Dr. DeWeese has continued study of the role played by both Msh2 and GSTP1 in cellular oxidative damage tolerance. Previous studies performed by Dr. DeWeese’s laboratory have revealed that inactivation of alleles encoding the DNA mismatch repair enzyme, Msh2, result in enhanced survival following exposure to oxidative damage inflicted by protracted, low-dose ionizing radiation, accumulation of potentially mutagenic oxidized DNA bases and increased mutation frequency.
Dr. DeWeese has expanded his study to other, more physiologically relevant oxidant stresses, including hypoxia. In this work, Dr. DeWeese has shown that exposure of mouse ES cells with inactivated Msh2 alleles to a hypoxia/reoxygenation event does not induce significant cell death, but it does induce a tenfold increase in the appearance of Hprt-mutant subclones. Moreover, Dr. DeWeese has identified a hotspot for hypoxia-induced mutations in the coding region of the murine Hprt gene. These data extend Dr. DeWeeses previous observations by revealing that Msh2 may be a general sensor of genomic DNA oxidant injury and that hypoxia can be a significant mutagenic stress in the face of altered DNA mismatch repair.
Dr. DeWeese also continues to perform experiments with important clinical translation potential. These have included in vitro and in vivo experiments using human prostate cancer cells combining a replication-restricted, PSA-selective oncolytic adenoviral vector with radiation. These experiments reveal a real and significant mathematical synergy between this vector and radiation, with at least a sixfold increase in tumor control over that expected if the two therapies were simply additive. Other experiments performed by Dr. DeWeese and his collaborators revealed that one mechanism of this synergy includes radiation-induced enhancement of viral vectors. These data, combined with results from Dr. DeWeeses recently completed Phase I study, provide the rationale for clinical translation of a combination of this replication-restricted, PSA-selective oncolytic adenoviral vector and radiation to the clinic to treat men with newly diagnosed, clinically localized prostate cancer. In the search for other unique and clinically translatable methods of augmenting tumor radiation response, Dr. DeWeese is systematically studying a new method of disrupting cellular protein expression, using expression of unique, plasmid-based siRNA to silence genes that produce proteins involved in DNA double-strand break repair. As cellular radiation inflicts significant DNA double-strand breaks, modulation of double-strand break repair holds the promise of increased radiation-induced cell death. It is well known that cells and animals with inactivation of DNA-PKcs alleles or cells treated with inhibitors of DNA-PKcs exhibit enhanced radiation sensitization. Dr. DeWeese's lab has also developed siRNA targets to ATM and ATR, similarly important in the repair of genotoxic stress resulting from radiation and chemotherapy. This work is proceeding rapidly and has been expanded to include incorporation of these siRNA constructs into an adenoviral-based delivery system.
Clinical Trial Keywords:
Prostate cancer, Gene therapy
- Kusano AS, Thomas CR Jr, Bonner JA, Deweese TL, Formenti SC, Hahn SM, Lawrence TS, Mittal BB. "Burnout in United States academic chairs of radiation oncology programs." Int J Radiat Oncol Biol Phys. 2014 Feb 1;88(2):363-8. doi: 10.1016/j.ijrobp.2013.09.027. Epub 2013 Nov 1.
- Wada S, Harris TJ, Tryggestad E, Yoshimura K, Zeng J, Yen HR, Getnet D, Grosso JF, Bruno TC, De Marzo AM, Netto GJ, Pardoll DM, DeWeese TL, Wong J, Drake CG. "Combined treatment effects of radiation and immunotherapy: studies in an autochthonous prostate cancer model." Int J Radiat Oncol Biol Phys. 2013 Nov 15;87(4):769-76.
- Song H, Hedayati M, Hobbs RF, Shao C, Bruchertseifer F, Morgenstern A, Deweese TL, Sgouros G. "Targeting aberrant DNA double-strand break repair in triple-negative breast cancer with alpha-particle emitter radiolabeled anti-EGFR antibody." Mol Cancer Ther. 2013 Oct;12(10):2043-54. doi: 10.1158/1535-7163.MCT-13-0108. Epub 2013 Jul 19.
- Alcorn S, Walker AJ, Gandhi N, Narang A, Wild AT, Hales RK, Herman JM, Song DY, Deweese TL, Antonarakis ES, Tran PT. "Molecularly targeted agents as radiosensitizers in cancer therapy--focus on prostate cancer." Int J Mol Sci. 2013 Jul 16;14(7):14800-32.
- Narang AK, Lam E, Makary MA, Deweese TL, Pawlik TM, Pronovost PJ, Herman JM. "Accuracy of marketing claims by providers of stereotactic radiation therapy."J Oncol Pract. 2013 Jan;9(1):57-62.