Callerio Foundation
NEWS - Verona, October 11-14 2012

WHAT’S NEW FROM THE PLATINUM COMPOUNDS WORLD?

Report on the 11th International Symposium on Platinum Coordination Compounds in Cancer Therapy


PHOTOGALLERY

The Symposium, the twelfth of the series (note that the first was held in Prague, in 1971, thus 40 years ago), took place in Verona, Italy, from October 11th to October 14th. The symposium was organized in five oral sessions and two poster sessions, and was attended by approximately 150 scientists, mainly coming from Europe, America, and Australia.

The scientific committee built up a program aiming at broaden the traditional themes (i.e. the preclinical and clinical pharmacology and pharmacodynamics) of platinum and other heavy metal compounds, to include emerging areas of interest, such as “stem cells, DNA-repair mechanisms, DNA-damaging agents”, in recognition of the recent, important developments in this field.

Great attention was dedicated to the resistance mechanisms, analysed at molecular level in many presentations. Among the putative markers of cisplatin resistance, biomolecules belonging to different classes and with different physiological and biochemical roles were mentioned, such as: integrins (cell surface adhesion molecules), IL-8 (a pro-inflammatory cytokine), GSH (an anti-oxidant tripeptide), but also fatty acids produced by mesenchymal stem cells, the transcription factor FOXO, and the dual-specificity phosphatases. In some cases resistance can be overcome putting emphasis on synthetic lethality, an emerging concept in cancer chemotherapy. Following this approach, the design of therapies is based not only on the clinical manifestations of the disease, but also on the underlying molecular and cellular biology of cancer. Synthetic lethality involves searching for genetic interactions of two mutations whereby the presence of either mutation alone has no effect on cell viability, but the combination of the two mutations results in cell death. The presence of one of these mutations in cancer cells but not in normal cells can therefore create opportunities to selectively kill cancer cells by mimicking the effect of the second genetic mutation with targeted therapy. As an example, synergistic effects can be achieved combining cisplatin with MAPK , or RPA inhibitors. Another way to overcome cisplatin resistance is by copper-lowering agents. In fact, one important mechanism of drug resistance is the deficiency of drug uptake owing to reduced expression of the copper transporter hCtr1 that transport Pt drugs also. The expression of hCtr1 is up-regulated under copper depleted conditions, and this can enhance cisplatin sensitivity. Improvements in the outcome are achieved also identifying the optimal combination of radiotherapy and platinums to induce immunogenic cell death (ICD). Both therapies promote various levels of ICD and it is intriguing to hypothesize that the superiority of concomitant versus sequential chemo-radiation observed in many clinical settings may be mediated by an ICD repositioning effect.

Beyond platinums, Gold and Ruthenium compounds have gained increased attention.
Gold(III)-peptidedithiocarbamato complexes show an enhanced bioavailability and tumour selectivity achieved by exploiting peptide transporters, and cytotoxic properties in vitro, and in vivo on xenograft models; mitochondria and proteasome seem to be the major targets. Among ruthenium compounds the most advanced in its development pipeline is NAMI-A, investigated in a phase II clinical trial in combination with gemcitabine on lung cancer. The study was divided in two stages: a) dose finding and incidence and severity of AEs determination; b) expanded cohort on 15 or more patients. The Maximum Tolerated Dose (MTD) in the adopted experimental setting was determined, as well as the main adverse effects.  Interestingly, stable disease was often observed (59% of patients), in addition to a partial remission. The choice of metals different from platinum is not the only one approach to explore new areas for the development of the future metal compounds. Low toxicity pro-drugs that exploit the chemical and biological features of different tumour microenvironments including hypoxia, acidity and enzyme-overexpression were reported. Beside this approach, which points out on new targets in the metal compound’s field, studies aimed at investigating and improving the penetration and effectiveness of anticancer agents throughout all regions of solid tumours, were also presented.

Platinum still continues to be the favourite metal of many chemists both as new platinum compounds and new formulations. An interesting compound is phenanthriplatin, a cisplatin derivative in which a chloride ion is replaced by phenantridine. The resulting cationic complex forms monofunctional adducts on DNA that do not significantly distort the duplex yet efficiently blocks transcription, stimulating a less effective repair and consequently inducing less resistance. Particularly intriguing are the polynuclear platinum complexes (PPCs) because of a completely new mechanism of cellular accumulation through Heparan Sulfate Proteoglycans (HSPGs). The identification of HSPGs as receptors arose from a novel extension of the phosphate clamp-arginine fork analogy, where the phosphate clamp is a new mode of DNA recognition characterized for PPCs. The glycosaminoglycans (GAGs, which are the protein-coupled oligosaccharide component in HSPG) are a major source of macromolecular polyanions surrounding almost every cell type, especially mammalian cells. GAGs are considered “extracellular DNA”, from their predicted helical nature. In the field of the new formulations, drug delivery systems with tumour-targeting potential are realised by encapsulating Pt(II)-based drugs in the cavity of apoferritin, or in supramolecular nanoclusters decorated with carboxymethyl cellulose, and have displayed a high loading capacity, and a pH-responsive controlled release. The final aim of these systems is to improve the efficacy and the applicability of Pt(II)-based drugs, and their selectivity. This latter can be achieved also by the combination of a PDT (Photo Dynamic Therapy) agent and a metal-based chemotherapeutic drug to get conjugates that exhibit remarkable phototoxicity.

Approximately half the people treated by chemotherapy for cancer receive a platinum drug. Cisplatin is part of first-line chemotherapy in ovarian cancer, bladder cancer, small cell lung cancer, non-small cell lung cancer, head and neck cancer, esophageal cancer, thymoma, osteogenic sarcoma, cervical cancer, and its analogue oxaliplatin in colorectal cancer. It is therefore evident the profound effect it has in oncology, justifying the continuous work to optimize its clinical applications. Efforts were done to improve dosing methods of cisplatin and carboplatin taking in to account their different pharmacokinetics characteristics.  In the case of cisplatin, a fixed dose is not recommended but, a dose-banding, consisting in the administration of the same dose to patients with similar body surface, may be applied with similar results and more practical advantages than a Body Surface Area BSA-dose. In the era of personalized therapy clinical trial also undergo revision. Two main aspects deserve attention: a) the patients fragmentation, done on the basis of the characteristics of the cancer disease and of the host, and leading to the choice of different therapeutic protocols; b) the identification and the use of biomarkers. Regarding this latter aspect, biomarker can be detected at genetic level, at mRNA level and at protein level, and clinicians are investigating which one of these should be studied. In addition, in the clinical setting many basic research studies find their prosecution. As examples, DNA repair pathways have been investigated as potential predictive markers, among them, ERCC1 or BRCA1 as resistance markers in NSCLC. Prospective ongoing phase III clinical trials results are awaited to confirm their predictive role and the feasibility of their assessment in clinical practice.

A session of the symposium was dedicated to Barnett Rosenberg, a tribute to his life and achievements. Unquestionably, the serendipitous discovery of cisplatin was Dr. Rosenberg’s greatest achievement, which led to the worldwide use of one of the most important anticancer drugs in the history of cancer chemotherapy. In addition to its spectacular results in testicular cancer, cisplatin is part of first-line chemotherapy in many cancer types. In addition it easily combines with radiotherapy and also is synergistic with a wide array of chemotherapy agents. There are few, if any, such dramatic stories in oncology. The clinical success of cisplatin, the first metal-based anticancer drug approved by the FDA in 1978, inspired a renaissance in the field of contemporary Bioinorganic Chemistry.

More informations at Symposium website.

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