Author: [email protected]

PIK3CA amplification is associated with poor prognosis among patients with curatively resected esophageal squamous cell carcinoma.

To investigate the clinicopathologic characteristics and the prognostic impact of PIK3CA gene amplification in curatively resected esophageal squamous cell carcinoma (ESCC). Using 534 curatively resected ESCCs, the PIK3CA gene copy number was evaluated with fluorescent in situ hybridization. PIK3CA amplification was defined as PIK3CA/centromere 3 ratio is ≥ 2.0 or average number of PIK3CA signals/tumor cell nucleus ≥ 5.0. PIK3CA mutations in exon 9 and 20, encoding the highly conserved helical and kinase domains were assessed by direct sequencing in 388 cases. PIK3CA amplification was detected in 56 (10.5%) cases. PIK3CA amplification was significantly associated with higher T-stage (P=0.026) and pathologic stage (P=0.053). PIK3CA amplification showed a significantly shorter disease free survival (DFS) compared with that of non-amplified group (33.4 vs 63.1 months, P=0.019). After adjusting for gender, tumor location, pathologic stage, histologic grade and adjuvant treatment, PIK3CA amplification was significantly associated with a shorter DFS (adjusted hazard ratio [AHR] 1.53; 95% CI, 1.10-2.17; P=0.02). Though the statistical insignificance, PIK3CA amplification showed tendency of shorter OS (52.1 vs 96.5 moths, P=0.116). PIK3CA mutations were detected in 6 (1.5%) of 388 cases; 5 cases with exon 9 mutations in E545K while one exon 20 mutation in H1047L. PIK3CA amplification is a frequent oncogenic alteration and associated with shorter survival, suggesting its role as a prognostic biomarker in resected ESCC. PIK3CA amplification may represent a promising therapeutic target for ESCC.

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Photoactivated drug delivery and bioimaging.

Among the various types of diseases, cancer remains one of the most leading causes of mortality that people are always suffering from and fighting with. So far, the effective cancer treatment demands accurate medical diagnosis, precise surgery, expensive medicine administration, which leads to a significant burden on patients, their families, and the whole national healthcare system around the world. In order to increase the therapeutic efficiency and minimize side effects in cancer treatment, various kinds of stimuli-responsive drug delivery systems and bioimaging platforms have been extensively developed within the past decades. Among them, the strategy of photoactivated approach has attracted considerable research interest because light enables the precise control, in a highly spatial and temporal manner, the release of drug molecules as well as the activation of bioimaging agents. In general, several appropriate photoresponsive systems, which are normally sensitive to ultraviolet (UV) or visible light irradiation to undergo the multiple reaction pathways such as photocleavage and photoisomerization strategy etc. have been mainly involved in the light activated cancer therapies. Considering the potential issues of poor tissue penetration and high photoctotoxicity of short wavelength light, the recently emerged therapies based on long-wavelength irradiation, e.g., near-infrared (NIR) light (700-1000 nm), have displayed distinct advantages in biomedical applications. The light irradiation at NIR window indicates minimized photodamage, deep penetration, and low autofluorescence in living cells and tissues, which are of clinical importance in the desired diagnosis and therapy. In this review article, we introduce the recent advances in light-activated drug release and biological imaging mainly for anticancer treatment. Various types of strategies such as photocage, photo-induced isomerization, optical upconversion, and photothermal release by which different wavelength ranges of light can play the important roles in the controlled therapeutic or imaging agents delivery, and activation will be systemically discussed. In addition, the challenges and future perspectives for photo-based cancer theranostics will be also summarized. For further resources related to this article, please visit the WIREs website.
© 2016 Wiley Periodicals, Inc.

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PAK5 is auto-activated by a central domain that promotes kinase oligomerization.

PAKs (p21 activated kinases) are an important class of Rho effectors which contain a Cdc42-Rac1 interaction and binding (CRIB) and a flanking auto-inhibitory domain (AID) which binds the C-terminal catalytic domain. The group II kinases PAK4 and PAK5 are considered significant therapeutic targets in cancer. Among human cancer cell lines we find PAK5 protein levels are much lower than those of PAK4, even in NCI-H446 which has the highest PAK5 mRNA expression among 317 lines screened. Although these two kinases are evolutionarily and structurally related, it has never been established why PAK4 is inactive while PAK5 has high basal activity. Experimentally, the AID of PAK5 is functionally indistinguishable from that of PAK4, pointing to other regions being responsible for higher activity of PAK5. Gel filtration indicates PAK4 is a monomer but PAK5 is dimeric. The central region of PAK5 (residues 109-420) is shown here to promote self-association, and an elevated activity, but has no effect on activation loop Ser602 phosphorylation. These residues allow PAK5 to form characteristic puncta in cells, and removing sequences involved in oligomerization suppresses kinase activity. Our model suggests PAK5 self-association interferes with AID binding to the catalytic domain, thus maintaining its high activity. Further, our model explains the observation that PAK5(1-180) inhibits PAK5in vitro.
©2016 The Author(s).

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Optical and nuclear imaging of glioblastoma with phosphatidylserine-targeted nanovesicles.

Multimodal tumor imaging with targeted nanoparticles potentially offers both enhanced specificity and sensitivity, leading to more precise cancer diagnosis and monitoring. We describe the synthesis and characterization of phenol-substituted, lipophilic orange and far-red fluorescent dyes and a simple radioiodination procedure to generate a dual (optical and nuclear) imaging probe. MALDI-ToF analyses revealed high iodination efficiency of the lipophilic reporters, achieved by electrophilic aromatic substitution using the chloramide 1,3,4,6-tetrachloro-3α,6α-diphenyl glycoluril (Iodogen) as the oxidizing agent in an organic/aqueous co-solvent mixture. Upon conjugation of iodine-127 or iodine-124-labeled reporters to tumor-targeting SapC-DOPS nanovesicles, optical (fluorescent) and PET imaging was performed in mice bearing intracranial glioblastomas. In addition, tumor vs non-tumor (normal brain) uptake was compared using iodine-125. These data provide proof-of-principle for the potential value of SapC-DOPS for multimodal imaging of glioblastoma, the most aggressive primary brain tumor.

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AbbVie and CytomX Announce Strategic Collaboration for Probody Drug Conjugates

On April 21, 2016 AbbVie (NYSE: ABBV) and CytomX Therapeutics, Inc. (Nasdaq: CTMX) reported that they have entered into a collaboration to co-develop and co-commercialize Probody Drug Conjugates against CD71, also known as transferrin receptor 1 (TfR1) (Press release, AbbVie, APR 21, 2016, View Source [SID:1234511255]).

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CD71 is highly expressed in a number of solid and hematologic cancers and has attractive molecular properties for efficient delivery of cytotoxic payloads to tumor cells. Probody therapeutics are designed to take advantage of unique conditions in the tumor microenvironment to enhance the tumor-targeting features of an antibody and reduce drug activity in healthy tissues.

"We believe that the Probody platform provides a differentiated opportunity to combine with our strength in antibody drug conjugates," said Steve Davidsen, Ph.D., vice president, oncology drug discovery, AbbVie. "We are encouraged by the promising preclinical data that CytomX has generated for their Probody drug conjugate programs to-date and look forward to working closely with their team. This collaboration will enable us to expand our innovative pipeline in antibody drug conjugates and leverage our strength in that area to previously unexplored targets."

"This collaboration is another important step toward achieving CytomX’s vision of transforming lives with safer, more effective therapies and allows us to further advance our broad pipeline of Probody therapeutics," stated Sean McCarthy, D.Phil., president and chief executive officer at CytomX. "AbbVie has demonstrated leadership in developing antibody drug conjugates and we look forward to collaborating with their team to realize the full potential of our CD71 Probody drug conjugate program and additional oncology targets."

Probody therapeutics are designed to remain inactive until they are activated by proteases in the tumor microenvironment. As a result, Probody therapeutics bind selectively to tumors and avoid binding to healthy tissue, to minimize toxicity and potentially create safer, more effective therapies. CytomX has generated preclinical data that demonstrates that Probody drug conjugates can safely and effectively target tumor antigens, such as CD71, that are not addressable by conventional antibody-drug conjugates.

Under the terms of the agreement, CytomX and AbbVie will co-develop a Probody drug conjugate against CD71, with CytomX leading pre-clinical and early clinical development. AbbVie will lead later development and commercialization, with global late-stage development costs shared between the two companies. CytomX will receive an upfront payment of $30 million and is eligible to receive up to $470 million in development, regulatory and commercial milestones, pending the achievement of pre-determined outcomes. AbbVie will lead global commercial activities with CytomX eligible to receive a profit share in the U.S. and tiered double-digit royalties on net product sales outside of the U.S. CytomX retains an option to co-promote in the U.S.

AbbVie also receives exclusive worldwide rights to develop and commercialize Probody drug conjugates against up to two additional, undisclosed targets. Should AbbVie ultimately pursue these targets, CytomX is eligible to receive additional milestone and royalty payments per target on any resulting products.