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View the Table of Contents for the August 1 issue of Cancer Research.
Konnikova et al. Page 6516
STAT3 activation is essential for the growth and survival of a surprisingly broad range of human cancers. Similarly, hTERT expression is considered one of the "hallmarks" of cancer. Konnikova et al. show that STAT3 directly regulates hTERT in a variety of different human tumor cells. In addition, they show that growth factors, cytokines, and oxidative stress can regulate hTERT expression in nontransformed primary cells in a STAT3-dependent manner. These results suggest that STAT3 activation is a major mechanism for hTERT up-regulation in human cancer and provides further impetus for targeting STAT3 in cancer therapy.
Belkhiri et al. Page 6583
Amplifications at 17q are frequent genetic changes in upper gastrointestinal carcinomas (UGCs). Belkhiri et al. have shown that Darpp-32 is a critical target that maps to 17q12q21 and is amplified and over-expressed in the majority of UGCs. A concomitant over-expression of Darpp-32 and its isoform t-Darpp was observed in two-thirds of UGCs. The over-expression of Darpp-32 or t-Darpp preserved the mitochondrial potential and provided a potent antiapoptotic effect against several known chemotherapeutic drugs. This potent antiapoptotic advantage in gastrointestinal cells was shown to be Bcl2-mediated, but p53-independent. These findings demonstrate previously unknown functions for Darpp-32 in cancer.
Tyminski et al. Page 6850
Tyminski et al. engineered an oncolytic HSV1 virus designated as MGH2, which destroys glioma tumor cells by replication. MGH2 delivers the prodrug-activating genes, CYP2B1 and shiCE, which activate the chemotherapy agents cyclophosphamide and CPT11, respectively. The study shows that when provided in combination, this oncolytic virus/chemotherapeutic drug combination was more effective than other therapeutic strategies using the drugs alone or in combination. Since the oncolytic virus is similar in genetic structure to one in clinical trials, this study indicates that future clinical trials should be designed to evaluate the impact of MGH2 and chemotherapy agents in combination.
Fantin et al. Page 6891
HER-2-overexpression is observed in a variety of human cancers and correlates with poor disease outcome. Most anti-HER–targeted therapies to date are aimed to neutralize HER-2 function. Fantin et al. have developed the first in class bifunctional peptide, termed BHAP, to disable both HER-2 activity and mitochondria function. BHAP shows in vitro and in vivo anticarcinoma activity against several HER-2–overexpressing human breast cancer cell lines, including those resistant to anti-HER–2 antibody treatment. This approach can be extended to the development of hybrid peptides against a number of cellular receptors implicated in the development and progression of cancer.
Lin et al. Page 6901
VEGF-C and its receptor, VEGFR3, have been postulated to play a major role in lymphogeneous metastasis by stimulating lymphangiogenesis. Using several human tumor models that preferentially metastasize to the lymph nodes, Lin et al. demonstrate potent dose-dependent inhibition of tumor-associated lymphangiogenesis and lymph node metastasis by recombinant AAV vectors engineered to systemically express a soluble VEGFR3 decoy receptor, sVEGFR3-Fc. In addition, the authors demonstrate that therapeutic serum levels of sVEGFR3-Fc required for inhibition of lymph node metastases are dependent on the levels of VEGF-C expressed by the primary tumor. Thus, AAV-mediated sVEGFR3-Fc gene transfer may represent a novel targeted strategy for blocking lymphangiogenic-mediated metastasis.