The aim of this review is to summarize advances that have been made in the delivery of phytochemicals for cancer therapy by the use of nanotechnology. Over recent decades, much research effort has been invested in developing phytochemicals as cancer therapeutic agents. However, several impediments to their wide spread use as drugs still have to be overcome. Among these are low solubility, poor penetration into cells, high hepatic disposition, and narrow therapeutic index. Rapid clearance or uptake by normal tissues and wide tissue distribution result in low drug accumulation in the target tumor sites can result in undesired drug exposure in normal tissues. Association with or encapsulation in nanoscale drug carriers is a potential strategy to address these problems. This review discussed lessons learned on the use of nanotechnology for delivery of phytochemicals that been tested in clinical trials or are moving towards the clinic.
Copyright © 2015. Published by Elsevier Inc.

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The MUC16 mucin is overexpressed and aberrantly glycosylated in ovarian carcinomas. Immunodetection of circulating MUC16 is one of the most used cancer biomarker assays, but existing antibodies to MUC16 fail to distinguish normal and aberrant cancer glycoforms. Although all antibodies react with the tandem-repeat region, their epitopes appear to be conformational dependent and not definable by a short peptide. Aberrant glycoforms of MUC16 may constitute promising targets for diagnostic and immunotherapeutic intervention, and it is important to develop well-defined immunogens for induction of potent MUC16 immunity. Here, we developed a MUC16 vaccine based on a 1.7TR (264 aa) expressed in Escherichia coli and in vitro enzymatically glycosylated to generate the aberrant cancer-associated glycoform Tn. This vaccine elicited a potent serum IgG response in mice and we identified two major immunodominant linear peptide epitopes within the tandem repeat. We developed one monoclonal antibody, 5E11, reactive with a minimum epitope with the sequence FNTTER. This sequence contains potential N- and O-glycosylation sites and, interestingly, glycosylation blocked binding of 5E11. In immunochemistry of ovarian benign and cancer lesions, 5E11 showed similar reactivity as traditional MUC16 antibodies, suggesting that the epitope is not efficiently glycosylated. The study provides a vaccine design and immunodominant MUC16 TR epitopes.
© The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: [email protected].

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On April 14, 2016 Asana BioSciences, LLC reported that it will present preclinical data regarding its product candidate, ASN007A, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, being held in New Orleans, Louisiana, from April 16-20, 2016 (Press release, Asana BioSciences, APR 14, 2016, View Source [SID:1234510836]). The presentation details are as follows:

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Abstract Number:
187
Title:
ASN007, a potent ERK 1/2 inhibitor with strong antitumor activity in multiple RAS mutant models
Presenter:
Sanjeeva Reddy, Ph.D., Asana BioSciences
Location:
Section 7, Poster Board Number 12
Date:
Sunday, April 17, 2016
Times:
1:00pm – 5:00pm

ERK kinases play a crucial role in RAS/MAPK pathway, which is upregulated in a wide variety of tumors through mutations in RAS or BRAF genes. ERK inhibitors are expected to treat a wide range of tumors with BRAF, MEK, NRAS, HRAS and KRAS mutations including colorectal, pancreatic, lung, breast, ovarian, melanoma and prostate. In addition, they have potential to overcome resistance to BRAF and MEK inhibitors in patients.

ASN007A is one of the lead compounds from Asana’s ERK 1/2 inhibitor program with low nanomolar IC50 values. It showed strong anti-proliferative activity in both BRAF and RAS mutant cell lines, as well as potent anti-proliferative activity in a number of KRAS, NRAS and HRAS mutant cell lines representing various histological tumor types. It demonstrated strong inhibition of tumor growth in multiple xenograft models in mice and was well tolerated at efficacious doses. Based on its profile in preclinical studies, ASN007A is a potential best-in-class molecule expected to show strong efficacy in BRAF and various RAS mutant cancers.

BCL2 blunts activation of the mitochondrial pathway to apoptosis and high-level expression is required for chronic lymphocytic leukemia (CLL) survival. Venetoclax (ABT-199) is a small molecule selective inhibitor of BCL2 currently in clinical trials for CLL and other malignancies. In conjunction with the phase I first-in-human clinical trial of venetoclax in patients with relapsed or refractory CLL (M12-175), we investigated the mechanism of action of venetoclax in vivo, explored whether in vitro sensitivity assays or BH3 profiling correlated with in vivo responses in patients, and determined whether loss of TP53 function affected responses in vitro and in vivo. In all samples tested, venetoclax induced death of CLL cells in vitro at concentrations achievable in vivo, with cell death evident within four hours. Apoptotic CLL cells were detected in vivo 6 or 24 hours after a single 20mg or 50mg dose in some patients. The extent of mitochondrial depolarisation by a BIM BH3 peptide in vitro was correlated with percentage reduction of CLL in the blood and bone marrow in vivo, while the LC50derived from standard cytotoxicity assays was not. CLL cell death in vitro and the depth of clinical responses were independent of deletion of chromosome 17p,TP53mutation and TP53 function. These data provide direct evidence that venetoclax kills CLL cells in a TP53-independent fashion by inhibition of BCL2 in patients, and support further assessment of BH3 profiling as a predictive biomarker for this drug.
Copyright © 2016 American Society of Hematology (ASH) (Free ASH Whitepaper).

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Notch is long recognized as a signaling molecule important for stem cell self-renewal and fate determination. Here, we reveal a novel adhesive role of Notch-ligand engagement in hematopoietic stem and progenitor cells (HSPCs). Using mice with conditional loss of O-fucosylglycans on Notch EGF-like repeats important for the binding of Notch ligands, we report that HSPCs with faulty ligand binding ability display enhanced cycling accompanied by increased egress from the marrow, a phenotype mainly attributed to their reduced adhesion to Notch ligand-expressing stromal cells and osteoblastic cells and their altered occupation in osteoblastic niches. Adhesion to Notch ligand-bearing osteoblastic or stromal cells inhibits wild type but not O-fucosylglycan-deficient HSPC cycling, independent of RBP-JK -mediated canonical Notch signaling. Furthermore, Notch-ligand neutralizing antibodies induce RBP-JK -independent HSPC egress and enhanced HSPC mobilization. We, therefore, conclude that Notch receptor-ligand engagement controls HSPC quiescence and retention in the marrow niche that is dependent on O-fucosylglycans on Notch.
© 2015 AlphaMed Press.

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