The Molecular Targets Core (MTC) provides comprehensive biomarker analyses that are integral and critical parts of oncology clinical trials. The Core has exceptional capabilities in highly sensitive, very specific, and extremely accurate measurements of investigational biomarkers with most of them cannot be measured or detected in a regular clinical diagnostic lab. The quantitative determination of these biomarkers in clinical specimens provides essential information to demonstrate the effectiveness of the experimental agents in inhibiting their intended targets and in achieving their biological effects in the patients in early phases of clinical trials. In correlative studies with clinical responses, some of the biomarkers may also provide an insight into those that may be predictive of the response in patients treated with novel or new agents.
Liang Cao, PhD
Head of the Core
Genetics Branch, CCR
Bldg 37, Rm 6134
Bethesda, MD 20892-1906
Clinical Trial Support: The main mission of the MTC is to enable pharmacodynamic and correlative protein biomarker investigations in the clinical trials of novel investigational agents for cancer. The Core utilizes highly sensitive immunoassays, mostly based on a unique electrochemiluminescence (ECL) technology that provides superior sensitivity, specificity, dynamic range, accuracy, and throughput needed for the analysis of clinical specimens. The Core provides the following capabilities and services.
- Identifying biomarkers informative of the activities of the investigation agents and design investigational questions in working with the clinical protocol principal investigators
- Participating in the preparation of clinical trials protocols with the integration of biomarker investigations to address protocol-specific investigational questions
- Developing and validating clinical biomarker assays for highly sensitive and reliable analysis of new to novel biomarkers that are informative of biological endpoints or correlative to clinical outcome
- Implementing biomarker investigations in clinical trials and performing assays to obtain critical biomarker data
- Analyzing the biomarker data, and in working with clinical investigators, generating conclusions that are informative to the effectiveness of the agents in inhibiting the intended targets and in leading to the desired biological responses, and providing data on markers potentially predictive of responses
Assistance in protein biomarker testing and assay development: Using Meso Scale Discovery (MSD) ECL technology, the Core will provide technical assistance in protein biomarker testing and analysis of biomarkers for in vitro and in vivo studies for investigators at NCI. It will also provide the know-how in new immunoassay assay development with ECL technology. When compared with traditional ELISA assays, the ECL-based immunoassay may have the following advantages:
- At least 10X increased sensitivity. This can be translated into new enablement for rare biomarkers or much-reduced samples usage for data generation.
- Accuracy and precision. The assays in many cases provide absolute quantification and are very reproducible.
- Much improved linear dynamic range with a very low background. The assay allows the accurate determination of biomarker levels without the need for multiple sample dilutions.
- Cost effective. The self-developed ECL assay is a cost-effective alternative to purchased ELISA kits. It may be an attractive option if a given assay is to be performed multiple times.
- Translational potential of the assays. The ECL-based assays are suitable for biomarker analysis of in vivo models. For instance, one may obtain potential quantitative information from dozens of cytokines and chemokines from a drop of mouse blood. These assays also have the potential to be validated for clinical tests.
The Molecular Targets Core currently develops technologies and assays that allow clinical investigators to examine the effects of drugs on intended targets and their associated pathways, as well as relevant biomarkers that are indicative of biological responses to the treatment. The Core has expertise in the following areas that are available to the clinical investigators:
- Biomarker assay development and validation. The Core uses highly sensitive immunoassays, mostly based on a unique electrochemiluminescence technology that provides superior sensitivity, specificity, dynamic range and throughput needed for the analysis of clinical specimens. There is a range of biomarker assays available for cell proliferation, tumor angiogenesis, cell signaling, and apoptosis.
- Implementation of biomarker analysis and correlative studies with clinical investigations at the NCI. The Core has the ability to perform biomarker testing and to analyze data for selected endpoints. The Core has an extensive number of engagements on current clinical trials at NCI.
The Core is interested in two major areas of translational cancer research:
- Molecular pathogenesis of pediatric sarcoma to understand the initiation of the pathogenic process and to identify cellular targets for targeted therapies. The lab recently performed a genome-wide identification of direct targets for the translocated oncogene PAX3-FKHR, using chromatin immunoprecipitation and second-generation DNA sequence analysis. Studies such as this one will likely facilitate our understanding of the roles of PAX3-FKHR in the development of alveolar rhabdomyosarcoma and assist in the identification and validation of downstream targets for preclinical evaluation.
- Preclinical evaluation of novel targeted therapies and the identification of predictive biomarkers to be implemented for clinical investigations. The lab focuses on biologics that modulate the cellular survival signal, thus leading to cancer cell death. These studies are focused on understanding the cellular markers associated with the response of tumors to investigational agents and the events associated with resistance.
Forms: Coming Soon
• Paoloni M, Mazcko C, Fox E, Fan T, Lana S, Kisseberth W, Vail D, Nuckolls K, Osborne T, Yalkowsy S, Gustafson D, Yu Y, Cao L, Khanna C. Modeling Rapamycin Pharmacokinetic and Pharmacodynamic Relationships in Dogs with Osteosarcoma. PLoS One. 5:e11013, 2010.
• Zucali PA, Pettini I, Lorenzi E, Merino M, Cao L, Tommaso LD, Lee HS, Incarbone M, Rodriguez WB, Simonelli M, Santoro A and Giaccone G. Insulin-like Growth Factor-1 Receptor and Phosphorylated AKT-serine 473 Expression in 132 Resected Thymomas and Thymic Carcinomas. Cancer 116:4686-95, 2010.
• Cao L, Yu Y, Bilke S, Walker RL, Mayeenuddin LH, Pineda M, Azorsa DO, Yang F, Helman LJ, Meltzer PS. Genome-wide Identification of PAX3-FKHR Binding Sites in Rhabdomyosarcoma Reveals Candidate Targets Genes Important for Development and Cancer. Cancer Res. 70:6497-508, 2010.
• Terzuoli E, Puppo M, Rapisarda A, Uranchimeg B, Cao L, Burger AM, Ziche M, Melillo G. Aminoflavone, a Ligand of the Aryl Hydrocarbon Receptor (AhR), Inhibits HIF-1α Expression in an AhR-independent Fashion. Cancer Res 70:6837-48, 2010.
• Mayeenuddin LH, Yu Y, Kang Z, Helman LJ, Cao L. Insulin-like Growth Factor 1 Receptor Antibody Induces Rhabdomyosarcoma Cell Death via a Process Involving AKT and Bcl-xL. Oncogene 29:6367-6377, 2010.
• Kelly RJ, Rajan A, Force J, Keen C, Cao L, Yu Y, Choyke PL, Turkbey B, Raffeld M, Xi L, Steinberg SM, Wright JJ, Lopez-Chavez A, Kummar S, Guttierrez M, Giaccone G. Evaluation of KRAS Mutations, Angiogenic Biomarkers and DCE-MRI in Patients with Advanced Non-small Cell Lung Cancer Receiving Sorafenib. Clin Cancer Res 17: 1190-1199, 2011.
• Kummar S, Gutierrez ME, Chen A, Turkbey IB, Allen D, Horneffer YR, Juwara L, Cao L, Yu Y, Kim YS, Trepel J, Chen H, Choyke P, Melillo G, Murgo AJ, Collins J, Doroshow JH. Phase I trial of Vandetanib and Bevacizumab Evaluating the VEGF and EGF Signal Transduction Pathways in Adults with Solid Tumours and Lymphomas. Eur J Cancer 47: 997-1005, 2011.
• Giaccone G, Rajan A, Berman A, Kelly R, Szabo E, Lopez-Chavez A, Trepel J, Lee MJ, Cao L, Espinoza-Delgado I, Spittler J, Loehrer PJ. Belinostat Phase II Study in Patients with Recurrent or Refractory Advanced Thymic Epithelial Tumors. J Clin Oncol 29: 2052-2059, 2011.
• Kang Z, Chen JJ, Yu Y, Li B, Sun SY, Zhang B, Cao L. Drozitumab, a Human Antibody to Death Receptor 5, Has Potent Anti-tumor Activity Against Rhabdomyosarcoma with the Expression of Caspase-8 Predictive of Response. Clin Cancer Res 17: 3181-3192, 2011.
• Speranza S, Gutierrez M, Kummar S, Strong J, Parker R, Collins J, Yu Y, Cao L, Murgo A, Doroshow J, Chen A. Phase I Study of the Synthetic Triterpenoid, 2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid (CDDO), in Advanced Solid Tumors. Cancer Chemo and Pharmacol 69:431-438, 2012.
• Kalra N, Zhang J, Yu Y, Ho M, Merino M, Cao L, Hassan R. Efficacy of anti-insulin-like growth factor I receptor (IGF-IR) monoclonal antibody cixutumumab in mesothelioma is highly correlated with IGF-IR sites/cell. Int J Cancer, 131:2143-52, 2012.
• Kang Z, Sun SY, Cao L. Activating Death Receptor DR5 as a Therapeutic Strategy for Rhabdomyosarcoma. ISRN Oncology 10:5402, 2012.
• Kang Z, Yu Y, Zhu JY, Walker R, Meltzer PS, Helman LJ, Cao L. Down-regulation of IGFBP2 is Associated with Resistance to IGF1R Therapy in Rhabdomyosarcoma. Oncogene, 2013.
• Harouaka R, Kang Z, Zheng S, Cao L. Circulating Tumor Cells: Advances in Isolation and Analysis, and Challenges for Clinical Applications. Pharmacol Ther 141:209-221. 2014.
• Rajan A, Carter CA, Kelly RJ, Cao L, Berman A, Thomas A, Khozin S,… Giaccone G. Phase II Study of Cixutumumab (IMC-A12) in Patients with Recurrent or Refractory Advanced Thymic Malignancies. Lancet Oncol. 15:191-200, 2014.