Current Drug Targets - Volume 17, Issue 15, 2016

Endothelial to mesenchymal transition (EndMT) is a poorly understood phenomenon that results in normal endothelial cells acquiring a mesenchymal phenotype. EndMT has been observed in a number of pathological conditions, from cancer to fibrosis to cardiovascular disease and the process itself may play an important mechanistic role in the development of these disease states.

Antiangiogenic resistance is a major problem in cancer therapeutics. Preclinical research has identified several compensatory proangiogenic pathways that arise upon vascular endothelial growth factor inhibition, several of which have led to the development of novel drugs. However, the combination of two or more targeted agents in the angiogenesis system is hampered by toxicity, as the system is involved in normal physiology. We propose a different approach for improving the efficacy of this drug class, which takes advantage of aberrant cancer metabolism. Several features distinguish cancer metabolism from that of normal cells, including increased glycolysis, glutaminolysis, and pentose-phosphate shunt, as well as an anaplerotic shift of the Krebs cycle. In addition, these aberrations are driven by most of the common mutations that can be targeted by drugs. Antiangiogenics may hamper the ability of cancer to sustain aberrant metabolism due to their impacts on nutrient and oxygen supplies, and thus they may induce some metabolic pathways to become essential for tumor survival (induced essentiality or contextual lethality, a type of synthetic lethality). Thus, some metabolic and signaling pathways that are otherwise nonessential may induce synthetic lethality when inhibited in combination with antiangiogenics. The key problems, however, are interpatient and intratumor heterogeneity, as not all patients with the same tumor type show the same metabolic traits and the same metabolic reprogramming in response to antiangiogenics. With each cancer there are heterogeneous hypoxic areas. Integrating dynamic tracking of metabolism may allow us to tailor our choices of companion drugs with antiangiogenics, taking advantage of window-of-opportunity designs.

The mechanisms of tumor growth and progression involve the activation of different processes such as neovascularization and angiogenesis. These processes involve tumoral cells and stromal cells. Hence, inhibiting angiogenesis affects tumor growth and proliferation in patients with different types of cancer. Nevertheless, tumoral cells and stromal components are responsible for the resistance to antiangiogenic therapies. The majority of tumors respond to this type of therapy; however, some tumors may be indifferent to antiangiogenic therapies (intrinsic resistance) and other tumors become resistant during treatment (acquired resistance). Different strategies have been proposed to prevent resistance. Preclinical studies and clinical trials are focused to fight this therapeutic approach in order to prevent or delay tumor resistance to antiangiogenic therapies.

One proposed mechanism through which antiangiogenics exert their effect in epithelial malignancies is by improving the status of the aberrant vascular network and secondarily facilitating the delivery of concurrently administrated cytotoxic agents. During this process, known as vascular normalization, the oxygenation of the tumor is usually improved. Many mechanisms of resistance have been proposed to evade the action of this drug class elicited through this mechanism of action. However, a less explored mechanism of action is vascular choking, as increased hypoxia is thought to be associated with the inevitable progression of certain tumor-promotion features. Here we review the available evidence regarding decreased blood flow as a mechanism of action of antiangiogenics at the preclinical and clinical level. Similar to vascular normalization, there are also escape mechanisms against chronic hypoxia generated by treatment with antiangiogenics. Among other compensatory responses, chronic hypoxia is related with the upregulation of lipidic anabolism. Therefore, we focus on how fatty acid synthase, a key player in this response, can be targeted to delay acquired resistance against antiangiogenics, including experimental data from our group. This effect seems to be specific to those cases in which the antiangiogenic treatment induces a hypoxic response, but not in models where the antiangiogenic agent induced normalizing effects. Whether antiangiogenics induce vascular normalization or a hypoxic environment seems to be tractable with a noninvasive PET-tracer: 18F-fluoromisonidazole PET.

Drug resistance remains an ongoing challenge for the majority of patients treated with inhibitors of the vascular endothelial growth factor (VEGF) pathway, a key regulator of tumor angiogenesis. Preclinical models have played a significant role in identifying multiple complex mechanisms of antiangiogenic treatment failure. Yet questions remain about the optimal methodology to study resistance that may assist in making clinically relevant choices about alternative or combination treatment strategies. The origins of antiangiogenic treatment failure may stem from the tumor vasculature, the tumor itself, or both together, and preclinical methods that define resistance are diverse and rarely compared. We performed a literature search of the preclinical methodologies used to examine resistance to VEGF pathway inhibitors and identified 109 papers from more than 400 that use treatment failure as the starting point for mechanistic study. We found that definitions of resistance are broad and inconsistent, involve only a small number of reagents, and derive mostly from in vitro and in vivo methodologies that often do not represent clinically relevant disease stages or progression. Together, this literature analysis highlights the challenges of studying inhibitors of the tumor microenvironment in the preclinical setting and the need for improved methodology to assist in qualifying (and quantifying) treatment failure to identify mechanisms that will help predict alternative strategies in patients.

Background: Sporadic data are available about pazopanib use in patients with metastatic renal cell carcinoma (mRCC) undergoing dialysis and no systematic review has been previously performed about this issue. Objective: The objective of the present mini-review is to provide an overview of clinical outcomes of pazopanib in this population, in order to support the clinical oncologist for the treatment choice and management. Results: All the literature ever published about mRCC dialysis patients receiving pazopanib, until August 2015, was evaluated: only two case series emerged from our search and one more patient from our department was also included, with a total of 11 mRCC dialysis patients overall. Moreover, we described our case of intrapatient dose titration of pazopanib during dialysis. Conclusion: The continued treatment schedule, the short half-life, the predominantly hepatic metabolism, the wide possibility of dose modulation, the favorable tolerability profile and the similar efficacy respect to sunitinib represent factors in favor of pazopanib as first line mRCC treatment in dialysis patients. The knowledge and the good management of toxicity during pazopanib treatment can lead, also in dialysis patients, to the best and longest application of the drug, taking into account the concept of a dose escalation guided by toxicity as a marker of efficacy. The review, together with our single case report, confirmed the efficacy, the good tolerability and the maneuverability of pazopanib treatment in mRCC patients undergoing dialysis.

Sox (SRY-related HMG-box) family genes are important regulators of cell development, homeostasis, and regeneration. Deregulation of certain members of the Sox gene family has been implicated in a number of human malignancies, including in sarcoma. Accumulating evidence suggests that Sox genes play crucial roles in sarcoma cell pathogenesis, growth, and proliferation. Here, we review the biological relevance of Sox2 and Sox9 genes in osteosarcoma, chondrosarcoma and chordoma; Sox2, Sox6, and Sox17 genes in Ewing’s sarcoma; Sox2, Sox9, and Sox10 genes in synovial sarcoma; Sox2 gene in fibrosarcoma; and Sox21 gene in liposarcoma. These findings potentiate the targeting of Sox genes for novel therapeutic interventions in sarcoma and may also hold valuable clinical potential to improve the care of patients with sarcoma.

Poor absorption, short half-life and resistance development are some of the major factors responsible for reduced drug efficacy. Lipophilic prodrugs can offer certain advantages to overcome these challenges. Chemical derivatization of hydrophilic agents with lipophilic pro-moieties can significantly elevate drug diffusion across absorptive membranes. Moreover, the desired linkage (ester vs. amide) may be selected to improve stability in vivo. Importantly, an appropriate selection of pro-moiety (targeting ligand) may promote drug specificity and selectivity. In this review article, an attempt has been made to summarize lipophilic prodrugs employed to improve delivery and efficacy of a wide range of poorly permeable but highly potent therapeutic agents. In addition, a brief overview on recent application of lipophilic prodrugs to promote encapsulation of hydrophilic agents in nano-sized drug carriers has been provided.

The chemical modifications of polysaccharides involve the use of chemical methods to modify some special structures or functional groups of polysaccharides on the main chains or side chains. The chemical methods include sulfation, phosphorylation, acetylation, carboxymethylation etc. Therefore, spatial structures, and physical and chemical properties of polysaccharides change, which enhance the biological activities of polysaccharides, e.g., immune regulation, antivirus, anti-tumor, anti-oxidation, etc.

Cirrhosis is a diffuse pathophysiological state of the liver considered to be the final stage of various liver injuries, characterized by chronic necroinflammatory and fibrogenetic processes, with subsequent conversion of normal liver architecture into structurally abnormal nodules, dense fibrotic septa, concomitant parenchymal exaustment and collapse of the liver tissue. Alcoholic liver disease and chronic infections due to HBV and/or HCV constitute the main causes of liver cirrhosis worldwide. During a lag time of 15 to 30 years, chronic liver diseases can lead to liver cirrhosis and its complications. Active hepatic inflammation plays a pivotal role in the inflammation- necrosis-regeneration process, which eventually leads to liver cirrhosis and hepatocellular carcinoma. Prognosis of liver cirrhosis is highly variable and influenced by several variables, such as etiology, severity of liver disease, presence of complications and comorbidities. In advanced cirrhosis, survival decreases to one or two years. Correct advanced diagnosis and selected treatment with different molecules may help in understanding mechanisms of fibrogenesis, the driving forces of cirrhosis’s pathogenesis, and the scrupulous approach to more effective therapeutic procedures. Prevention of fibrosis with further deterioration of liver function through specific treatments is always required, through the removal of the underlying causes of liver disease. Advanced liver disease, with subsequent complications, requires targeted treatment. Therefore, the aim of this review is to assess the diagnosis and treatment of liver cirrhosis on the pathophysiological bases, searching for relevant studies published in English using the PubMed database from 2011 to the present.

Gastric and gastro-esophageal cancers (GC/GEJ) appear as the second cancer-related death worldwide. Diagnosis is made at an advanced stage offering a curative attempt in less than 50% of cases. Despite the improvements of the systemic cytotoxic chemotherapy regimens, the prognosis of patients with metastatic GC/GEJ cancer remains poor. Recent insights in biochemical pathways have permitted to identify potential targets. The extracellular domain of HER2 receptors is implicated in cells’ proliferation and in the anti-apoptotic process occurring in GC/GEJ cancers. Trastuzumab, a monoclonal antibody targeting HER2, in addition to chemotherapy permitted to obtain more than one year of survival in HER2-positive advanced GC/GEJ cancers. Recently, ramucirumab, a humanized monoclonal antibody targeting VEGFR-2 receptor demonstrated its efficacy as a second line treatment for patients with advanced GC/GEJ cancer. These encouraging results have justified evaluating targeted therapies in GC/GEJ cancers. In this review, we summarize targeted therapies that might present clinical efficacy in the treatment of advanced GC/GEJ cancers.