Clinically we have attempted to develop novel agents that alter the biology of the cancer. Specifically, we have been interested for many years in inhibiting angiogenesis as a means to treat prostate cancer. The progression of prostate cancer from a latent to an aggressive form depends on the acquisition of the angiogenic phenotype. Without angiogenesis, the primary prostate tumor is confined to 1-2 mm in size, and remains indolent. Angiogenesis is also required at sites of secondary colonizations in order for prostate cancer metastases to proliferate and expand. Prostate tumors found in autopsy specimens from men without clinical prostate cancer have very low blood vessel content, compared to prostate cancer specimens from men with clinically-evident disease. Siegal and colleagues reported that microvessel density (MVD) was significantly higher in prostate cancer tissue, than in adjacent hyperplastic or benign tissue. Numerous studies have been conducted to evaluate the use of MVD in prostate cancer samples as a prognostic and/or diagnostic marker. Most studies have demonstrated that MVD does help predict pathological stage and patient outcome. Using specimens from radical prostatectomies, Weidner et al., correlated increased angiogenesis in primary tumor specimens with metastatic disease. Several other studies also found MVD to independently predict the outcome of patients with prostate cancer. A recent study did not find MVD to be a useful prognostic indicator for men with clinically localized prostate cancer.? ? Angiogenesis is driven by an imbalance of positive and negative regulators. One of the most potent positive regulators of angiogenesis is the vascular endothelial growth factor (VEGF). Prostate cancer cells produce VEGF at very high concentrations compared to normal prostate tissue. Such elevated levels of VEGF contribute to prostate cancer progression by inducing angiogenesis in the stroma via paracrine signalling. Using different sublines of LNCap cell lines, Balbay and colleagues demonstrated that the metastatic potential of human prostate cancer cell lines in an athymic mice model correlated with their VEGF expression. VEGF production is regulated by androgens in both normal and malignant prostate tissues. When prostate cancer cells progress to an androgen-independent state, VEGF regulation by androgens is also lost. Cellular hypoxia then becomes the main regulator of VEGF. VEGF acts upon two high affinity tyrosine kinase family receptors, Flt-1/ VEGFR-1 and Flk-1/ VEGFR-2. While previously believed to be specific to endothelial cells, these VEGF receptors have recently been localized to several types of tumors, including prostate. A recent study reports that Flt-1 is present in BPH and PIN, but lost in prostate cancer cells and with tumor dedifferentiation, implicating a role for this receptor in prostatic transformation to malignancy. Another member of the VEGF family, VEGF C, which binds to VEGF receptor-3 (VEGFR-3/ Flt-4) is also produced by prostate cancer cells and has recently been implicated in lymph node metastasis. Thus, the strong interplay between prostate cancer progression and angiogenesis are quickly being realized as this field unfolds. Antiangiogenic agents which we have clinically evaluated include: suramin, CAI, thalidomide, TNP-470, COL3, and somatuline. Currently, we are assessing docetaxel with or without thalidomide, and ketoconazole with or without alendronate (an MMP inhibitor) in patients with androgen indepedent prostate cancer. We have initiated a phase I clinical trial with CC5013 and 2ME (angiogenesis inhibitors).? ? The angiogenic property of thalidomide reported by D'Amato and colleagues has prompted its clinical evaluation in various solid tumors including prostate cancer.

Agency
National Institute of Health (NIH)
Institute
Division of Clinical Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01SC006538-12
Application #
7292013
Study Section
(MOB)
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2005
Total Cost
Indirect Cost
Name
Clinical Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Ning, Yang-Min; Figg, William D; Dahut, William L (2009) Reversal of docetaxel resistance with bevacizumab and thalidomide. Clin Genitourin Cancer 7:E37-8
Ge, Yun; Byun, Jung S; De Luca, Paola et al. (2008) Combinatorial antileukemic disruption of oxidative homeostasis and mitochondrial stability by the redox reactive thalidomide 2-(2,4-difluoro-phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione (CPS49) and flavopiridol. Mol Pharmacol 74:872-83
Li, Haiqing; Raia, Valentina; Bertolini, Francesco et al. (2008) Circulating endothelial cells as a therapeutic marker for thalidomide in combined therapy with chemotherapy drugs in a human prostate cancer model. BJU Int 101:884-8
Li, Haiqing; Price, Douglas K; Figg, William D (2007) ADH1, an N-cadherin inhibitor, evaluated in preclinical models of angiogenesis and androgen-independent prostate cancer. Anticancer Drugs 18:563-8
Lakhani, Nehal J; Sparreboom, Alex; Xu, Xia et al. (2007) Characterization of in vitro and in vivo metabolic pathways of the investigational anticancer agent, 2-methoxyestradiol. J Pharm Sci 96:1821-31
Gojo, Ivana; Jiemjit, Anchalee; Trepel, Jane B et al. (2007) Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias. Blood 109:2781-90
Ge, Yun; Montano, Idalia; Rustici, Gabriella et al. (2006) Selective leukemic-cell killing by a novel functional class of thalidomide analogs. Blood 108:4126-35
Warfel, Noel A; Lepper, Erin R; Zhang, Chunyu et al. (2006) Importance of the stress kinase p38alpha in mediating the direct cytotoxic effects of the thalidomide analogue, CPS49, in cancer cells and endothelial cells. Clin Cancer Res 12:3502-9
Lepper, Erin R; Smith, Nicola F; Cox, Michael C et al. (2006) Thalidomide metabolism and hydrolysis: mechanisms and implications. Curr Drug Metab 7:677-85
Sion, Amy M; Figg, William D (2006) Lysyl oxidase (LOX) and hypoxia-induced metastases. Cancer Biol Ther 5:909-11

Showing the most recent 10 out of 47 publications