Connie I. Diakos

Cancer-related inflammation and treatment effectiveness

Inflammation is a recognised hallmark of cancer that substantially contributes to the development and progression of malignancies. In established cancers, there is increasing evidence for the roles that local immune response and systemic inflammation have in progression of tumours and survival of patients with cancer. This knowledge provides an opportunity to target these inflammatory responses to improve patient outcomes. In this Review, we examine the complex interplay between local immune responses and systemic inflammation, and their influence on clinical outcomes, and propose potential anti-inflammatory interventions for patients with cancer.

The Lymphocyte-to-monocyte Ratio is a Superior Predictor of Overall Survival in Comparison to Established Biomarkers of Resectable Colorectal Cancer.

Objective: The study aims to investigate the prognostic value of the lymphocyte-to-monocyte ratio (LMR) in patients with colorectal cancer (CRC) undergoing curative resection and to compare it to established biomarkers including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), modified Glasgow prognostic score (mGPS), and combined BRAF-mismatch repair (MMR) status. Background: The prognostic significance of systemic inflammatory markers in CRC such as the NLR, PLR, and mGPS has been well defined. Commonly used genetic markers such as combined BRAF-MMR status have also been found to be prognostic. Recent evidence, although limited, suggests that the preoperative LMR may be prognostic in CRC. Methods: Data from the Northern Sydney Local Health District from January 1998 to December 2012 were retrospectively collected. Of 3281 consecutive patients identified, 1623 patients who underwent curative resection were deemed eligible for inclusion. The relation between the LMR, clinicopathologic variables, and other biomarkers were analyzed in Kaplan-Meier log-rank survival analysis and then multivariate Cox regression models looking for association with overall survival (OS). Results: In multivariate analysis of all patients, elevated LMR was associated with better OS (hazard ratio 0.569, 95% confidence interval: 0.478–0.677, P < 0.001) independent of age (P < 0.001), T stage (P < 0.001), N stage (P < 0.001), and grade (P = 0.049). The NLR, PLR, and combined BRAF-MMR status were not independently significant. In multivariate subgroup analysis of 389 patients with mGPS, LMR remained the only independently significant biomarker (hazard ratio 0.620, 95% confidence interval: 0.437–0.880, P = 0.007). Conclusions: The LMR is an independent predictor of OS in patients with CRC undergoing curative resection and appears to be superior to pre-existing biomarkers.

Synthesis, characterisation and in vitro cytotoxicity studies of a series of chiral platinum(II) complexes based on the 2-aminomethylpyrrolidine ligand: X-ray crystal structure of [PtCl2(R-dimepyrr)] (R-dimepyrr = N-dimethyl-2(R)-aminomethylpyrrolidine)

A series of platinum(II) complexes were synthesised based on the enantiomerically pure amino acid proline. Novel synthetic pathways were developed, adapted from standard peptide chemistry, to produce the 2-aminomethylpyrrolidine (pyrr) ligand and its derivatives with differing arrangements of methyl substituents at the exocyclic amine sites. The crystal structure of [PtCl(2)(R-dimepyrr)] (R-dimepyrr=N,N-dimethyl-2(R)-aminomethylpyrrolidine) is reported and the five-membered ligand ring has been shown to be in an envelope conformation. Cytotoxicity studies were carried out on the ovarian cancer A2780 tumour cell line and its cisplatin-resistant variant, A2780cisR. Remarkably good activity was seen for several of the drugs when compared to cisplatin despite the addition of substantial steric bulk to the amine groups, and there was a lack of cross-resistance with cisplatin seen for some compounds.

Equivocal ALK fluorescence in-situ hybridization (FISH) cases may benefit from ancillary ALK FISH probe testing.

Accurate assessment of anaplastic lymphoma kinase (ALK) gene rearrangement in non‐small‐cell lung cancers (NSCLCs) is critical to identify patients who are likely to respond to crizotinib. The aim of this study was to evaluate the ALK/EML4 TriCheck FISH probe in a series of NSCLCs enriched for tumours with equivocal ALK status.

Cancer-related systemic inflammation: The challenges and therapeutic opportunities for personalized medicine.

Over the last decade there has been significant progress towards the development of personalized or “precision” medicine for many patients with cancer. However, there still remain subpopulations of cancer patients that do not possess a tumor mutation profile that is successfully targeted by the newer molecular anticancer drugs and further personalized approaches are needed. The presence of cancer‐related systemic inflammation represents an underappreciated subpopulation of cancer patients needing personalized therapy. For ∼25% of all advanced cancer patients, regardless of histological subtype, the patients with systemic inflammation have significantly poorer response to chemotherapy and also shorter overall survival compared to those cancer patients without inflammation. The development of cancer‐related systemic inflammation involves interactions between host and tumor cells that are potential new drug targets in cancer chemotherapy. In this review we discuss the challenges and clinical opportunities to develop new therapeutic strategies for this underappreciated drug target.

Prognostic and predictive biomarkers in neuroendocrine tumours

Neuroendocrine tumours are extremely heterogeneous malignancies. Despite marked heterogeneity in clinical course and prognosis, few biomarkers exist to help predict prognosis and guide treatment. Many tumour-based biomarkers (Ki-67, mitotic count, genetic/epigenetic changes and microRNAs) exist, but only Ki-67 and mitotic count have strong evidence to support their routine use. Blood-based markers are easily repeatable, but currently established biomarkers (chromogranin A and urinary 5-HIAA) are difficult to measure accurately in practice. Structural imaging is used routinely via the TNM system. Functional imaging such as 68Ga-based and FDG PET may become valuable biomarkers with their increasing availability, aided by ongoing quantitative research. Multiple nomograms have been proposed to integrate the above factors, but most have not been prospectively validated and are difficult to use in practice. Further research should aim to establish robust new biomarkers and integrate existing ones to help optimise NET treatment.

Can metal complexes serve as hypoxia activated prodrugs? Investigations of a Co(III) complex of the MMP inhibitor marimastat

For many years proof that the hypoxic nature of malignant tumours can be used to selectively target anticancer drugs has been sought. Several classes of potential redox activated anticancer drugs have been developed to take advantage of the reducing environment resulting from the hypoxia. Drug complexes with redox active metal centres as carriers have been investigated, but have largely been employed with cytotoxic drugs that require release of the drug intracellularly, complicating the design of such complexes. MMP inhibitors, a new class of anticancer drug, conversely act in the extracellular environment and we have investigated inhibitor complexes with several redox active transition metals. Marimastat is an MMP inhibitor with potent in-vitro antimetastatic activity and was recently in Phase III clinical trials for a variety of cancer types. We have synthesised a Co(II1) complex of marimastat incorporating the tetradentate ligand tpa (tris(2-methylpyridyl)amine) as a carrier ligand. The complex was structurally characterised in the solid state by single crystal X-ray diffraction, the first example of a crystal structure containing marimastat. 2D COSY and NOESY NMR spectra showed that the complex exists in two isomeric forms in solution, corresponding to the cis and trans isomers yet only crystallises in one of these forms. Biological testing of the complex in mice with 4T1.2 tumours showed interesting and unexpected outcomes. Initial results of the tumour growth inhibition study showed that a significant inhibition of growth was exhibited by the complex over the free inhibitor and the control. However, the metastatic potential of both free marimastat and the complex were higher than the control indicating likely problems with the experimental protocol. Further experiments are needed to determine the potential of such complexes as hypoxia activated prodrugs but there appears at least to be some promise.

Steric Determinants of Pt/DNA Interactions and Anticancer Activity.

Studies directed at establishing the structural features that control Pt/DNA interactions and the anticancer activity of Pt drugs are described. [1H, 15N]-HSQC 2D NMR spectroscopic studies of the reactions of cisplatin with oligonucleotides containing ApG and GpA binding sites reveal dramatic differences in the rates of formation of monofunctional adducts at the two sites. When the reactant is cis-[Pt(NH3)2(OH2)2]2+ no such differences are observed suggesting that outer-sphere interactions between the reactant and the oligonucleotide may play a substantial role in determining the rates. Rates of closure to the bifunctional adducts are similar to those observed for cisplatin. Studies of the adduct profiles formed by sterically bulky and/or optically active complexes reveal that steric interactions play a major role in mediating the binding of Pt(ll) to DNA but that hydrogen bonds play less of a role. In vitro cytotoxic activities for these complexes do not always follow the trends that would be expected on the basis of the adduct profiles.

A data-driven, knowledge-based approach to biomarker discovery: application to circulating microRNA markers of colorectal cancer prognosis

Recent advances in high-throughput technologies have provided an unprecedented opportunity to identify molecular markers of disease processes. This plethora of complex-omics data has simultaneously complicated the problem of extracting meaningful molecular signatures and opened up new opportunities for more sophisticated integrative and holistic approaches. In this era, effective integration of data-driven and knowledge-based approaches for biomarker identification has been recognised as key to improving the identification of high-performance biomarkers, and necessary for translational applications. Here, we have evaluated the role of circulating microRNA as a means of predicting the prognosis of patients with colorectal cancer, which is the second leading cause of cancer-related death worldwide. We have developed a multi-objective optimisation method that effectively integrates a data-driven approach with the knowledge obtained from the microRNA-mediated regulatory network to identify robust plasma microRNA signatures which are reliable in terms of predictive power as well as functional relevance. The proposed multi-objective framework has the capacity to adjust for conflicting biomarker objectives and to incorporate heterogeneous information facilitating systems approaches to biomarker discovery. We have found a prognostic signature of colorectal cancer comprising 11 circulating microRNAs. The identified signature predicts the patients’ survival outcome and targets pathways underlying colorectal cancer progression. The altered expression of the identified microRNAs was confirmed in an independent public data set of plasma samples of patients in early stage vs advanced colorectal cancer. Furthermore, the generality of the proposed method was demonstrated across three publicly available miRNA data sets associated with biomarker studies in other diseases.MiRNA biomarker discovery: a network-based, knowledge-driven approachThe identification of robust and reproducible molecular markers is one of the biggest challenges in personalised cancer medicine. The increasing use of systems biology approaches has prompted researchers to integrate heterogeneous data into existing knowledge bases whose incorporation into the biomarker discovery workflow may adjust for data heterogeneity and limitation, and offer more precise, robust and consistent biomarkers. In this study, we have sought to determine network-based miRNA biomarker signatures from the plasma of colorectal cancer patients that hold prognostic utility. We performed miRNA profiling and then constructed an miRNA-mediated gene regulatory network and developed a multi-objective optimisation-based computational framework to identify miRNA biomarkers using both the miRNA expression profile and knowledge from this miRNA-mediated regulatory network. We have demonstrated the ability of the proposed approach in identifying robust, accurate and reproducible biomarkers.

Radiation, inflammation and the immune response in cancer

Radiation is an important component of cancer treatment with more than half of all patients receive radiotherapy during their cancer experience. While the impact of radiation on tumour morphology is routinely examined in the pre-clinical and clinical setting, the impact of radiation on the tumour microenvironment and more specifically the inflammatory/immune response is less well characterised. Inflammation is a key contributor to short- and long-term cancer eradication, with significant tumour and normal tissue consequences. Therefore, the role of radiation in modulating the inflammatory response is highly topical given the current wave of targeted and immuno-therapeutic treatments for cancer. This review provides a general overview of how radiation modulates the inflammatory and immune response—(i) how radiation induces the inflammatory/immune system, (ii) the cellular changes that take place, (iii) how radiation dose delivery affects the immune response, and (iv) a discussion on research directions to improve patient survival, reduce side effects, improve quality of life, and reduce financial costs in the immediate future. Harnessing the benefits of radiation on the immune response will enhance its maximal therapeutic benefit and reduce radiation-induced toxicity.