Oncolytic virotherapy for pancreatic ductal adenocarcinoma: A glimmer of hope after years of disappointment?

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and highly lethal malignancies. Existing therapeutic interventions have so far been unsuccessful in improving prognosis, and survival remains very poor. Oncolytic virotherapy represents a promising, yet not fully explored, alternative strategy for the treatment of PDAC. Oncolytic viruses (OVs) infect, replicate within and lyse tumor cells specifically and stimulate antitumor immune responses. Multiple challenges have hampered the efficacy of oncolytic virotherapy for PDAC, the most significant being the desmoplastic and immunosuppressive pancreatic tumor microenvironment (TME). The TME limits the access of therapeutic drugs and the infiltration of effector T cells and natural killer (NK) cells into the tumor mass. Additionally, cancer cells promote the secretion of immunosuppressive factors and develop mechanisms to evade the host immune system. Because of their oncolytic and immune-stimulating properties, OVs are the ideal candidates for counteracting the pancreatic immunosuppressive TME and for designing combination therapies that can be clinically exploited in clinical trials that seek to improve the prognosis of PDAC.     

Metastatic cancer stem cells: A new target for anti-cancer therapy?

Over the past few years, supporting evidence for the cancer stem cell hypothesis has been provided for an increasing number of tumor entities. According to this hypothesis, only a small population of undifferentiated cells with stem cell characteristics has the ability to form tumors through asymmetric division and subsequent differentiation of the progeny into the heterogeneous cell types that comprise a tumor. Recently, we were able to show that cancer stem cells are not only responsible for tumorigenesis, but that they contain a subpopulation characterized by CXCR4 expression which is exclusively capable of disseminating and subsequently providing the substrate for tumor metastasis. Of note, these recent advances in our understanding of cancer stem cell biology raise more questions than they answer. Some of these arising questions regarding the targeted elimination of these cancer stem cells will be addressed in this perspective.     

Can mosquitoes be bitten? A new hope for anti-malarial drug design

The crystal structure of PfPK5, a cyclin-dependent kinase from Plasmodium falciparum, is the first CDK structure determined from a nonhuman source and represents a potential new target for anti-malarial drug development.     

RNA interference: new mechanisms for targeted treatment?

Nucleic acid-based sequence-specific therapeutic intervention offers the potential for treatment of particular cancers without side effects. RNA interference (RNAi) induced by small interfering RNA (siRNA) (19-21 bp) is a normal cellular mechanism leading to highly specific and extraordinarily efficient degradation of the corresponding mRNA. The mechanism of RNAi as well as strategies for the design and delivery of siRNA are described. The growing role of RNAi in target validation for cancer-specific genetic aberrations is discussed. We attempt an early assessment of the potential for using RNAi technologies to treat cancer directly, especially hematologic malignancies. Promising targets for specific gene silencing in hematologic oncology include oncogenic fusion proteins and oncogenes activated by point mutations. Potency and specificity of gene silencing are the major advantages of the new RNAi technology over other nucleic acid-based gene targeting approaches. Crucial questions for pharmaceutical interventions remain. Advances in the areas of delivery, systemic spreading and duration of the silencing effect are necessary before the methodology can enter clinical oncology.     

A glimmer of hope for diabetics?

Diabetes affects 150 million people worldwide and results from abnormal function of pancreatic islets. The scarcity of human tissue donors has focused interest in developing renewable sources of insulin-producing cells appropriate for engraftment. Advances in stem cell technology and transdifferentiation techniques have provided powerful tools to study pancreatic development, function and disease. Recent results from these two approaches could have significant implications for future therapies of diabetes.     

2010: A new beginning for biodiversity?

Proclaimed “International Year of Biodiversity”, will 2010 hold all its promises? Reminder: initiated by the Convention on Biological Diversity ratified after the global summit in Rio de Janeiro, delegations from more than one hundred countries gathered in Johannesburg in 2002 and committed themselves to slowing the erosion of biodiversity by 2010. The European Union was more ambitious (or reckless?) and even spoke about halting this erosion (European Environment Agency, Progress towards the European 2010 biodiversity target, 2009) [1]! Well, that date has come and the overall appraisal that has been made formally in Nagoya in October this year was not so brilliant (see Leadley et al., 2010) [2]–but the same slogan has been launched for 2020! The aim here is not to repeat that appraisal, but, after considering the broad outlines, to evoke some of the issues and challenges that inevitably result from the great question of the protection and management of global biodiversity.     

Pancreatic cancer and SBRT: A new potential option?

Local control remains a major issue for patients with unresectable, locally advanced pancreatic cancer (LAPC). The role of radiation therapy in the management of LAPC represents an area of some controversy. Stereotactic body radiotherapy is an emerging treatment option for LAPC as it can provide a therapeutic benefit with significant advantages for patients’ quality of life over standard conventional chemoradiation. The objective of this review is to present the rationale for stereotactic body radiotherapy in LAPC, as well as to discuss the potential limitations and caveats of the currently available studies.     

Senescent cells: A new Achilles’ heel to exploit for cancer medicine?

Cellular senescence is a typical tumor‐suppressive mechanism that restricts the proliferation of premalignant cells. However, mounting evidence suggests that senescent cells, which also persist in vivo, can promote the incidence of aging‐related disorders principally via the senescence‐associated secretory phenotype (SASP), among which cancer is particularly devastating. Despite the beneficial effects of the SASP on certain physiological events such as wound healing and tissue repair, more studies have demonstrated that senescent cells can substantially contribute to pathological conditions and accelerate disease exacerbation, particularly cancer resistance, relapse and metastasis. To limit the detrimental properties while retaining the beneficial aspects of senescent cells, research advancements that support screening, design and optimization of anti‐aging therapeutic agents are in rapid progress in the setting of prospective development of clinical strategies, which together represent a new wave of efforts to control human malignancies or mitigate degenerative complications.     

Mesenchymal stem cells: weapons or dangers for cancer treatment?

Mesenchymal stem cells (MSC) have attracted recent attention for their cell therapy potential, based in particular on their immunosuppressive properties, which have served as the basis for the treatment of autoimmune diseases. Interestingly, MSC have been used in cell therapy strategies to deliver therapeutical genes. Cell therapy approaches taking advantages of MSC have been proposed, as MSC display a potential tropsim for tumors. However, all these strategies raise a series of questions about the safety of MSC, as MSC could enhance tumor growth and metastasis. This review summarizes recent findngs about MSC in carcinogenesis.     

Pyroptosis,a target for cancer treatment?

Pyroptosis is a newly discovered form of programmed cell death mediated by the gasdermin protein, that is accompanied by inflammation and immune response. A growing body of evidence suggests that pyroptosis is closely related to cancer, and it is becoming a new cancer research topic. Studies have suggested that different cancer cells activate pyroptosis in different ways and that the effects of pyroptosis vary in different cancer backgrounds. In this article, we briefly introduce the definition, characteristics, and activation pathways of pyroptosis. Then we review the complex effects of pyroptosis on cancer development, which generally include inhibition of cancer cell viability, impacts on the invasion and migration of cancer cells, improvement of antitumor immunity, and enhancement of chemotherapy sensitivity. We also discuss drugs and compounds that can induce pyroptosis, as well as the interaction between pyroptosis and apoptosis. Elucidating the mechanisms of the complex effects of pyroptosis is likely to pave the way for therapeutic approaches for cancer in the future.

     

Histone methyltransferases: a new class of therapeutic targets in cancer treatment?

Epigenetic gene regulation contributes, together with genetic alterations, to cancer development and progression. In contrast to genetic disorders, the possibility of reversing epigenetic alterations has provided original targets for therapeutic application. In the last years, work has been focused on the pharmacological restoration of epigenetic regulation balance using epidrugs which yield hopes for novel strategy in cancer therapy. Histone acetylation and DNA methylation are epigenetic modifications which have been closely linked to the pathology of human cancers, and inhibitors of both enzyme classes for clinical use are at hands. Novel findings accumulated during the last years both in chemistry and biomedical applications give rise to new targeted treatments against cancer. Since their links with pathogenesis and progression of cancer were recognized, histone methyltransferases emerge as promising therapeutic targets in cancer treatment.     

Visceral pain: gut microbiota,a new hope?

Background

Visceral pain is a complex and heterogeneous disorder, which can range from the mild discomfort of indigestion to the agonizing pain of renal colic. Regulation of visceral pain involves the spinal cord as well as higher order brain structures. Recent findings have linked the microbiota to gastrointestinal disorders characterized by abdominal pain suggesting the ability of microbes to modulate visceral hypersensitivity and nociception to pain.

Main body

In this review we describe the neuroanatomical basis of visceral pain signaling and the existing evidence of its manipulation exerted by the gut microbiota. We included an updated overview of the potential therapeutic effects of dietary intervention, specifically probiotics and prebiotics, in alleviating hypersensitivity to visceral pain stimuli.

Conclusions

The gut microbiota dramatically impacts normal visceral pain sensation and affects the mechanisms mediating visceral nociception. Furthermore, manipulation of the gut microbiota using prebiotics and probiotics plays a potential role in the regulation of visceral pain disorders.