Clinical and Experimental Progression of a New Model of Human Prostate Cancer and Therapeutic Approach

Abstract

We report the clinical evolution of a prostate cancer, metastasizing to lungs and bones, recurring locally, and escaping from anti-androgen therapy. Key event of biological progression of the patient's tumor was the coincidence of allelic imbalance accumulation and of bone metastases occurrence. The recurrent tumor was established as the transplantable xenograft PAC120 in nude mice, where it grew locally. PAC120 displayed the same immunophenotype of the original tumor (positive for keratin, vimentin, prostatic acid phosphatase, and Leu-7) and expressed human HOXB9, HOXA4, HER-2/neu, and prostate-specific antigen genes, as detected by reverse transcriptase-polymerase chain reaction. It formed lung micrometastases detected by mRNA expression of human genes. Cytogenetic analysis demonstrated numerous alterations reflecting the tumor evolution. PAC120 was still hormone-dependent; its growth was strongly inhibited by the new gonadotropin-releasing hormone antagonist FE 200486 but weakly by gonadotropin-releasing hormone superagonist D-Trp(6)-luteinizing-hormone releasing hormone (decapeptyl). Tumor growth inhibition induced by anti-hormone therapy was linked to the hormone deprivation degree, more important and more stable with FE 200486 than with D-Trp(6)-luteinizing-hormone releasing hormone. Surgical castration of mice led to tumor regressions but did not prevent late recurrences. Transition to hormone-independent tumors was frequently associated with a mucoid differentiation or with a neuroendocrine-like pattern. Independent variations of mRNA expression of HER-2/neu and prostate-specific antigen were observed in hormone-independent tumors whereas HOXB9 gene expression was constant. In conclusion, PAC120 xenograft, a new model of hormone-dependent prostate cancer retained the progression potential of the original tumor, opening the opportunity to study the hormone dependence escape mechanism.

AZD3514: A Small Molecule That Modulates Androgen Receptor Signaling and Function In Vitro and In Vivo

“…ARD1, a compound with similar biologic properties to AZD3514 inhibits androgen-independent HID28 prostate tumor growth in vivo We subsequently wanted to assess whether the AZD3514 mechanism of action could deliver in vivo efficacy in a castrate-resistant setting using the murine HID28 model, an androgen-independent variant of PAC120 prostate tumors (43). Oral dosing with AZD3514 at 100 mg/kg in the mouse had poor pharmacokinetic (PK) profile ( Supplementary Fig.…”

Mucinous differentiation features associated with hormonal escape in a human prostate cancer xenograft

“…PAC120 reproduced the morphological and biological characteristics of the original tumour as published (de Pinieux et al, 2001), with a compact, lobular pattern and sparse gland lumens ( Figure 1A). During serial transplantation, PAC120 displayed a very stable morphology and histology (neither mucinous nor neuroendocrine differentiation were observed), and remained hormone-dependent for 29 passages over 7 years.…”

“…The parental tumour PAC120, a hormone-dependent human prostate cancer xenograft transplantable into nude mice, was established in our laboratory (de Pinieux et al, 2001). The original PAC120 tumour appeared 7 months after grafting, and was maintained by serial transplantation during several passages (p4 -p29) by subcutaneous implantation of tumour fragments.…”

“…PAC120 is a human prostate cancer xenograft obtained by urethral resection of a recurrent prostate cancer, and direct subcutaneous engraftment into nude mice (de Pinieux et al, 2001). PAC120 is androgen-responsive, but recurs as hormone-refractory disease following transplantation in castrated mice.…”

Correlation between genetic alterations and growth of human malignant glioma xenografted in nude mice

“…After xenograft, all but one glioma lost their glial differentiation and presented a dedifferentiated phenotype in contrast with xenografts derived from other human cancers that maintained several of their histological characteristics (Rofstad et al, 1990a, b;Poupon et al, 1993;Kolfschoten et al, 2000;Bras-Goncalves et al, 2001;de Pinieux et al, 2001;Krasagakis et al, 2001).…”