About Our Research
Our laboratory focuses on drug discovery for therapeutically inhibiting cancer cell motility. We have been at the forefront of targeting pro-motility pathways, and understanding how those pathways are associated with transformation to a metastatic phenotype.
Therapeutically inhibiting cancer cell motility in humans
Our group has been leaders in targeting pro-motility pathways in humans. Through a comprehensive series of studies, we have characterized a series of central pathways that regulate human prostate cancer (PCa) cell motility and associated transformation to a metastatic phenotype. We have identified and synthesized small molecules targeting those pathways, demonstrated efficacy in pre-clinical models, and conducted prospective phase I and II human trials. We were the first to successfully therapeutically target pro-motility/pro-metastatic pathways in humans in any cancer type, and we did so in PCa.
Our group has extensive experience moving small molecule therapeutics, many synthesized and discovered by our group, from the bench towards and into the clinic.
- After defining the intracellular pharmacokinetics of modified backbone oligonucleotides, our group developed an improved means to deliver them intracellularly, demonstrating that c-myc targeted antisense is effective in an ex vivo bone marrow purging setting.
- After demonstrating that specific oligonucleotides directly and specifically inhibit bcr-abl kinase activity, we showed their ability to specifically inhibit the growth of patients' CML cells.
- After demonstrating that high-dose tamoxifen inhibits PCa cell growth via PKC inhibition, we demonstrated activity in men with advanced PCa.
- As discussed above, we successfully therapeutically targeted pro-motility pathways in humans. In recent work, we demonstrated that MKK4/MEK4 pathway activation drives human PCa metastasis, and developed a high throughput screening platform for compounds that inhibit MKK4 activity.
- Additionally, using a novel drug discovery strategy, wherein chemistry is used to probe biology, we synthesized and patented the small molecule which inhibits human PCa cell motility and metastasis at nM concentrations and is highly selective. This molecule is currently the focus of two federally funded peer-reviewed grants.
We have led the field in several aspects. We identified inhibition of cancer cell motility as an important chemoprevention target. Dr. Bergan founded one of only five NCI-funded Early Phase Chemoprevention Clinical Trials Consortia, serving as PI from 2000 to 2015.
- Local delivery of therapeutics. This avoids systemic toxicity and provides a high therapeutic index. Efficacy was shown with topical delivery in high-risk breast, with photodynamic therapy in high risk oral cavity and we have ongoing trials of aerosolized delivery (lung), topical delivery (breast) and oral delivery (colon).
- Demonstrating that spectral imaging can measure therapy-induced reversion of cancer-associated macromolecular/chromatin changes. We demonstrated efficacy using aspirin in high-risk colon. Local delivery circumvents systemic toxicity, and will markedly expand use. Spectral imaging allows real time therapeutic efficacy assessment for the first time, can be used across epithelial surfaces, and will transform the field.