Aim 1: Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world. Advanced HCC has a poor prognosis and systemic therapy with cytotoxic chemotherapeutics agents shows no survival benefit. Two phase III randomized trials conducted in Western and Asian populations with advanced HCC showed improved survival with sorafenib monotherapy, leading to regulatory approval for its use; it is widely considered the current standard of care for advanced HCC. Nevertheless, the survival benefit associated with sorafenib is modest and more effective systemic therapies are badly needed. A multi-center phase I/II single-arm study evaluated the safety, pharmacokinetics, pharmacodynamics, and activity of foretinib, an oral multikinase inhibitor of MET, ROS, RON, AXL, TIE-2, and VEGFR2, in the first-line setting in advanced hepatocellular carcinoma (HCC) patients. In the phase I part, advanced HCC patients were dose-escalated on foretinib (30-60 mg) once daily (QD) using the standard 3+3 design. Once the maximum tolerated dose (MTD) was determined, an additional 32 patients were dosed at the MTD in the phase II expansion cohort for assessment of efficacy and safety. Exploratory analyses were conducted to assess potential biomarkers that might correlate with clinical efficacy and survival. The MTD of foretinib was established as 30 mg QD. The most frequent adverse events were hypertension, decreased appetite, ascites, and pyrexia. When dosed at 30 mg QD in the first-line setting, foretinib demonstrated promising anti-tumor activity. According to the modified Response Evaluation Criteria in Solid Tumors (mRECIST), the objective response rate was 22.9%, the disease stabilization rate 82.9% and the median duration of response 7.6 months. The median time to progression was 4.2 months and the median overall survival (OS) was 15.7 months. Fifteen candidate biomarkers whose levels in the circulation were significantly altered in response to foretinib treatment were elucidated. Multivariate analyses identified IL6 and IL8 as independent predictors of OS. We conclude that foretinib demonstrated promising anti-tumor activity and good tolerability in the first-line setting in Asian advanced HCC patients. Baseline plasma levels of IL6 or IL8 might predict the response to foretinib.
Aim 2 : Developing an imaging agent targeting the hepatocyte growth factor receptor protein (Met) status of cancerous lesions would aid in the diagnosis and monitoring of Met-targeted tyrosine kinase inhibitors (TKIs). A peptide targeting Met labeled with [99mTc] had high affinity in vitro (Kd=3.3nM) and detected relative changes in Met in human cancer cell lines. In vivo [99mTc]-Met peptide (AH-113018) was retained in Met expressing tumors and high expressing Met tumors (MKN-45) were easily visualized and quantitated using SPECT or optical imaging. In further studies MKN-45 mouse xenografts treated with PHA 665752 (Met TKI) or vehicle were monitored weekly for tumor responses by [99mTc]-Met peptide imaging and measurement of tumor volumes. Tumor uptake of [99mTc]-Met peptide was significantly decreased as early as one week after PHA 665752 treatment corresponding to decreases in tumor volumes. These results were comparable to Cy5**-Met peptide (AH-112543) fluorescence imaging using the same treatment model. [99mTc] or Cy5**-Met peptide tumor uptake was further validated by histological (necrosis, apoptosis) and immunoassay (total Met, p Met, and plasma shed Met) assessments in imaged and non-imaged cohorts. These data suggest that [99mTc] or Cy5**-Met peptide imaging may have clinical diagnostic, prognostic and therapeutic monitoring applications. In a separate study designed to characterize the role of HGF/Met signaling in prostate cancer and identify potential biomarkers of pathway activation, we measured Met protein content in prostate biopsies guided by fused magnetic resonance and ultrasound imaging, and measured soluble Met (sMet) protein concentration in plasma samples from patients presenting evidence of prostate cancer. 345 patients had plasma samples drawn prior to image-guided biopsy of the prostate. Of these, 32% had benign biopsies. Of the 236 that were positive for prostate adenocarcinoma (PCa), 132 treated by total prostatectomy had Gleason scores of 6 (17%), 7, (55%), 8 (16%), or 9 - 10 (12%). 23% had evidence of local invasion. Plasma samples were also obtained from 80 healthy volunteers. Tissue Met and plasma sMet were measured by two-site immunoassay; values were compared among clinically defined groups using non-parametric statistical tests to determine significant differences or correlations. We found that PCa tumor Met correlated significantly with plasma sMet, but median values were similar among benign and malignant groups. Median plasma sMet values were also similar among those groups, though both medians were significantly above normal. Median Met content in primary PCa tumors and sMet concentrations were independent of Gleason score, final pathologic stage, and age. Our findings indicate that plasma sMet is not predictive of PCa or its severity in patients with organ-confined or locally invasive disease. Quantitative analysis of Met protein content and activation state in PCa tumor biopsy samples was highly feasible and may have value in follow-up to genomic and/or transcriptomic-based screens that show evidence of oncogenically relevant MET gene features that occur at relatively low frequency in PCa.
Aim 3 : Signaling by human hepatocyte growth factor (hHGF) via its cell surface receptor (MET) drives mitogenesis, motogenesis and morphogenesis in a wide spectrum of target cell types and embryologic, developmental and homeostatic contexts. Oncogenic pathway activation also contributes to tumorigenesis and cancer progression, including tumor angiogenesis and metastasis, in several prevalent malignancies. The HGF gene encodes full-length hHGF and two truncated isoforms known as NK1 and NK2. NK1 induces all three HGF activities at modestly reduced potency, whereas NK2 stimulates only motogenesis and enhances HGF-driven tumor metastasis in transgenic mice. Prior studies have shown that mouse HGF (mHGF) also binds with high affinity to human MET. We recently showed that, like NK2, mHGF stimulates cell motility, invasion and spontaneous metastasis of PC3M human prostate adenocarcinoma cells in mice through human MET. To identify target genes and signaling pathways associated with motogenic and metastatic HGF signaling, i.e., the HGF invasive program, gene expression profiling was performed using PC3M cells treated with hHGF, NK2 or mHGF. Results obtained using Ingenuity Pathway Analysis software showed significant overlap with networks and pathways involved in cell movement and metastasis. Interrogating The Cancer Genome Atlas project also identified a subset of 23 gene expression changes in PC3M with a strong tendency for co-occurrence in prostate cancer patients that were associated with significantly decreased disease-free survival.
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