of PDX modelling that are relevant to these questions and highlights the merits of shared PDX resources to advance cancer medicine from the perspective of EurOPDX, an international initiative devoted to PDX-based research.

An intact canonical NF-κB pathway is required for inflammatory gene expression in response to hypoxia.

Hypoxia is a feature of the microenvironment in a number of chronic inflammatory conditions due to increased metabolic activity and disrupted perfusion at the inflamed site. Hypoxia contributes to inflammation through the regulation of gene expression via key oxygen-sensitive transcriptional regulators including the hypoxia-inducible factor (HIF) and NF-κB. Recent studies have revealed a high degree of interdependence between HIF and NF-κB signaling; however, the relative contribution of each to hypoxia-induced inflammatory gene expression remains unclear. In this study, we use transgenic mice expressing luciferase under the control of NF-κB to demonstrate that hypoxia activates NF-κB in the heart and lungs of mice in vivo. Using small interfering RNA targeted to the p65 subunit of NF-κB, we confirm a unidirectional dependence of hypoxic HIF-1α accumulation upon an intact canonical NF-κB pathway in cultured cells. Cyclooxygenase-2 and other key proinflammatory genes are transcriptionally induced by hypoxia in a manner that is both HIF-1 and NF-κB dependent, and in mouse embryonic fibroblasts lacking an intact canonical NF-κB pathway, there is a loss of hypoxia-induced inflammatory gene expression. Finally, under conditions of hypoxia, HIF-1α and the p65 subunit of NF-κB directly bind to the cyclooxygenase-2 promoter. These results implicate an essential role for NF-κB signaling in inflammatory gene expression in response to hypoxia both through the regulation of HIF-1 and through direct effects upon target gene expression.

Vascular-targeted photodynamic therapy with BF2-chelated Tetraaryl-Azadipyrromethene agents: a multi-modality molecular imaging approach to therapeutic assessment.

Background:Photodynamic therapy (PDT) is a treatment modality for a range of diseases including cancer. The BF2-chelated tetraaryl-azadipyrromethenes (ADPMs) are an emerging class of non-porphyrin PDT agent, which have previously shown excellent photochemical and photophysical properties for therapeutic application. Herein, in vivo efficacy and mechanism of action studies have been completed for the lead agent, ADMP06.Methods:A multi-modality imaging approach was employed to assess efficacy of treatment, as well as probe the mechanism of action of ADPM06-mediated PDT.Results:Tumour ablation in 71% of animals bearing mammary tumours was achieved after delivery of 2 mg kg−1 of ADPM06 followed immediately by light irradiation with 150 J cm−2. The inherent fluorescence of ADPM06 was utilised to monitor organ biodistribution patterns, with fluorescence reaching baseline levels in all organs within 24 h. Mechanism of action studies were carried out using dynamic positron emission tomography and magnetic resonance imaging techniques, which, when taken together, indicated a decrease in tumour vascular perfusion and concomitant reduction in tumour metabolism over time after treatment.Conclusion:The encouraging treatment responses in vivo and vascular-targeting mechanism of action continue to indicate therapeutic benefit for this new class of photosensitiser.

The hydroxylase inhibitor dimethyloxallyl glycine attenuates endotoxic shock via alternative activation of macrophages and IL-10 production by B1 cells.

Localized tissue hypoxia is a feature of infection and inflammation, resulting in the upregulation of the transcription factors hypoxia-inducible factor 1&agr; and nuclear factor &kgr;B (NF-&kgr;B) via inhibition of oxygen sensing hydroxylase enzymes. Previous studies have demonstrated a beneficial role for the hydroxylase inhibitor dimethyloxallyl glycine (DMOG) in inflammatory conditions, including experimental colitis, by regulating the activity of hypoxia-inducible factor 1 and NF-&kgr;B. We have demonstrated in vivo that pretreatment with DMOG attenuates systemic LPS-induced activation of the NF-&kgr;B pathway. Furthermore, mice treated with DMOG had significantly increased survival in LPS-induced shock. Conversely, in models of polymicrobial sepsis, DMOG exacerbates disease severity. Dimethyloxallyl glycine treatment of mice promotes M2 polarization in macrophages within the peritoneal cavity, resulting in the downregulation of proinflammatory cytokines such as TNF-&agr;. In addition, in vivo DMOG treatment upregulates IL-10 expression, specifically in the peritoneal B1 cell population. This study demonstrates cell type-specific roles for hydroxylase inhibition in vivo and provides insight into the mechanism underlying the protection conveyed by DMOG in models of endotoxic shock.ABBREVIATIONS-MØ-macrophage; DMOG-dimethyloxallyl glycine

Effects of insulin-like growth factors I and II on tumour-necrosis-factor-alpha-induced apoptosis in early murine embryos

The proposition that members of the insulin-like growth factor superfamily act as rescue factors from apoptosis in murine preimplantation embryos was tested. The cytokine tumour necrosis factor alpha (TNFalpha) was used to induce apoptosis. Zygotes were cultured for 5 days to the blastocyst stage in the presence or absence of TNFalpha and in the presence or absence of the insulin-like growth factors, IGF-I or IGF-II. Tumour necrosis factor alpha significantly increased the percentage of apoptotic cells and reduced the total cell count in Day 5 blastocysts. When IGF-I or IGF-II were added to the culture medium in the presence of TNFalpha, the cell number and apoptotic dead cell index (DCI) were restored to control values. Insulin-like growth factor-I alone had a greater effect on total cell number than IGF-II alone, but did not significantly decrease the apoptotic DCI. In contrast, IGF-II significantly reduced the number of apoptotic cells. This study shows that IGFs may play a role as apoptotic survival factors in the early mouse embryo.

The VEGF/Rho GTPase signalling pathway: A promising target for anti-angiogenic/anti-invasion therapy

It has become increasingly apparent that current antiangiogenic therapy elicits modest effects in clinical settings. In addition, it remains challenging to treat cancer metastasis through antiangiogenic regimes. Rho GTPases are essential for vascular endothelial growth factor (VEGF)-mediated angiogenesis and are involved in tumour cell invasion. This review discusses novel therapeutic strategies that interfere with Rho GTPase signalling and further explores this network as a target for anticancer therapy through interference with tumour angiogenesis and invasion. Recent findings describe the development of innovative Rho GTPase inhibitors. Positive clinical effects of Rho GTPase targeting in combination with conventional anticancer therapy is of increasing interest.

Recent advances in molecular imaging biomarkers in cancer: application of bench to bedside technologies.

Molecular imaging is the visualization, characterization and measurement of biological processes at the molecular and cellular level. In oncology, molecular imaging approaches can be directly applied as translational biomarkers of disease progression. In this article, selected imaging modalities are discussed with respect to this role. Recent studies focusing on emerging imaging biomarkers and new developments in the field are highlighted. Importantly, because ex vivo or tissue-based imaging now represents an important tool in the discovery and validation of oncology biomarkers, special attention is given to this resurgent field.