Research & Publications +
Dr. DeWeese has continued study of the role played by both Msh2 and GSTP1 in cellular oxidative damage tolerance. Previous studies performed by Dr. DeWeeses 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. As an example of his recent work, 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 hot-spot 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.
Chatterjee, A.; Mambo, E.; Zhang, Y.; Deweese, T.; Sidransky, D. Targeting of mutant hogg1 in mammalian mitochondria and nucleus: effect on cellular survival upon oxidative stress. BMC Cancer. 2006;6:235.
Coffey, D.S.; Getzenberg, R.H.; DeWeese, T.L. Hyperthermic biology and cancer therapies: a hypothesis for the "Lance Armstrong effect". Jama. 2006 Jul 26;296(4):445-448.
Song, D.Y.; DeWeese, T.L. Can PSA nadir predict prostate cancer outcomes following radiotherapy? Nature clinical practice. 2006 Sep;3(9):464-465.
Song, D.Y.; Jabbour, S.; DeWeese, T.L. Emerging Concepts in Improving the Therapeutic Outcome of Locally Advanced Prostate Cancer Using Radiation Therapy. In: Chung, L.W.; Isaacs, W.B.; Simons, J.W., editors, Prostate Cancer: Biology, Genetics and the New Therapeutics. New Jersey: Humana Press; 2006.
Bajaj, G.K.; Zhang, Z.; Garrett-Mayer, E.; Drew, R.; Sinibaldi, V.; Pili, R.; Denmeade, S.R.; Carducci, M.A.; Eisenberger, M.A.; DeWeese, T.L. Phase II study of imatinib mesylate in patients with prostate cancer with evidence of biochemical relapse after definitive radical retropubic prostatectomy or radiotherapy. Urology. 2007 Mar;69(3):526-531.
Donawho, C.K.; Luo, Y.; Luo, Y.; Penning, T.D.; Bauch, J.L.; Bouska, J.J.; Bontcheva-Diaz, V.D.; Cox, B.F.; DeWeese, T.L.; Dillehay, L.E.; Ferguson, D.C.; Ghoreishi-Haack, N.S.; Grimm, D.R.; Guan, R.; Han, E.K.; Holley-Shanks, R.R.; Hristov, B.; Idler, K.B.; Jarvis, K.; Johnson, E.F.; Kleinberg, L.R.; Klinghofer, V.; Lasko, L.M.; Liu, X.; Marsh, K.C.; McGonigal, T.P.; Meulbroek, J.A.; Olson, A.M.; Palma, J.P.; Rodriguez, L.E.; Shi, Y.; Stavropoulos, J.A.; Tsurutani, A.C.; Zhu, G.D.; Rosenberg, S.H.; Giranda, V.L.; Frost, D.J. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clinical cancer research : an official journal of the American Association for Cancer Research. 2007 May 1;13(9):2728-2737.
Feng, M.; Hanlon, A.L.; Pisansky, T.M.; Kuban, D.; Catton, C.N.; Michalski, J.M.; Zelefsky, M.J.; Kupelian, P.A.; Pollack, A.; Kestin, L.L.; Valicenti, R.K.; DeWeese, T.L.; Sandler, H.M. Predictive factors for late genitourinary and gastrointestinal toxicity in patients with prostate cancer treated with adjuvant or salvage radiotherapy. Int J Radiat Oncol Biol Phys. 2007 Aug 1;68(5):1417-1423.
Song, D.Y.; DeWeese, T.L. Defining the appropriate measure of success for adjuvant radiation following prostatectomy. Nature clinical practice. 2007 Aug;4(8):416-417.
Stephenson, A.J.; Scardino, P.T.; Kattan, M.W.; Pisansky, T.M.; Slawin, K.M.; Klein, E.A.; Anscher, M.S.; Michalski, J.M.; Sandler, H.M.; Lin, D.W.; Forman, J.D.; Zelefsky, M.J.; Kestin, L.L.; Roehrborn, C.G.; Catton, C.N.; DeWeese, T.L.; Liauw, S.L.; Valicenti, R.K.; Kuban, D.A.; Pollack, A. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol. 2007 May 20;25(15):2035-2041.
Swartz, M.J.; Janson, K.; Deweese, T.L.; Song, D.Y. Radiation therapy for prostate cancer: the role for dose escalation. Comprehensive therapy. 2007 Winter;33(4):216-222.
Walsh, P.C.; DeWeese, T.L.; Eisenberger, M.A. Clinical practice. Localized prostate cancer. N Engl J Med. 2007 Dec 27;357(26):2696-2705.
Yu, H.H.; Song, D.Y.; Tsai, Y.Y.; Thompson, T.; Frassica, D.A.; DeWeese, T.L. Perineural invasion affects biochemical recurrence-free survival in patients with prostate cancer treated with definitive external beam radiotherapy. Urology. 2007 Jul;70(1):111-116.
DeWeese, T.L. Radiation Therapy for Prostate Cancer. In: Wein, K., Novick, Partin, and Peters, editor. Vol. Tenth Edition, Cambell-Walsh Urology: Elsevier Science; 2008. p. In Press.
Harris, T.J.; Hipkiss, E.L.; Borzillary, S.; Wada, S.; Grosso, J.F.; Yen, H.R.; Getnet, D.; Bruno, T.C.; Goldberg, M.V.; Pardoll, D.M.; DeWeese, T.L.; Drake, C.G. Radiotherapy augments the immune response to prostate cancer in a time-dependent manner. Prostate. 2008 Sep 1;68(12):1319-1329.
Trabulsi, E.J.; Valicenti, R.K.; Hanlon, A.L.; Pisansky, T.M.; Sandler, H.M.; Kuban, D.A.; Catton, C.N.; Michalski, J.M.; Zelefsky, M.J.; Kupelian, P.A.; Lin, D.W.; Anscher, M.S.; Slawin, K.M.; Roehrborn, C.G.; Forman, J.D.; Liauw, S.L.; Kestin, L.L.; DeWeese, T.L.; Scardino, P.T.; Stephenson, A.J.; Pollack, A. A multi-institutional matched-control analysis of adjuvant and salvage postoperative radiation therapy for pT3-4N0 prostate cancer. Urology. 2008 Dec;72(6):1298-1302; discussion 1302-1294.
Trock, B.J.; Han, M.; Freedland, S.J.; Humphreys, E.B.; DeWeese, T.L.; Partin, A.W.; Walsh, P.C. Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. Jama. 2008 Jun 18;299(23):2760-2769.
Yegnasubramanian, S.; Haffner, M.C.; Zhang, Y.; Gurel, B.; Cornish, T.C.; Wu, Z.; Irizarry, R.A.; Morgan, J.; Hicks, J.; DeWeese, T.L.; Isaacs, W.B.; Bova, G.S.; De Marzo, A.M.; Nelson, W.G. DNA hypomethylation arises later in prostate cancer progression than CpG island hypermethylation and contributes to metastatic tumor heterogeneity. Cancer Res. 2008 Nov 1;68(21):8954-8967.
Antonarakis, E.S.; Heath, E.I.; Walczak, J.R.; Nelson, W.G.; Fedor, H.; De Marzo, A.M.; Zahurak, M.L.; Piantadosi, S.; Dannenberg, A.J.; Gurganus, R.T.; Baker, S.D.; Parnes, H.L.; DeWeese, T.L.; Partin, A.W.; Carducci, M.A. Phase II, randomized, placebo-controlled trial of neoadjuvant celecoxib in men with clinically localized prostate cancer: evaluation of drug-specific biomarkers. J Clin Oncol. 2009 Oct 20;27(30):4986-4993.
Ford, E.C.; Gaudette, R.; Myers, L.; Vanderver, B.; Engineer, L.; Zellars, R.; Song, D.Y.; Wong, J.; Deweese, T.L. Evaluation of safety in a radiation oncology setting using failure mode and effects analysis. Int J Radiat Oncol Biol Phys. 2009 Jul 1;74(3):852-858.
Lin, J.; Sinibaldi, V.J.; Carducci, M.A.; Denmeade, S.; Song, D.; Deweese, T.; Eisenberger, M.A. Phase I trial with a combination of docetaxel and (153)Sm-lexidronam in patients with castration-resistant metastatic prostate cancer. Urol Oncol. 2009 Dec 3.
McNeill, D.R.; Lam, W.; DeWeese, T.L.; Cheng, Y.C.; Wilson, D.M., 3rd. Impairment of APE1 function enhances cellular sensitivity to clinically relevant alkylators and antimetabolites. Mol Cancer Res. 2009 Jun;7(6):897-906.
Sanguineti, G.; DeWeese, T.L. Evaluating advanced technologies in radiation oncology: when and how should randomized trials be done? Oncology (Williston Park). 2009 Apr 15;23(4):390, 393.
Sharma, P.; Wisniewski, A.; Braga-Basaria, M.; Xu, X.; Yep, M.; Denmeade, S.; Dobs, A.S.; DeWeese, T.; Carducci, M.; Basaria, S. Lack of an effect of high dose isoflavones in men with prostate cancer undergoing androgen deprivation therapy. J Urol. 2009 Nov;182(5):2265-2272.
Susil, R.C.; McNutt, T.R.; Deweese, T.L.; Song, D. Effects of Prostate-Rectum Separation on Rectal Dose From External Beam Radiotherapy. Int J Radiat Oncol Biol Phys. 2009 Nov 24.
DeWeese, T.L.; Laiho, M. Molecular Determinants of Radiation. New York: Springer; 2010.
Kachhap, S.K.; Rosmus, N.; Collis, S.J.; Kortenhorst, M.S.; Wissing, M.D.; Hedayati, M.; Shabbeer, S.; Mendonca, J.; Deangelis, J.; Marchionni, L.; Lin, J.; Hoti, N.; Nortier, J.W.; DeWeese, T.L.; Hammers, H.; Carducci, M.A. Downregulation of homologous recombination DNA repair genes by HDAC inhibition in prostate cancer is mediated through the E2F1 transcription factor. PLoS One. 2010;5(6):e11208.
Li, S.; Kleinberg, L.R.; Rigamonti, D.; Wharam, M.D., Jr.; Rashid, A.; Jackson, J.; Djajaputra, D.; He, S.; Creasey, T.; DeWeese, T.L. Clinical results of a pilot study on stereovision-guided stereotactic radiotherapy and intensity modulated radiotherapy. Technol Cancer Res Treat. 2010 Dec;9(6):603-617.
Susil, R.C.; McNutt, T.R.; DeWeese, T.L.; Song, D. Effects of prostate-rectum separation on rectal dose from external beam radiotherapy. Int J Radiat Oncol Biol Phys. 2010 Mar 15;76(4):1251-1258.