Professor Lam's research interest is diverse with focus on technology development, and application of these technologies to basic research and clinical medicine, particularly in the development of cancer therapeutics, imaging agents and diagnostics. There are over 20 full-time researchers (post-doctoral fellows and graduate students) working in Dr. Lam's laboratory. In addition, some clinical fellows, medical residents, undergraduate students and high school students have been working in Dr. Lam's laboratory on a part-time basis. Below are specific projects on-going in Lam laboratory.

1. Development of new synthetic and screening techniques in peptide and small-molecule combinatorial chemistry.
We are currently developing new chemistry and solid-support for the synthesis of small molecule combinatorial library, and new approaches to build peptide libraries with constrained secondary structure and macrocyclic structure. We have developed novel bilayer beads and encoding methods for one-bead one-compound combinatorial libraries. We are also developing new methods to develop high throughput screening assays for combinatorial libraries.

2. Protein tyrosine kinases, biochemistry, diagnostics, imaging agents, and drug development.
This project involves the application of the "one-bead one-compound" combinatorial library method to identify peptide and peptidomimetic substrates for a number of protein kinases. Current emphasis in our laboratory is to convert these leads to potent and specific protein kinase inhibitors. Some of these compounds have biological activities on intact cells. The ultimate goal is to develop drugs against a number of different cancers in which protein kinases are important. We are also developing high-density novel peptide substrate microarrays to profile protein kinase activity. We have just initiated a project on the development of novel PET imaging agents to detect specific protein kinase activity in cells.

3. Development of peptide-targeted therapy for cancer.
This project involves the screening of the "one-bead one-compound" combinatorial libraries with intact cells to identify peptide ligands that bind to specific receptors on cancer cells. These peptides will be identified, re-synthesized, and characterized. Those peptides that are specific for the cancer cell lines will be conjugated to DOTA for the chelation of Y-90, and used as targeting agents for human cancer. In addition, the same conjugates can be used to chelate Cu-64 for PET imaging. We are also developing liposomal anti-cancer drug and Abraxane (Taxol human serum albumin nanoparticle) decorated with tumor targeting peptides. In addition, we are developing tumor targeting peptide-fluorophor and use optical imaging to detect cancer in xenograft models. The cancer types we are currently focusing on include lymphoma, lung cancer and ovarian cancer.

4. Chemical Micro-array Technology Development, and Cancer Proteomics: application of combinatorial chemistry for drug targets and drug leads identification
This project involves the development of a novel chemical micro-array method to immobilize chemical ligands (identified from combinatorial library screening) on microscope slides and then use these micro-arrays as high throughput platform to analyze biochemical and cellular properties of a large number of tumor specimens. This technology will be used to profile protein kinase activities and protease activities in serum.

5. Development of Novel Techniques for Cancer Proteomics:
This project involves the development of a novel high-throughput method for identifying unique molecular alterations in tumor tissues by examining billions of molecular interactions concurrently.

6. Development of Novel Molecular Imaging Agents:
This project involves the use of the stat of the art combinatorial chemistry approaches to develop novel molecular imaging agents: PET imaging agents that target cell surface receptors, protein kinase specific substrate for PET imaging, development of novel imaging agents for proteases, development of novel optical imaging agents.

7. Development of unique diagnostic glyco-markers for human cancers:
In collaboration with Professor Carlito Lebrilla of UCD Chemistry Department, we have used highly sensitive mass spectroscopic technique to detect and identify several unique sugar molecules in serum of ovarian cancer patients. We are currently validating these markers in a large number of sera obtained from normal subject and cancer patients.

Selected Recent References

• Xu QC, Lam KS: Chemical microarray in proteomics. Journal of Biomedicine & Biotechnology, 5: 257-266 , 2003.
• Liu R, Hsieh C, Lam KS: New approaches to identifying drugs to inactivate oncogenes. Seminar in Cancer Biology, 14: 13-21, 2004.
• Song A, Wang X, Zhang J, Marik J, Lebrilla CB, and Lam KS. Synthesis of hydrophilic and flexible linkers for peptide derivatization in solid phase. Bioorganic and Medicinal Chemistry Letters, 14: 161-165, 2004.
• Wang X, Zhang J, Song A, Lebrilla CB, and Lam KS. Encoding method for OBOC small molecule libraries using a biphasic approach for ladder-synthesis of coding tags. J Am Chem Soc , 126: 5740-5749, 2004.
• Yao NH, He WY, Lam KS, and Liu G. Solid-phase synthesis of o-glycosylated Fmoc protected amino acids and quantitation by high resolution magic angle spinning NMR (HR/MAS NMR). The Journal of Combinatorial Chemistry, 6: 214-219, 2004.
• Song A, Zhang J, Lebrilla CB, Lam KS. Solid-phase synthesis and spectral properties of 2-alkylthio-6H-pyrano[2,3-f]benzimidazole-6-ones: a combinatorial approach for 2-alkylthioimidazocoumarins. Journal of Combinatorial Chemistry 6:604-610, 2004.
• Mikawa M, Wang H, Liu R, Lam KS, Lau DH. Novel peptide ligands for 4 1 integrin over-expressed in bronchiolalveolar cancer cells. Molecular Cancer Therapeutics, 3: 1329-1334, 2004.
• Wang X, Peng L, Liu R, Xu B, and Lam KS. Application of topologically segregated bi-layer beads in "one-bead one-compound" combinatorial libraries. The Journal of Peptide Research, 65:130-138, 2005.
• Yao NH, Liu G, He WY, Niu C, Carlson JR, Lam KS, Solid-phase synthesis and antibacterial evaluations of N-demethylvancomycin derivatives. Bioorganic and Medicinal Chemistry Letters, 15: 2325-2329, 2005.
• Aina O, Marik J, Liu R, Lau DH, and Lam KS: Identification of novel targeting peptides for human ovarian cancer cells using OBOC combinatorial libraries. Molecular Cancer Therapeutics, 4:806-813, 2005.
• Aina OH, Marik J, Gandour-Edwards R, Lam KS. Near-infrared optical imaging of ovarian cancer xenografts with novel 3-integrin binding peptide "OA02". Molecular Imaging, 4:439-447, 2005.
• Liu R, Wang X, Song A, Bao T, Lam KS. Development and applications of topologically segregated bilayer beads in one-bead one-compound combinatorial libraries. QSAR Combi. Sci., 24:1127-1140, 2005.