Zhou Wang, PhD, and Daniel Shevrin, MD
Prostate cancer patients treated with androgen ablation therapy (AAT) inevitably relapse with androgen refractory tumors and often suffer from side effects caused by AAT. In an attempt to delay cancer progression to androgen-independence and to improve the quality of life, Dr. Nicholas Bruchovsky developed intermittent androgen ablation therapy (IAAT). Many prostate cancer patients are being treated with IAAT, sometimes together with a 5a-reductase inhibitor (finasteride or dutasteride). However, the efficacy of IAAT is not defined, and the survival benefits associated with finasteride or dutasteride administration in IAAT have not been addressed. Furthermore, the criteria for switching from off-cycle to on-cycle in IAAT are not clear. With the support of our patient advocacy members, we decided to address the above questions regarding IAAT. We have developed our research hypothesis that blocking testosterone (T) to dihydrotestosterone (DHT) conversion by 5a-reductase inhibitor during the off-cycle (when T is recovering) supra-induces tumor-suppressive androgen-response genes and enhances the efficacy of IAAT. Recent preliminary studies using a subcutaneous LNCaP xenograft tumor model strongly support the above hypothesis. Administration of finasteride during the off-cycle in IAAT significantly enhanced the induction of tumor suppressive androgen-response gene U19, retarded the tumor growth, and prolonged the survival of the host. To improve IAAT, we propose following four Specific Aims:
- Determine the effect of 5a-reductase inhibition on IAAT using LuCaP35, another AR-positive prostate xenograft tumor model. One difference between LuCaP35 and LNCaP is that the androgen receptor (AR) in LuCaP35 is wild-type, whereas the AR in LNCaP has a mutation in the ligand-binding domain.
- Determine whether 5a-reductase inhibition enhances the expression of tumor-suppressive androgen-responsive genes in LuCaP35 prostate tumor regrowth during IAAT in nude mice.
- Determine the effect of altering the interval of off-cycle in IAAT in animal models.
- Conduct a phase II clinical trial to test the hypothesis that 5a-reductase inhibition during the off-cycle of IAAT enhances androgen-response gene expression in prostate cancer cells, the primary endpoint, and prolongs serum PSA doubling time, a secondary endpoint. The success of this translational project will enhance/optimize IAAT and provide a strong rationale for a phase III clinical trial to determine if dutasteride administration in IAAT can delay the progression to androgen-independence and prolong the survival of patients with metastatic prostate cancer.
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Susan Crawford, MD, Jennifer Doll, Ph.D., and Chung Lee, PhD
Obesity has become a major health epidemic in the United States, affecting nearly 30% of the population, and it significantly increases the risk of developing a wide spectrum of diseases including cancer. Although large studies have demonstrated a consistent link between men with a body mass index (BMI) >30 kg/m2 and an increased risk of death from prostate cancer (PCa), studies evaluating the risk of PCa in obese men are not conclusive. Adipose tissue functions as an endocrine organ and is a rich source of soluble proteins including leptin and pigment epithelium-derived factor (PEDF). Leptin levels are elevated in obese individuals, and it functions to maintain normal body weight since mice null for leptin or the leptin receptor become obese. Leptin can also induce angiogenesis and stimulate the proliferation of androgen-insensitive PCa cells, and its levels are elevated in the serum of PCa patients with more aggressive disease. In contrast to leptin's tumor promoting activities, our data revealed that PEDF is a potent inhibitor of angiogenesis that can suppress PCa cancer cell growth in vivo by inducing apoptosis of the supporting vasculature. Moreover, PEDF null mice develop progressive prostatic PIN with high stromal vascularity and have increased deposition of adipose tissue in the abdominal and pelvic regions with increased leptin and leptin receptor expression in target tissues, including the prostate stroma. In PCa patients, PEDF levels in serum were significantly lower in patients with higher Gleason scores. From these data, we hypothesized that PEDF is an important negative regulator of prostate growth and of adipogenesis, in part, through negative regulation of leptin. Therefore, obesity can promote an imbalance in local and circulating leptin and PEDF levels leading to a pro-tumorigenic environment. This study intends to (a) elucidate the roles of PEDF and leptin in tumor progression and identify the signaling pathways between these molecules, (b) determine if Gleason score correlates with circulating levels of free leptin and PEDF in PCa patients, and (c) to assess if prostate tissue expression levels of leptin, PEDF and their receptors, or adipocyte density, have prognostic value.
Obesity is an increasing public health problem in the United States and the risk of certain cancers are higher in obese individuals. The biology underlying the link between these two diseases remains unclear. Our preliminary studies suggest that a signaling network exists between fat cells, leptin and pigment epithelium derived factor and dysregulation of any one of these factors can promote a pro-tumorigenic environment. The studies proposed here have the potential to provide mechanistic insight into the enhanced cancer risk in obese patients and could identify new prognostic markers for prostate cancer.
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Ralph Weichselbaum, MD, and Walter Stadler, MD
Outcomes for patients with high-risk localized prostate cancer treated with standard radiotherapy and androgen ablation are unacceptable. The addition of radiation sensitizing agents to radiotherapy is useful in other locally advanced cancers such as lung and rectal cancer. TNF-alpha is a potent radiosensitizing antitumor agent, but toxicity limits its use as a systemic drug. Ad.Egr-TNF.11D (TNFeradeTM, GenVec, Gaithersburg, MD) is a replication deficient E1, E3, E4 deleted adenoviral vector that encodes radio-inducible DNA sequences upstream from a cDNA for human TNF-alpha. Ad.Egr-TNF.11D is activated following radiation to produce intratumoral therapeutic levels of TNF-alpha and enhanced tumor regression via vascular destruction and thrombosis. To develop this concept clinically an early phase clinical trial of Ad.Egr-TNF.11D, radiotherapy, and androgen ablation to determine if the combination is safe in these patients will be conducted.
It is recognized that addition of inducible local TNF is unlikely to be sufficient for this population and that additional measures need to be explored. Furthermore, markers for predicting which patients are most likely to benefit need to be developed. In regards to the former, activation of NFkB by both TNF and radiation may be critical to promoting survival and inhibiting both the cancer and endothelial cell death required for successful treatment. Therefore, it will be determined if inhibition of NFkB activation through use of the triterpenoid CDDO or an adenoviral vector that inhibits NFkB by encoding a non-degradable ("super-repressor") form of IKBa (Ad.CMV.IkBa) further enhances the activity of Ad.Egr-TNF.11D and radiotherapy in preclinical prostate cancer models.
Finally, it has been demonstrated that STAT1 is induced by radiation and preliminary evidence suggests that upregulation of STAT1 predicts for resistance to irradiation, raising the hypothesis that patients with baseline elevated tumor STAT1 levels will respond less well to standard radiation. It will thus be determined if STAT1 and NFkB overexpression are associated with recurrence in a historical group of locally advanced prostate cancer patients with the prediction that the association will be stronger in patients treated with radiotherapy than in patients treated with surgery.
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Raymond Bergan, MD, and William Catalona, MD
Genistein is a NCI high priority putative prostate cancer (PCa) chemopreventive agent. Our preliminary studies demonstrate that genistein inhibits PCa cell detachment and invasion, which are initial steps in the metastatic cascade. We hypothesize that genistein will also inhibit PCa metastasis by inhibiting the movement of prostate cancer cells from the prostate gland into the circulation in man.
In preliminary in vitro studies, we demonstrated that genistein inhibits activation of the pro-cell-motility signaling p38-HSP27 (heat shock protein 27) pathway, while enhancing activation of the anti-motility ALK-2 signaling pathway. In mice, we have shown that genistein inhibits human PCa cell detachment and metastasis. Our first SPORE trial was a phase I clinical trial, and it defined genistein's pharmacology in PCa patients. Our second SPORE trial was a phase 2 pre-prostatectomy design. It demonstrated that (1) genistein was well tolerated, (2) that it inhibited prostate cell detachment, and (3) that it selectively modulated genes that regulate prostate cell motility.
In this proposal, we propose three Aims:
- To determine whether genistein affects motility associated genes and regulatory proteins in human prostate tissue. Using banked prostate tissue from our second SPORE trial, our studies will determine whether genistein alters the function of relevant regulatory pathways in prostate cells.
- Evaluate in an animal model whether modulation of pro-cell-motility HSP27 has an impact on genistein's ability to inhibit metastases. Human PCa cells engineered to express altered levels of HSP27 will be orthotopically implanted into mice. We will evaluate their ability to form metastasis, with and without genistein treatment.
- To conduct a Phase II clinical trial to determine whether genistein inhibits movement of PCa cells from the prostate gland into the circulation in high risk pre-prostatectomy patients. We will implement a third SPORE trial to test this hypothesis. Subjects with clinically-localized, high-risk PCa with measurable circulating prostate cells will be accrued on to a prospective phase 2, randomized trial of genistein versus placebo. The resultant effects of genistein on circulating levels of prostate cells will be assessed by a quantitative RT/PCR assay for PSA.
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