Activation of the fibroblast growth factor receptor FGFR4 by FGF19 drives hepatocellular carcinoma (HCC), a disease with few, if any, effective treatment options. While a number of pan-FGFR inhibitors are being clinically evaluated, their application to FGF19-driven HCC may be limited by dose-limiting toxicities mediated by FGFR1-3 receptors. To evade the potential limitations of pan-FGFR inhibitors, we generated H3B-6527, a highly selective covalent FGFR4 inhibitor, through structure-guided drug design. Studies in a panel of 40 HCC cell lines and 30 HCC PDX models showed that FGF19 expression is a predictive biomarker for H3B-6527 response. Moreover, coadministration of the CDK4/6 inhibitor palbociclib in combination with H3B-6527 could effectively trigger tumor regression in a xenograft model of HCC. Overall, our results offer preclinical proof of concept for H3B-6527 as a candidate therapeutic agent for HCC cases that exhibit increased expression of FGF19. .

Purpose: Vascular endothelial growth factor receptor-1 (VEGFR-1) plays important roles in promotion of tumor growth by mediating cellular functions in tumor vascular endothelium and cancer cells. Blockade of VEGFR-1activation has been shown to inhibit pathologic angiogenesis and tumor growth, implicating VEGFR-1 as a potential therapeutic target for the treatment of cancer. We have thus developed a VEGFR-1 antagonist human monoclonal antibody designated as IMC-18F1 and evaluated its antitumor activity in preclinical experimental models to show the therapeutic potential of the antibody for cancer treatment in clinic. Experimental Design: Human IgG transgenic mice were used for generation of anti-VEGFR-1 antibodies. Anti-VEGFR-1-specific blocking antibodies were identified using solid-phase binding and blocking assays. Inhibitory antitumor cell activity of IMC-18F1 was assessed in cell-based kinase and growth assays. Pharmacokinetic/pharmacodynamic studies were done to determine the association of antibody blood level with antitumor efficacy of the antibody in vivo. Antitumor efficacy of the anti-VEGFR-1antibodies as monotherapy and in combination with cytotoxic agents was evaluated in human breast cancer xenograft models.

Purpose: Combination therapies that target the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) pathways, are being actively tested for the treatment of cancer. In evaluating combination strategies, the ideal combination would be one in which the treatments interact in a way that is synergistic with regard to antitumor effects. Here, we have evaluated the interaction between anti-EGFR antibody Erbitux (cetuximab) and anti-VEGFR2 antibody, DC101, in preclinical models of pancreatic (BxPC-3) and colon (GEO) cancer. Experimental Design: Analysis of the interaction between cetuximab and DC101 in vivo used a novel method for establishing the upper 95% confidence limits for the combination index (CI) of isobologram analyses, where CI < 1 indicates synergy. Assessment of tumor cell proliferation, apoptosis, VEGF production, and hypoxia, as well as tumor vascularization, was performed to gain insights into the mechanistic basis for synergy between agents targeting different tumor compartments. Results: Monotherapy ED 50 values for tumor growth inhibition ranged from1.8 to 2.3 mg/kg and 10.5 to 16.6 mg/kg for cetuximab and DC101, respectively. From the dose response of the combination treatment, it was determined that cetuximab and DC101 are synergistic in the BxPC-3 (CI = 0.1, P < 0.01) and GEO (CI = 0.1, P < 0.01) models. Overlapping effects on the tumor cell and vascular compartments form a basis for the interaction, with VEGF production and hypoxiainducible factor 1apotentially acting as molecular links between EGFR and VEGFR2 inhibition. Conclusions: Results show antitumor synergy for combined EGFR and VEGFR2 targeted therapy, supporting the significant therapeutic potential of this combination strategy.

SCH 56592 (posaconazole), a new triazole antifungal agent, was tested in vitro, and its activity was compared to that of itraconazole against 39 Aspergillus strains and to that of fluconazole against 275 Candida and 9 Cryptococcus strains. The SCH 56592 MICs for Aspergillus ranged from <0.002 to 0.5 g/ml, and those of itraconazole ranged from <0.008 to 1 g/ml. The SCH 56592 MICs for Candida and Cryptococcus strains ranged from <0.004 to 16 g/ml, and those of fluconazole ranged from <0.062 to >64 g/ml. SCH 56592 showed excellent activity against Aspergillus fumigatus and Aspergillus flavus in a pulmonary mouse infection model. When administered therapeutically, the 50% protective doses (PD 50 s) of SCH 56592 ranged from 3.6 to 29.9 mg/kg of body weight, while the PD 50 s of SCH 56592 administered prophylactically ranged from 0.9 to 9.0 mg/kg; itraconazole administered prophylactically was ineffective (PD 50 s, >75 mg/kg). SCH 56592 was also very efficacious against fluconazole-susceptible, -susceptible dose-dependent, or -resistant Candida albicans strains in immunocompetent or immunocompromised mouse models of systemic infection. The PD 50 s of SCH 56592 administered therapeutically ranged from 0.04 to 15.6 mg/kg, while the PD 50 s of SCH 56592 administered prophylactically ranged from 1.5 to 19.4 mg/kg. SCH 56592 has excellent potential for therapy against serious Aspergillus or Candida infections.Of the estimated 100,000 known species of fungi, only about 180 have been shown to cause disease in humans, and only about 10% of these are encountered in most clinical settings (8). However, fungal infections have substantially increased over the past two decades, and invasive forms are important causes of morbidity and mortality (2, 16). The major increase in fungal infections is related to increased numbers of immunocompromised patients including those with human immunodeficiency virus infection-AIDS or cancer and bone marrow or solid organ transplant recipients, who are at risk of developing invasive fungal infections (5,7,12,16). Disseminated candidiasis, pulmonary aspergillosis, and mycoses caused by emerging opportunistic fungi are the most common of these serious mycoses (7,16,38). As a result, there is a developing consensus that prophylactic therapy should be used for these high-risk patients (12). Fluconazole (FLC) is used for prevention of fungal infections in some of these patients, but it is not active against Aspergillus or other filamentous fungi. However, there is great concern about the development of resistant Candida due to prophylactic use of FLC (4,10,15,18,23,35,37). Clearly, alternative antifungal agents are needed for both therapeutic and prophylactic use. SCH 56592 (SCH; posaconazole) is a new triazole antifungal agent with broad-spectrum activity against fungi including strains of Aspergillus and Candida resistant to FLC (9,11,19,24,30,33). This report describes the in vitro activity of SCH against Aspergillus and Candida and its efficacy in clinically relevant experimental infection models ...

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