The main aims, in brief, are to (1) test the efficacy of image-guided hypofractionated intensity modulated radiotherapy (IMRT) in a Phase III randomized trial of prostate cancer patients with intermediate-to-high risk prostate cancer, (2) establish the relationship of abnormal bcl-2 and bax expression to patient outcome after radiotherapy (RT) with and without androgen deprivation (AD), and (3) determine if antisense strategies based on reducing bcl-2 expression will improve prostate cancer response to AD, RT, and AD+RT using tumor models. Radiotherapy, given alone or in combination with AD, remains the mainstay of treatment for intermediate-to-high risk patients. The best methods for administering RT, integrating AD+RT, and further promoting cell killing via manipulation of the apoptotic pathway remain to be established. The primary hypotheses of the work proposed are that (1) freedom from biochemical and/or disease failure (FFF) may be significantly enhanced using IMRT to deliver higher biologic doses in a hypofractionated regimen, (2) the abnormal expression of the key apoptotic pathway proteins bcl-2 and bax adversely effect radiation response, and (3) bcl-2 and bax control prostate cancer response to AD, RT and AD+RT such that the modulation of these apoptotic pathway proteins via antisense bcl-2 (AS-bcl-2) and/or antisense cAMP-dependent protein kinase A type I (AS-PKA) will render prostate cancer cells more sensitive to these treatments. The clinical trial compares FFF and toxicity after 76 Gy in 38 fractions to 70.2 Gy in 26 fraction (biologically equivalent to 84.3 Gy assuming an alpha/beta of 1.5) in 300 patients. Bcl-2 and bax will be measured immunohistochemically in diagnostic tissue prospectively from this trial and retrospectively from two Radiation Therapy Oncology Group trials (86-10 and 92-02), and correlated with patient outcome. The effect of altering bcl-2 expression with AS-bcl-2 and AS-PKA on cell death in vitro and orthotopic tumor growth in vivo will be determined using wild type, bcl-2 overexpressing, and androgen deprivation resistant LNCaP cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA101984-02
Application #
6801820
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Xie, Heng
Project Start
2003-09-17
Project End
2008-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
2
Fiscal Year
2004
Total Cost
$561,406
Indirect Cost
Name
Fox Chase Cancer Center
Department
Type
DUNS #
073724262
City
Philadelphia
State
PA
Country
United States
Zip Code
19111
Pollack, Alan; Kwon, Deukwoo; Walker, Gail et al. (2017) Prospective Validation of Diagnostic Tumor Biomarkers in Men Treated With Radiotherapy for Prostate Cancer. J Natl Cancer Inst 109:1-8
Shaikh, Talha; Li, Tianyu; Handorf, Elizabeth A et al. (2017) Long-Term Patient-Reported Outcomes From a Phase 3 Randomized Prospective Trial of Conventional Versus Hypofractionated Radiation Therapy for Localized Prostate Cancer. Int J Radiat Oncol Biol Phys 97:722-731
Udayakumar, Thirupandiyur S; Stoyanova, Radka; Shareef, Mohammed M et al. (2016) Edelfosine Promotes Apoptosis in Androgen-Deprived Prostate Tumors by Increasing ATF3 and Inhibiting Androgen Receptor Activity. Mol Cancer Ther 15:1353-63
Huang, Kris T; Stoyanova, Radka; Walker, Gail et al. (2015) Post-radiotherapy prostate biopsies reveal heightened apex positivity relative to other prostate regions sampled. Radiother Oncol 115:101-6
Pollack, Alan; Dignam, James J; Diaz, Dayssy A et al. (2014) A tissue biomarker-based model that identifies patients with a high risk of distant metastasis and differential survival by length of androgen deprivation therapy in RTOG protocol 92-02. Clin Cancer Res 20:6379-88
Pollack, Alan; Walker, Gail; Horwitz, Eric M et al. (2014) Reply to M.J. Brenner et al and I.R. Vogelius et al. J Clin Oncol 32:1853-4
Pollack, Alan; Walker, Gail; Horwitz, Eric M et al. (2013) Randomized trial of hypofractionated external-beam radiotherapy for prostate cancer. J Clin Oncol 31:3860-8
Stoyanova, Radka; Pahlajani, Niraj H; Egleston, Brian L et al. (2013) The impact of dose-escalated radiotherapy plus androgen deprivation for prostate cancer using 2 linked nomograms. Cancer 119:1080-8
Pahlajani, Niraj; Ruth, Karen J; Buyyounouski, Mark K et al. (2012) Radiotherapy doses of 80 Gy and higher are associated with lower mortality in men with Gleason score 8 to 10 prostate cancer. Int J Radiat Oncol Biol Phys 82:1949-56
Okera, Meena; Bae, Kyoungwha; Bernstein, Eric et al. (2011) Evaluation of nuclear factor ?B and chemokine receptor CXCR4 co-expression in patients with prostate cancer in the Radiation Therapy Oncology Group (RTOG) 8610. BJU Int 108:E51-8

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