May Han

Non-charged thiamine analogs as inhibitors of enzyme transketolase.

Inhibition of the thiamine-utilizing enzyme transketolase (TK) has been linked with diminished tumor cell proliferation. Most thiamine antagonists have a permanent positive charge on the B-ring, and it has been suggested that this charge is required for diphosphorylation by thiamine pyrophosphokinase (TPPK) and binding to TK. We sought to make neutral thiazolium replacements that would be substrates for TPPK, while not necessarily needing thiamine transporters (ThTr1 and ThTr2) for cell penetration. The synthesis, SAR, and structure-based rationale for highly potent non-thiazolium TK antagonists are presented.

A Pharmacodynamic/Pharmacokinetic Study of Ficlatuzumab in Patients With Advanced Solid Tumors and Liver Metastases

Purpose: This study evaluated the safety, tolerability, pharmacodynamics, pharmacokinetics, and antitumor activity of ficlatuzumab, a humanized hepatocyte growth factor (HGF) inhibitory monoclonal antibody, as monotherapy in patients with advanced solid tumors and liver metastases. Patients and Methods: Patients with p-Met (phosphorylated c-Met)–positive tumors enrolled in three dose-escalation cohorts, receiving ficlatuzumab 2, 10, or 20 mg/kg once per 14-day cycle. Pharmacodynamic changes in liver tumor biopsies and serum, pharmacokinetics, safety, and clinical activity were assessed. Results: No dose-limiting toxicities occurred in the 19 patients enrolled (n = 6, 2 mg/kg; n = 7, 10 mg/kg; n = 6, 20 mg/kg). The most frequent diagnosis was colorectal cancer (n = 15; 79%). The most common treatment-emergent adverse events were asthenia, peripheral edema, hepatic pain (32% each), and cough (26%). Laboratory abnormalities of decreased serum albumin were present in all patients. Ficlatuzumab at 20 mg/kg lowered median levels of tumor p-Met (−53%), p-ERK (−43%), p-Akt (−2%), and increased median HGF levels (+33%), at the last on-study time point relative to baseline. Mean serum HGF levels increased with ficlatuzumab dose and number of treatment cycles. Ficlatuzumab exhibited linear pharmacokinetics and long terminal half-life (7.4–10 days). Best overall response was stable disease in 28% of patients, including 1 patient with pancreatic cancer with stable disease >1 year. Conclusions: Ficlatuzumab exhibited good safety/tolerability and demonstrated ability to modulate the HGF/c-Met pathway and downstream signaling in the tumor in patients with advanced solid tumors. Safety, pharmacodynamic, and pharmacokinetic data for ficlatuzumab confirmed the recommended phase II dose of 20 mg/kg once per 14-day cycle. Clin Cancer Res; 20(10); 2793–804. ©2014 AACR.

Abstract C173: Anti‐tumor activity of SCH 900105 (AV299), an anti‐HGF antibody, in non‐small cell lung cancer models

Hepatocyte growth factor (HGF) is the soluble ligand for the c‐Met receptor tyrosine kinase. Signaling through the HGF/c‐Met pathway mediates a plethora of cellular activities that are involved in cancer cell dysregulation, tumorigenesis, and metastasis including cell proliferation and survival, angiogenesis, migration, invasion and drug resistance. HGF/c‐Met autocrine and paracrine regulatory loops have been reported in a number of non‐small cell lung cancer studies. Furthermore, studies have shown that HGF/c‐Met pathway upregulation via either c‐Met amplification or HGF secretion can result in intrinsic or acquired resistance to EGFR TKIs in lung adenocarcinoma. SCH 900105, formerly known as AV‐299, is a humanized IgG1 antibody with high affinity to HGF that neutralizes all its biological functions tested with sub‐nM potency. It is currently in phase 1 clinical trials that demonstrated good safety and tolerability. Anti‐tumor activity of SCH 900105 was observed in HGF autocrine and paracrine in vivo tumor models, such as GMB, pancreatic cancer and multiple myeloma. Anti‐tumor efficacy of SCH 900105 was evaluated in paracrine models of the HGF‐dependent NCI‐H596 NSCLC cell line xenografted in SCID mice engineered to produce human HGF. In these models, SCH 900105 treatment resulted in dose‐dependent decrease in tumor growth with concurrent increases in serum and tumor concentration of SCH900105 and increases in serum SCH 900105/HGF complex. Treatment also led to significant reduction in phospho‐c‐Met and phospho‐Akt levels in tumor lysates. Concurrently, increases in cleaved caspase‐3 and decreases in Ki67 and CD31 staining were also observed. Anti‐tumor activity of SCH 900105 was also explored in combination with EGFR inhibitors, erlotinib and Cetuximab that resulted in increased efficacy. SCH900105 treatment resulted in decreased phospho‐c‐Met levels with concurrent increases in phospho‐EGFR levels. Conversely, erlotinib treatment decreased phospho‐EGFR with concurrent increases in phospho‐Met levels. The combination of SCH900105 with Cetuximab resulted in complete response in all animals treated without tumor re‐growth 50 days after treatment withdrawal. Potent anti‐tumor activity of SCH 900105 in combination with EGFR inhibitors observed in these preclinical models suggests testing the combination in NSCLC is warranted in the clinic. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C173.

Abstract C181: Preclinical efficacy and pharmacodynamics of SCH 900105 (AV‐299) an anti‐HGF antibody in an intracranial glioblastoma model

Hepatocyte growth factor (HGF) is a pluripotent growth factor produced predominantly by mesenchymal or stromal cells, and binds to the well‐characterized tyrosine kinase receptor, c‐Met. The HGF/c‐Met pathway is frequently deregulated in different types of human cancers and is thought to play an important role in regulating tumor growth, invasion, metastasis and drug resistance. HGF/c‐Met autocrine and paracrine loops have been reported in a number of human cancers including breast, lung, bladder, gastric, head and neck, glioma, multiple myeloma, leukemias, and certain sarcomas. SCH 900105, formerly known as AV‐299, is a potent, humanized anti‐HGF antibody. It is currently in phase 1 clinical trials that demonstrated good safety and tolerability. It has been shown to neutralize HGF binding to c‐Met and inhibits its biological function in vitro, such as cell signaling, growth, motility, invasion and drug resistance. SCH 900105 was also shown to have potent anti‐tumor activity in autocrine and paracrine GBM, NSCLC, pancreatic and multiple myeloma xenograft models both as monotherapy and in combinations with chemotherapeutics or targeted agents. In vivo efficacy of systemically administered SCH 900105 was evaluated in an intracranial autocrine U87MG model. In these studies, SCH 900105 treatment resulted in significant survival benefit over an IgG treated control group. Immunohistochemistry staining for SCH 900105 in the intracranial tumor tissue suggested adequate tumor penetration of the antibody. Treatment also led to significantly decreased tumor phospho‐c‐Met, increased cleaved caspase‐3, as well as decreased Ki67 and CD31 staining. Greater survival benefit was also seen when SCH 900105 was combined with temozolomide in U87 intracranial model. These findings suggest evaluating SCH 900105 in GBM is warranted. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C181.

Phase 1b Trial of Ficlatuzumab, a Humanized Hepatocyte Growth Factor Inhibitory Monoclonal Antibody, in Combination With Gefitinib in Asian Patients With NSCLC

Hepatocyte growth factor (HGF)/c‐Met pathway dysregulation is a mechanism for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Ficlatuzumab (AV‐299; SCH 900105), a humanized IgG1κ HGF inhibitory monoclonal antibody, prevents HGF/c‐Met pathway ligand–mediated activation. This phase 1b study assessed the safety/tolerability, pharmacokinetics/pharmacodynamics, and antitumor activity of ficlatuzumab plus gefitinib in Asian patients with previously treated advanced non–small cell lung cancer (NSCLC). Patients received intravenous ficlatuzumab either 10 mg/kg (cohort 1; n = 3) or 20 mg/kg (cohort 2; n = 12) every 2 weeks plus oral gefitinib 250 mg daily. Patients tolerated the drug combination well. Four treatment‐related grade 3/4 adverse events were reported in 3 patients (cohort 2). Pharmacokinetic profiles for ficlatuzumab and gefitinib were consistent with prior single‐agent trials. Partial responses were achieved in 5 patients (4 confirmed), all in cohort 2; objective response rate (ORR) was 33% (duration, 1.9–6.4 months). Responding patients had no prior EGFR TKI treatment, 2 without an EGFR mutation. Four additional patients had disease stabilization (cohort 2; duration, 2.7–9.1 months; 42% ORR). The recommended phase 2 dose for ficlatuzumab plus gefitinib 250 mg/day was 20 mg/kg every 2 weeks. This drug combination has shown preliminary dose‐related antitumor activity in advanced NSCLC.

Abstract 644: Anti-tumor activities of antibodies targeting the RON receptor and a biomarker of response

RON is a receptor tyrosine kinase of the MET family. Stimulation by its ligand, Macrophage Stimulating Protein (MSP), activates a signaling cascade leading to cell growth, migration, invasion and resistance to apoptosis. In animal models, RON overexpression in breast and lung results in tumor growth and metastasis. RON receptor activation in animal models also play a role in tumor-host interactions such as osteolytic bone destruction and tumor associated macrophage infiltration. RON overexpression has been demonstrated in several solid tumors including pancreatic, breast, ovarian and colon. RON overexpression is correlated with disease progression and shorter survival in ovarian and colon cancer. Several isoforms of RON have been reported, including a potentially oncogenic form, RON Δ160 in CRC. Given the strong evidence for the involvement of RON in numerous aspects of tumor biology, investigating an anti-RON antibody as cancer therapy is warranted. We have identified and characterized a panel of antagonistic murine anti-human RON antibodies. Humanization of two antibodies resulted in Superhumanized™ anti-RON antibodies that are capable of inhibiting MSP dependent RON downstream signaling, cell migration and invasion in vitro. The anti-RON antibodies have subnanomolar binding affinity to wildtype RON and RON Δ160 receptors. The lead antibody is capable of internalizing and degrading the receptor in vitro and in vivo. The antibodies are capable of inhibiting growth of engineered murine models that are driven by wildtype or RON Δ160 receptor, as well as traditional human cancer xenografts. Given the complex role of RON in tumor biology, identification of response biomarkers is crucial for identifying the patient populations most likely to benefit from treatment. A multi-gene biomarker potentially predictive of tumor response to RON antibody, the RON pathway index, was tested and validated using a panel of human cancer cell line xenografts. Current results demonstrate a statistically significant correlation between the degree of tumor growth inhibition by anti-RON antibody treatment and RON pathway index value. Thus, we have identified a biomarker of tumor response to anti-RON antibody that can potentially help us identify tumor types or tumor subtypes of interest in the clinic. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 644. doi:10.1158/1538-7445.AM2011-644