Introduction: moving beyond chemotherapy

Epithelial ovarian cancer and related cancers arising in extrauterine Mullerian epithelium are generally chemosensitive—particularly to the platinum drugs, cisplatin and carboplatin, that form the backbone of first-line treatments upon diagnosis even at early stages. Doublets of platinums with paclitaxel have represented the standard-of-care since the late 1990s, with further notable advances taking place by intraperitoneal administration (in Gynecologic Oncology Group studies) after optimal surgical cytoreduction is achieved, and by divided doses of paclitaxel (in a Japanese GOG study). Adding another agent to improve on these results has otherwise proven to be quite challenging. Nevertheless, continued forays into introducing ‘targeted therapies’ are beginning to bear fruit, and form part of this Translational Cancer Research ( TCR ) supplement. The purpose of this supplement is to provide a summary of the advances in tumor biology and a glimpse into where targeted therapeutics are moving, and their successes to date

Integrating targeted drugs with taxanes and platinums: opportunities and challenges

In ovarian cancer, multiple attempts to adjust the standard taxane/platinum doublet by adding cytotoxic therapy or varying scheduling, dosage, and delivery have been met with limited success. Alternative methods to improve the grim prognosis of ovarian cancer, including molecular therapies, are currently under investigation. Efforts have been made to study tyrosine kinase inhibitors (including imatinib and pazopanib), Src kinase inhibitors and histone deacetylase inhibitors (HDACi) in combination with taxanes/platinums in order to improve efficacy. Unfortunately, while many pre-clinical and early phase clinical trials argue that the utilization of these molecular targets may enhance survival, only modest benefit has been seen in larger clinical trials. Other agents that have been evaluated include proteasome inhibitors, folate receptor antagonists, MEK inhibitors and opiate antagonists. In this review, we discuss the mechanisms of these targeted therapies and highlight the current and ongoing clinical trials that utilize these targeted agents in combination with taxanes and platinums in advanced ovarian cancer

Pegylated liposomal doxorubicin (PLD): enhanced skin toxicity in areas of vitiligo

Pegylated liposomal doxorubicin (PLD, Doxil, Caelyx) is widely used for the treatment of ovarian cancer. It is a stable formulation encapsulating doxorubicin in a ‘Stealth’ (i.e., pegylated) liposome with a half-life of about 72 hours. This drastically altered pharmacology confers on it a considerably lower risk of cardiotoxicity, no acute emesis, and near absence of alopecia or problems with extravasation necrosis. On the other hand, PLD's dose-limiting toxicity is cutaneous. Since the original phase I report, cutaneous toxicities reported with PLD fall into four common categories: the well known hand-foot syndrome (also called palmoplantar erythrodysesthesia, or PPE), a diffuse follicular rash, intertrigo-like eruption, and hyperpigmentation including melanotic macules

Should we hail the Red King: evolutionary consequences of a mutualistic lifestyle in genomes of lichenized fungi

The Red Queen dynamic is often brought into play for antagonistic relationships. However, the coevolutionary effects of mutualistic interactions, which predict slower evolution for interacting organisms (Red King), have been investigated to a lesser extent. Lichens are a stable, mutualistic relationship of fungi and cyanobacteria and/ or algae, which originated several times independently during the evolution of fungi. Therefore, they represent a suitable system to investigate the coevolutionary effect of mutualism on the fungal genome. We measured substitution rates and selective pressure of about 2000 protein-coding genes (plus the rDNA region) in two different classes of Ascomycota, each consisting of closely related lineages of lichenized and non-lichenized fungi. Our results show that independent lichenized clades are characterized by significantly slower rates for both synonymous and non-synonymous substitutions. We hypothesize that this evolutionary pattern is connected to the lichen life cycle (longer generation time of lichenized fungi) rather than a result of different selection strengths, which is described as the main driver for the Red Kind dynamic. This first empirical evidence of slower evolution in lichens provides an important insight on how biotic cooperative interactions are able to shape the evolution of symbiotic organisms

Co-existence of breast and ovarian cancers in BRCA germ-line mutation carriers

The co-existence of breast and ovarian cancers in the same individual should raise suspicion of a hereditary process. Patients with either BRCA1 or BRCA2 germ-line mutations have an average risk of 39% and 11% respectively of developing ovarian cancer by the age of 70; they have a risk of 35–85% of developing breast cancer in their lifetime. We report here unusual pathologic features in a BRCA2 germ-line mutation carrier recently diagnosed with synchronous breast and ovarian cancers, and summarize the findings in six other women who were diagnosed with ovarian cancer either simultaneously with the diagnosis of breast cancer or at varying times after the diagnosis. While in most instances this may be a coincidental occurrence in highly susceptible individuals, the patient we highlight raises the provocative hypothesis that at times breast cancer metastasizes to the ovaries of mutation carriers and stimulates the development of an ovarian cancer as well as other cancers. In addition, these ovarian cancers may have different mechanisms of metastases predisposing them to travel to unusual sites

Trebouxia lynnae sp. nov. (former Trebouxia sp. TR9): biology and biogeography of an epitome lichen symbiotic microalga

Two microalgal species, Trebouxia jamesii and Trebouxia sp. TR9, were detected as the main photobionts coexisting in the thalli of the lichen Ramalina farinacea. Trebouxia sp. TR9 emerged as anew taxon in lichen symbioses and was successfully isolated and propagated in in vitro culture andthoroughly investigated. Several years of research have confirmed the taxon Trebouxia sp. TR9 tobe a model/reference organism for studying mycobiont–photobiont association patterns in lichensymbioses. Trebouxia sp. TR9 is the first symbiotic, lichen-forming microalga for which an exhaustivecharacterization of cellular ultrastructure, physiological traits, genetic and genomic diversity is available.The cellular ultrastructure was studied by light, electron and confocal microscopy; physiologicaltraits were studied as responses to different abiotic stresses. The genetic diversity was previouslyanalyzed at both the nuclear and organelle levels by using chloroplast, mitochondrial, and nucleargenome data, and a multiplicity of phylogenetic analyses were carried out to study its intraspecificdiversity at a biogeographical level and its specificity association patterns with the mycobiont.Here, Trebouxia sp. TR9 is formally described by applying an integrative taxonomic approach and ispresented to science as Trebouxia lynnae, in honor of Lynn Margulis, who was the primary modernproponent for the significance of symbiosis in evolution. The complete set of analyses that werecarried out for its characterization is provided

A Phase 2 study of cisplatin analog CI-973 in the treatment of patients with refractory, advanced ovarian cancer

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71591/1/j.1525-1438.1996.06040257.x.pd

Cross Taxon Congruence Between Lichens and Vascular Plants in a Riparian Ecosystem

Despite that congruence across taxa has been proved as an effective tool to provide insights into the processes structuring the spatial distribution of taxonomic groups and is useful for conservation purposes, only a few studies on cross-taxon congruence focused on freshwater ecosystems and on the relations among vascular plants and lichens. We hypothesized here that, since vascular plants could be good surrogates of lichens in these ecosystems, it would be possible to assess the overall biodiversity of riparian habitats using plant data only. In this frame, we explored the relationship between (a) species richness and (b) community composition of plants and lichens in a wetland area located in central Italy to (i) assess whether vascular plants are good surrogates of lichens and (ii) to test the congruence of patterns of species richness and composition among plants and lichens along an ecological gradient. The general performance of plant species richness per se, as a biodiversity surrogate of lichens, had poor results. Nonetheless, the congruence in compositional patterns between lichens and vascular plants varied across habitats and was influenced by the characteristics of the vegetation. In general, we discussed how the strength of the studied relationships could be influenced by characteristics of the data (presence/absence vs. abundance), by the spatial scale, and by the features of the habitats. Overall, our data confirm that the more diverse and structurally complex the vegetation is, the more diverse are the lichen communities it hosts