The liver is the most common organ for metastasis of various cancers, including pancreatic, ovarian, colorectal, gastric cancers and melanoma. Uveal melanoma metastasizes in 40% of patients and upon metastasis targets the liver in 90% of these cases. The most common primary malignant liver cancer worldwide is hepatocellular carcinoma (HCC). The use of blind liver biopsy as a diagnostic tool for liver cancer has many limitations including risks associated with the procedure and sampling bias and it cannot be performed repeatedly for longitudinal studies. Improving noninvasive imaging methodology would be a significant advance in early detection of small primary cancers and liver metastases for precision medicine. There is a critical need to develop MRI contrast agents capable of detecting primary and metastatic liver cancers earlier in their development than currently possible, and to provide insight into the biology of metastases through biomarkers for precision treatment. We have successfully met all of the proposed aims and milestones for Phase I. The main commercial goal of Inlighta Biosciences is to develop novel imaging reagents for preclinical and clinical applications. Our concerted efforts in this Phase II application are directed towards non-invasive earlier detection of uveal melanoma liver metastasis using novel protein contrast agents ProCA32 and its variant with capability to molecular imaging biomarker chemokine receptor 4 (CXCR4), an important biomarker for cell migration and tumor metastasis. We will obtain essential data required for filing IND applications for both reagents leading to clinical translation.
Aim 1 is to optimize and validate in vivo imaging capabilities of ProCA32s in tumor detection assessing in mice and monkey. We will also validate CXCR4 targeting and monitor CXCR4 expression levels in liver metastasis mouse models.
Aim 2 is to perform the safety and toxicity profiles protein contrast agents required for IND by determining serum, cell and in vivo stability, PK/PD, toxicity, and immunogenicity. Success in our proposed studies will have immediate clinical implications in the diagnosis of liver metastasis from various cancers, primary liver cancer, and other liver diseases.
Our proposed studies in precision imaging with unprecedented sensitivity and accuracy address major medical gaps including early detection of small lesion and biomarker expression especially for high risk patients and monitoring the dynamic changes of biomarkers during disease progression and following therapeutic treatment. Success in our proposed studies will have immediate clinical implications in the diagnosis of liver metastasis from various cancers, primary liver cancer, and other liver diseases, accurate staging/following up of high-risk patients, evaluating treatment effect, and image- guided interventions.
| Liao, Albert; Mittal, Pardeep; Lawson, David H et al. (2018) Radiologic and Histopathologic Correlation of Different Growth Patterns of Metastatic Uveal Melanoma to the Liver. Ophthalmology 125:597-605 |
| Reddish, Florence N; Miller, Cassandra L; Gorkhali, Rakshya et al. (2017) Calcium Dynamics Mediated by the Endoplasmic/Sarcoplasmic Reticulum and Related Diseases. Int J Mol Sci 18: |
| Zou, Juan; Jiang, Jason Y; Yang, Jenny J (2017) Molecular Basis for Modulation of Metabotropic Glutamate Receptors and Their Drug Actions by Extracellular Ca2. Int J Mol Sci 18: |
| Pu, Fan; Xue, Shenghui; Yang, Jenny J (2016) ProCA1.GRPR: a new imaging agent in cancer detection. Biomark Med 10:449-52 |
| Pu, Fan; Salarian, Mani; Xue, Shenghui et al. (2016) Prostate-specific membrane antigen targeted protein contrast agents for molecular imaging of prostate cancer by MRI. Nanoscale 8:12668-82 |
