Research and Clinical Interests
Sensing, imaging, regulation, and control of oncogene expression in cells and animal models with nucleic acid derivatives.
Cancer covers a broad spectrum of diseases, in every tissue of the body. Tissues are composed of cells, which normally grow slowly, under the tight control of a network of regulatory genes. The slow accumulation of activating mutations in growth genes, and inactivating mutations in suppressor genes, eventually allows a cell to grow out of control. Relapse is due to the development of resistant cells, rather than the escape of sensitive cells, suggesting the need for new approaches to treatment of the disease.
This laboratory is developing cancer gene-specific RNA and DNA derivatives against cancer genes in the signal transduction pathway for use as diagnostics and therapeutics for cancers. The biological systems being studied include the CCND1, HER2, EGFR, and KRAS2 cancer genes in breast cancer, ovarian cancer, pancreatic cancer, colon cancer and lung cancer. To move our approaches into the clinic, we must identify the most efficacious RNA and DNA target sequences, their mechanisms and physiological effects. We must design and synthesize potent RNA and DNA analogs capable of surviving in the bloodstream following administration must be synthesized, and we must determine their structures.
To see active cancer gene mRNAs from outside the body, we synthesize peptide analogs that enable receptor-specific uptake of peptide nucleic acids (PNA)that hybridize to target mRNAs in the cytoplasm. By adding a radionuclide chelator to one end of a PNA-peptide, we can radioimage cancerous or precancerous regions by single photon emission computed tomography (SPECT) or positron emission tomography (PET). By using a branched dendrimer PNA-peptide with multiple chelators to bind gadolinium, we might see cancer gene mRNA by magnetic resonance imaging (MRI). With a near infrared fluorophore, we can observe the target mRNAs by optical imaging.
Three-dimensional touch-and-feel molecular modeling and surgical simulation are being integrated with our genetic imaging scans. This study includes touch-and-feel simulations of the kinetic pathway of ligand docking with macromolecules in order to cull out kinetically unfavorable ligand designs. Both the genetic imaging approach and the virtual reality approach are being applied to the problem of varying levels of MAOA mRNA and D2DR mRNA in certain brain cells to react strongly to cocaine. We are developing genetic imaging agents to visualize and quantitate those two neural mRNAs in vivo.
On the therapeutic side, we can destroy IRS1 cancer gene mRNA in breast cancer cells and MKP1, BIM, and BCL2 cancer gene mRNAs in acute lymphoblastic leukemia cells with short interfering RNA (siRNA) sequences. We can stop KRAS2 cancer gene mRNA production in pancreas cancer cells with PNA-peptide sequences.
Infections that develop on medical implants inflict great damage. We can stop infections before they start by covalently bonding therapeutics, such as antibiotics, chemotherapeutics, peptides, or oligonucleotides, to titanium and other implant materials.