ZIA BC 011124 (ZIA) | |||
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Title | Oncogenic Met Signaling in Urologic Malignancies | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Bottaro, Donald | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $356,352 | Project Dates | 00/00/0000 - 00/00/0000 |
Fiscal Year | 2017 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Digestive Diseases (10.0%) |
Bladder (25.0%) Brain (10.0%) Breast (5.0%) Cervical Cancer (5.0%) Kidney Cancer (27.0%) Kidney Disease (25.0%) Liver Cancer (5.0%) Nervous System (10.0%) Ovarian Cancer (5.0%) Prostate (15.0%) Stomach (5.0%) Urinary System (50.0%) Wilm's Tumor (2.0%) |
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Research Type | |||
Cancer Initiation: Oncogenes & Tumor Suppressor Genes Systemic Therapies - Discovery and Development |
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Abstract | |||
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 plas |