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Cirrhosis is a liver disease that leads to increased intrahepatic resistance, portal hypertension (PH), and splanchnic hyperemia resulting in ascites, variceal bleeding, and hepatorenal syndrome. Terlipressin, a prodrug that converts to a short half-life vasopressin receptor 1 A (V1a) full agonist [8-Lys]-Vasopressin (LVP), is an intravenous treatment for PH complications, but hyponatremia and ischemic side effects require close monitoring. We developed PHIN-214 which converts into PHIN-156, a more biologically stable V1a partial agonist. PHIN-214 enables once-daily subcutaneous administration without causing ischemia or tissue necrosis and has a 10-fold higher therapeutic index than terlipressin in healthy rats. As V1a partial agonists, PHIN-214 and PHIN-156 exhibited maximum activities of 28 % and 42 % of Arginine vasopressin (AVP), respectively. The potency of PHIN-156 and LVP relative to AVP is comparable for V1a (5.20 and 1.65 nM, respectively) and V1b (102 and 115 nM, respectively) receptors. However, the EC50 of PHIN-156 to the V2 receptor was 26-fold higher than that of LVP, indicating reduced potential for dilutional hyponatremia via V2 agonism compared to terlipressin/LVP. No significant off-target binding to 87 toxicologically relevant receptors were observed when evaluated in vitro at 10 µM concentration. In bile duct ligated rats with PH, subcutaneous PHIN-214 reduced portal pressure by 13.4 % ± 3.4 in 4 h. These collective findings suggest that PHIN-214 could be a novel pharmacological treatment for patients with PH, potentially administered outside of hospital settings, providing a safe and convenient alternative for managing PH and its complications.

Deficit of oxygen and nutrients in the tumor microenvironment (TME) triggers abnormal angiogenesis that produces dysfunctional and leaky blood vessels, which fail to adequately perfuse tumor tissues. Resulting hypoxia, exacerbation of metabolic disturbances, and generation of an immunosuppressive TME undermine the efficacy of anticancer therapies. Use of carefully scheduled angiogenesis inhibitors has been suggested to overcome these problems and normalize the TME. Here, we propose an alternative agonist-based normalization approach using a derivative of the C-type natriuretic peptide (dCNP). Multiple gene expression signatures in tumor tissues were affected in mice treated with dCNP. In several mouse orthotopic and subcutaneous solid tumor models including colon and pancreatic adenocarcinomas, this well-tolerated agent stimulated formation of highly functional tumor blood vessels to reduce hypoxia. Administration of dCNP also inhibited stromagenesis and remodeling of the extracellular matrix and decreased tumor interstitial fluid pressure. In addition, treatment with dCNP reinvigorated the antitumor immune responses. Administration of dCNP decelerated growth of primary mouse tumors and suppressed their metastases. Moreover, inclusion of dCNP into the chemo-, radio-, or immune-therapeutic regimens increased their efficacy against solid tumors in immunocompetent mice. These results demonstrate the proof of principle for using vasculature normalizing agonists to improve therapies against solid tumors and characterize dCNP as the first in class among such agents. Editor's summary: Tumors often have abnormal and dysfunctional blood vessels that are in part responsible for poor drug delivery and thus reduced efficacy of treatment. Here, Lu et al. have developed a derivative of the C-type natriuretic peptide (dCNP) to normalize vascular structures of tumors to improve therapy efficacy. They demonstrated that this modified dCNP had superior pharmacokinetic and pharmacodynamic properties as compared with native CNP. In addition, administration of dCNP to multiple mouse models remodeled tumor blood vessels and improved antitumorigenic activity of standard monotherapies. This represents a promising compound that could improve therapeutic efficacy of multiple therapies for patients with cancer that requires further study. —Dorothy Hallberg [ABSTRACT FROM AUTHOR]

We evaluated the mitigating effects of fibroblast growth factor 4 and 7 (FGF4 and FGF7, respectively) in comparison with long acting protected graft copolymer (PGC)-formulated FGF4 and 7 (PF4 and PF7, respectively) administered to C57BL/6J mice a day after exposure to LD50/30 (15.7 Gy) partial body irradiation (PBI) which targeted the gastrointestinal (GI) system. The PGC that we developed increased the bioavailability of FGF4 and FGF7 by 5- and 250-fold compared to without PGC, respectively, and also sustained a 24 hr presence in the blood after a single subcutaneous administration. The dose levels tested for mitigating effects on radiation injury were 3 mg/kg for the PF4 and PF7 and 1.5 mg each for their combination (PF4/7). Amifostine administered prior to PBI was used as a positive control. The PF4, PF7, or PF4/7 mitigated the radiation lethality in mice. The mitigating effect of PF4 and PF7 was similar to the positive control and PF7 was better than other mitigators tested. The plasma citrulline levels and hematology parameters were early markers of recovery and survival. GI permeability function appeared to be a late or full recovery indicator. The villus length and crypt number correlated with plasma citrulline level, indicating that it can act as a surrogate marker for these histology evaluations. The IL-18 concentrations in jejunum as early as day 4 and TPO levels in colon on day 10 following PBI showed statistically significant changes in irradiated versus non-irradiated mice which makes them potential biomarkers of radiation exposure. Other colon and jejunum cytokine levels are potentially useful but require larger numbers of samples than in the present study before their full utility can be realized.