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Phase I/II translational trial evaluating the molecular determinants of pazopanib plus interferon alpha efficacy in advanced renal cell carcinoma. The expression levels of TNF- a, endoglin and PDL1 correlated with response at eight weeks after treatment initiation. This suggests a crucial role of vascular remodelling and inflammatory-mediated immune cell infiltration for an optimal response to pazopanib plus interferon alpha combination. Introduction: The therapeutic repertoire available for advanced renal cell carcinoma (RCC), including tyrosine kinase inhibitors (TKIs) and immunotherapy, required for molecular biomarkers for response. Patients and Methods: This was a phase I to II trial on the combination of pazopanib with interferonalpha (INF-2A) as first-line treatment for advanced RCC. The primary endpoint was recommended phase II dose (RP2D) and efficacy in terms of objective response rate (ORR, RECIST 1.1 criteria). Secondary endpoints included safety and a translational study of molecular biomarkers in serum and exosomes from peripheral blood samples at three-time points: baseline, 8 weeks of treatment, and progression of the disease. Results: Between July 2011 and July 2017, 53 eligible patients were treated and followed up (I, n = 20; II, n = 33). Pazopanib 800 mg + INF-2A 3 MIUs showed a manageable safety profile; therefore, it was selected for dose expansion. Overall, grade 3/4 toxicities were reported in 24 (72.7%) patients. The ORR was 27.2%. The 12-month OS rate was 83.6% (median not reached), and after 30.9 months of followup, 24 (72.7%) patients were still alive. CCL2, IL8, TNF- a, and PD-L1 were significantly overexpressed after treatment initiation, while TGF- ß1 and CCL5 were significantly decreased. TNF- a, endoglin, and PDL1 expression are correlated with the response after treatment initiation. Conclusion: The trial did not reach its pre-specified target ORR. However, OS was longer than expected with pazopanib monotherapy. Changes in the molecular profile suggest a crucial role of vascular remodeling and inflammatory-mediated immune cell infiltration in optimal response to pazopanib plus INF-2A. [ABSTRACT FROM AUTHOR]

The formation of new blood vessels plays a crucial for the development and progression of pathophysiological changes associated with a variety of disorders, including carcinogenesis. Angiogenesis inhibitors (anti-angiogenics) are an important part of treatment for some types of cancer. Some natural products isolated from marine invertebrates have revealed antiangiogenic activities, which are diverse in structure and mechanisms of action. Many preclinical studies have generated new models for further modification and optimization of anti-angiogenic substances, and new information for mechanistic studies and new anti-cancer drug candidates for clinical practice. Moreover, in the last decade it has become apparent that galectins are important regulators of tumor angiogenesis, as well as microRNA. MicroRNAs have been validated to modulate endothelial cell migration or endothelial tube organization. In the present review we summarize the current knowledge regarding the role of marine-derived natural products, galectins and microRNAs in tumor angiogenesis. [ABSTRACT FROM AUTHOR]

A benefit of anti-angiogenic drugs is improved tumor immune tolerance. Regulatory T cells (Tregs) in the tumor microenvironment mediate tumor immune tolerance and anti-angiogenic drugs not only indirectly affect Tregs via dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) but they can also act directly on Tregs causing immunosuppression. Specifically, these drugs may induce differentiation and chemotaxis and reduce the number and function of Tregs by targeting vascular endothelial growth factor receptor 2 (VEGFR-2) and neuropilin-1 (NRP-1) on the cell surface. Recently, anti-angiogenic drugs have been documented to promote a new way of thinking about tumor immunotherapy: clinical application of Tregs and related immunosuppressive molecules may be promising targets for synergistic tumor immunotherapy. [ABSTRACT FROM AUTHOR]

Background & Aims: Based on the success of sorafenib, several anti-angiogenic therapies are currently evaluated in advanced hepatocellular carcinomas. Few biological data are currently available from patients that may help understanding mechanisms of acquired resistance to these drugs. Herein, we report translational data from a post-treatment surgical specimen in a patient who experienced acquired resistance to sunitinib. Methods: Clinical, radiological, and pathological data were collected before treatment, under treatment, and at the time of tumor progression. In addition, a biomolecular analysis was performed at the time of progression. Results: In this patient with non-alcoholic steatohepatitis, initial response to sunitinib was followed by tumor progression within 6months of treatment, requesting salvage surgical resection. Surprisingly, pathological examination on post-treatment specimens revealed the presence of two juxtaposed tissue components containing either sarcomatoid-like mesenchymal cells or well- to moderately-differentiated hepatocellular carcinoma cells. Cancer cells retain a high α-fetoprotein expression in both components. However, while cells from carcinoma expressed E-cadherin but no vimentin, cancer cells from the mesenchymal component highly expressed vimentin and lost E-cadherin protein expression as measured by immunostaining. HMGA2 and Ki67 mRNA were also expressed at higher levels in mesenchymal than in carcinoma cells. Conclusion: This case report suggests the occurrence of an epithelial-to-mesenchymal transition in discrete areas of hepatocellular carcinomas developing resistance to sunitinib. [Copyright &y& Elsevier]

Abstract: Most of patients with hepatocellular carcinoma (HCC) cannot benefit from surgical therapies. Among nonsurgical options, only radiofrequency can challenge surgery for small size tumours. Conformal radiotherapy is likely highly efficient on solitary tumours, but controlled studies are warranted to conclude. Other options are purely palliative. Transarterial hepatic chemoembolization is the goal-standard for multifocal hepatocellular carcinoma and sorafenib for hepatocellular carcinoma with portal vein invasion, leading to modest but significant benefit on survival rates. Yttrium-90 radioembolization is under evaluation through controlled studies, and could be of major interest for multifocal hepatocellular carcinoma with or without portal venous invasion. [ABSTRACT FROM AUTHOR]

[Display omitted] • Metronomic chemotherapy is optimized with tuned drug doses and drug-free breaks. • Innate immunity can be just as essential in antitumor efficacy as adaptive. • Conventional maximum tolerated dose administration can often be immunosuppressive. • Optimal drug scheduling may vary based on drug mechanism/target and cancer type. • Metronomic chemotherapy may be delivered with current biomaterials for clinical ease. Metronomic chemotherapy has been shown to elicit anti-tumor immune response and block tumor angiogenesis distinct from that observed with maximal tolerated dose (MTD) therapy. This review delves into the mechanisms behind anti-tumor immunity and seeks to identify the differential effect of dosing regimens, including daily low-dose and medium-dose intermittent chemotherapy (MEDIC), on both innate and adaptive immune populations involved in observed anti-tumor immune response. Given reports of VEGF/VEGFR blockade antagonizing anti-tumor immunity, drug choice, dose, and selective delivery determined by advanced formulations/vehicles are highlighted as potential sources of innovation for identifying anti-angiogenic modalities that may be combined with metronomic regimens without interrupting key immune players in the anti-tumor response. Engineered drug delivery mechanisms that exhibit extended and local release of anti-angiogenic agents both alone and in combination with chemotherapeutic treatments have also been demonstrated to elicit a potent and potentially systemic anti-tumor immune response, favoring tumor regression and stasis over progression. This review examines this interplay between various cancer models, the host immune response, and select anti-cancer agents depending on drug dosing, scheduling/regimen, and delivery modality. [ABSTRACT FROM AUTHOR]