Research in the Boothman Laboratory examines cellular responses to DNA damage caused by therapeutic agents. Ionizing radiation (IR) is a major therapeutic modality used for treating nearly all cancers. Yet, gene expression responses that afford sensitivities/resistance to this agent are still unresolved. Cellular responses under investigation are: signal transduction processes, gene/protein expression changes, post-translational regulation affecting function, cellular and molecular biology of apoptosis, and cellular and molecular biology of cancer and aging.
When exposed to a given chemo- and/or radio-therapy, cancer cells try to repair and evade these treatments to survive and spread. Understanding these ‘resistance-based stress-response mechanisms’ at a molecular level is revealing new and novel therapies. Our laboratory focuses on three aspects of these evasion pathways:
- The IGF-1-sCLU "Axis of Evil": Our laboratory has discovered that during cell stress responses a common pathway that is turned on in cancer cells is the insulin-like growth factor-1 (IGF-1)– secreted clusterin (sCLU) protein expression pathway. This is a “drugable” pro-survival pathway that when eliminated can kill and/or block the spread (metastasis) of cancer. Cancer cells, particularly of the breast, prostate, pancreatic, lung, glioma and colon, readily induce this expression axis in response to stress, and often constitutively express the pathway for survival or to metastasize to other parts of the body. Our laboratory, in conjunction with the laboratories of Drs. Gao and Bachoo, is developing inhibitors (chemical as well as small interfering RNAs) that can be delivered by nanoparticle micelles for the treatment of these cancers. Effects on primary, but especially metastatic, disease are expected.
- Giving Cancer A "Kiss of Death": We have developed a novel drug derived from the bark of a South American rainforest tree, ß-lapachone. This drug selectively kills cancers, such as breast, prostate, nonsmall cell lung, pancreatic and colon that have elevated levels of an enzyme called NQO1 (NAD(P)H:quinone oxidoreductase). The compound, made in a weak formulation, has just entered Phase II trials for use against human pancreatic cancers. Advantages of the compound are that it can kill cancers irrespective of their p53, multi-drug resistance, EGFR or other signal transduction malfunctions, and growth status. This is the first drug that targets a specific enzyme that is made in high levels in cancers and not in normal tissue, and then kills independently of their growth state. Our ability to insert the drug into nanoparticles and enhance the amount and its efficacy against these specific cancers is a major advance in biomedicine and bioengineering.
- Exploiting "Repair" to Enhance Tumor-Cell Killing: A major reason for the formation of cancer is the lack of high-fidelity DNA repair processes caused by mutations in specific pathways. Our laboratory is interested in two different repair systems that affect cancer formation and therapy. These are the DNA mismatch repair and the DNA double strand break repair pathways. We have identified specific proteins that are controlled by these two processes. When expression or the activities of these proteins are eliminated in cancer cells, cancers become hypersensitive to radio- and/or chemo-therapies. Methods for delivering specific inhibitors to decrease the functions of these proteins are being developed using nanoparticle delivery and imaging.