Cell Regulation Genetics and Development Pharmacological Science
Non-degree Program:
Physician Scientist Training Program SURF
Affiliations:
Hamon Center for Therapeutic Oncology Komen Alliance Breast Cancer Research Moncrief Radiation Oncology Center Radiation Oncology Simmons Comprehensive Cancer Center
The mission of the laboratory of Dr. David A. Boothman is to understand the differential responses of normal versus cancer cells to stressful insults (i.e., carcinogenic insults or insults brought about by radiotherapy or chemotherapy). Understanding these cell stress events at a molecular level when correlated with cell death, increased metastatic responses or survival will ultimately allow us to exploit these pathways for improved cancer-selective therapies. When exposed to a given chemo- and/or radio-therapy, cancer cells try to repair and evade these treatments in order to survive and spread. Understanding these ?resistance-based stress response mechanisms? at molecular levels will reveal new and novel targets for improved efficacious therapies. Our laboratory focuses on three aspects of these evasion pathways:
1. 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.
2. Giving Cancer A ?Kiss of Death?: We have developed a novel drug derived from the bark of a South American rainforest tree, ?-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 recently 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.
3. 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.
RESEARCH INTERESTS
Repair of DNA Double-Strand Breaks and Mismatch lesions
Stress-Inducible and Noncaspase-Mediated Gene Apoptosis
Targeted Cancer Therapeutics
IGF-1 Pathway Regulation
G2 Checkpoint Arrest
RECENT PUBLICATIONS
Nasongkla N, Shuai X, Ai H, Weinberg BD, Pink J, Boothman DA, Jingming G, "cRGD-functionalized Polymer Micelles for Targeted Doxorubicin or β-lapachone Delivery" Angew Chem Int Ed Engl, 43(46):6323-6327, November 2004
Meyers M, Mqazurek A, Schmutte C, Fishel R, Boothman DA, "DNA Mismatch Repair Detection and Cellular Responses to Damage Caused by 5-fluoro-2’-deoxyuridine Exposure" J Biol Chem, 280(7):5516-26, February 2005
Wagner, MW, Li, LS, Morales, JC, Galindo, CL, Garner, HR, Bornmann, WG, and Boothman, DA., "Role of c-Abl in MMR-dependent G2 arrest responses." Journal of Biological Chemistry, 283:21382-21393, May 2008
Li, LS, Morales, JC, Hwang, A, Wagner, MW, and Boothman, DA., "DNA mismatch repair-dependent activation of c-Abl/p73a/GADD45a-mediated apoptosis." Journal of Biological Chemistry, 283:21394-21403, May 2008
Bey EA, Bentle MS, Reinicke KE, Dong Y, Yang CR, Girard L, Minna JD, Bornmann WG, Gao J, Boothman DA., "An NQO1-and PARP-1-mediated cell death pathway induced in non-small-cell lung cancer cells by beta-lapachone." Proceedings of the National Academy of Sciences, (28)/104::11832-11837, August 2007
SIGNIFICANT PUBLICATIONS
Criswell T, Beman M, Araki S, Leskov K, Cataldo E, May LD, Boothman DA, "Delayed Activation of IGF-1R/Src/MAPK Signaling After IR Regulates Clusterin Expression, a Pro-survival Protein" J Biol Chem, 280(14):14212-21, April 2005
Sawada M, Sun W, hayes P, Keskov K, Boothman DA, Matuyama S, "Ku70 Suppresses the Apoptotic Translocation of Bax to Mitochondria" Nat Cell Biol, 5(4):320-9, April 2003
Leskov KS, Klokov DY, Li J, Kinsella TJ, Boothman DA, "Synthesis and Functional Analyses of Nuclear Clusterin: a Cell Death Protein" J Biol Chem, 278(13):11590-600, March 2003
1. Boothman DA, Meyers M, Lee SW., "Isolation of X-ray-inducible transcripts from radioresistant human melanoma cells." Proceedings of the National Academy of Sciences, 90:7200-7204, October 1993
5. Pink JJ, Planchon SM, Tagliarino C, Wuerzberger-Davis SM, Varnes ME, Siegel D, Boothman DA., "NAD(P)H:quinone oxidoreductase (NQO1) activity is the principal determinant of ?-lapachone cytotoxicity." Journal of Biological Chemistry, 275:5416-5422, November 2000
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