Recombinant human placental growth factor-2 in post-infarction left ventricular dysfunction: a randomized, placebo-controlled, preclinical study.

Placental growth factor (PlGF)-2 induces angio- and arteriogenesis in rodents but its therapeutic potential in a clinically representative post-infarction left ventricular (LV) dysfunction model remains unclear. We, therefore, investigated the safety and efficacy of recombinant human (rh)PlGF-2 in the infarcted porcine heart in a randomized, placebo-controlled blinded study. We induced myocardial infarction (MI) in pigs using 75 min mid-LAD balloon occlusion followed by reperfusion. After 4 w, we randomized pigs with marked LV dysfunction (LVEF < 40%) to receive continuous intravenous infusion of 5, 15, 45 µg/kg/day rhPlGF-2 or PBS (CON) for 2 w using osmotic pumps. We evaluated the treatment effect at 8 w using comprehensive MRI and immunohistochemistry and measured myocardial PlGF-2 receptor transcript levels. At 4 w after MI, infarct size was 16-18 ± 4% of LV mass, resulting in significantly impaired systolic function (LVEF 34 ± 4%). In the pilot study (3 pigs/dose), PIGF administration showed sustained dose-dependent increases in plasma concentrations for 14 days without systemic toxicity and was associated with favorable post-infarct remodeling. In the second phase (n = 42), we detected no significant differences at 8 w between CON and PlGF-treated pigs in infarct size, capillary or arteriolar density, global LV function and regional myocardial blood flow at rest or during stress. Molecular analysis showed significant downregulation of the main PlGF-2 receptor, pVEGFR-1, in dysfunctional myocardium. Chronic rhPIGF-2 infusion was safe but failed to induce therapeutic neovascularization and improve global cardiac function after myocardial infarction in pigs. Our data emphasize the critical need for properly designed trials in representative large animal models before translating presumed promising therapies to patients.

PhAc-ALGP-Dox, a Novel Anticancer Prodrug with Targeted Activation and Improved Therapeutic Index.

Clinical use of doxorubicin (Dox) is limited by cumulative myelo- and cardiotoxicity. This research focuses on the detailed characterization of PhAc-ALGP-Dox, a targeted tetrapeptide prodrug with a unique dual-step activation mechanism, designed to circumvent Dox-related toxicities and is ready for upcoming clinical investigation. Coupling Dox to a phosphonoacetyl (PhAc)-capped tetrapeptide forms the cell-impermeable, inactive compound, PhAc-ALGP-Dox. After extracellular cleavage by tumor-enriched thimet oligopeptidase-1 (THOP1), a cell-permeable but still biologically inactive dipeptide-conjugate is formed (GP-Dox), which is further processed intracellularly to Dox by fibroblast activation protein-alpha (FAPα) and/or dipeptidyl peptidase-4 (DPP4). In vitro, PhAc-ALGP-Dox is effective in various 2D- and 3D-cancer models, while showing improved safety toward normal epithelium, hematopoietic progenitors, and cardiomyocytes. In vivo, these results translate into a 10-fold higher tolerability and 5-fold greater retention of Dox in the tumor microenvironment compared with the parental drug. PhAc-ALGP-Dox demonstrates 63% to 96% tumor growth inhibition in preclinical models, an 8-fold improvement in efficacy in patient-derived xenograft (PDX) models, and reduced metastatic burden in a murine model of experimental lung metastasis, improving survival by 30%. The current findings highlight the potential clinical benefit of PhAc-ALGP-Dox, a targeted drug-conjugate with broad applicability, favorable tissue biodistribution, significantly improved tolerability, and tumor growth inhibition at primary and metastatic sites in numerous solid tumor models.

Head and neck squamous cell carcinoma: role of the human papillomavirus in tumour progression.

High risk human papilloma viruses (HPVs) have been shown to be independent risk factors for anogenital tract cancers, and have also been detected in head and neck squamous cell carcinomas (HNSCC). The aim of our study was to determine the prevalence of HPV DNA in a group of 47 squamous cell carcinomas of the oropharynx and the oral cavity, and to compare the clinical behaviour of HPV positive and negative tumours. We also assessed the proliferation index, as evaluated by Ki67 immunohistochemistry positivity, and the level of p53 reactivity. HPV DNA was found in 50% of carcinomas of the oropharynx and 36% in those of the oral cavity, the only genotype detected being HPV 16. Patients with HPV-positive carcinomas had a better overall survival than those with HPV-negative carcinomas. Our data suggest that HPV-positive oropharyngeal cancers comprise a distinct disease entity with an improved prognosis.