Anna Ferrari, M.D.

Immunotherapy in the treatment of advanced prostate cancer
Djavan, Bob; Nelson, Kathleen; Kazzazi, Amir; Bruhn, Aron; Sadri, Helen; Gomez-Pinillos, Alejandro; Ferrari, Anna C
2011 Oct;18(5):5865-5874, Canadian journal of urology
Prostate cancer is a complex disease, and treatment selection is informed by numerous variables depending on the stage of disease. Moreover, patient expectations and the impact of treatment-related adverse events may influence treatment choices. Available treatment options over the course of the disease have included surgery, radiation therapy, hormonal therapy, immunotherapy, and chemotherapy. This complexity requires an understanding of a wide range of treatment options and the support of a multidisciplinary team that involves urologists, radiation oncologists, diagnostic radiologists, pathologists, and medical oncologists. Collaboration among these physicians allows for a comprehensive treatment strategy that addresses the individual needs of the patient throughout the course of his disease. Prior to 2004, treatment options for metastatic castrate-resistant prostate cancer (CRPC) were limited to therapies for palliation of pain and reduction of skeletal-related events. Over the past 7 years, four therapeutic options-three within the last 2 years-that provide a survival benefit in this setting have been approved. These therapies have diverse mechanisms, perhaps reflecting the complex nature of advanced prostate cancer. Among them is sipuleucel-T, the first autologous immunotherapy approved for any cancer. This review will discuss the rapidly changing treatment environment for metastatic CRPC and the increased exploration of immunotherapeutic approaches to advanced prostate cancer
— id: 139745, year: 2011, vol: 18, page: 5865, stat: Journal Article,

Induction of bicalutamide sensitivity in prostate cancer cells by an epigenetic Puralpha-mediated decrease in androgen receptor levels
Liu, Xiaomei; Gomez-Pinillos, Alejandro; Liu, Xiaojun; Johnson, Edward M; Ferrari, Anna C
2010 Feb 1;70(2):179-189, Prostate
BACKGROUND: Increased androgen receptor (AR) levels support resistance to apoptosis and hormone therapy in advanced prostate cancer (PC). We recently linked the overexpression of AR in androgen-independent LNCaP cells (AI-cells) and tissues from castration-resistant patients to decreased nuclear levels of Pur-alpha (Puralpha) and loss from a protein complex bound to repressor sequences (ARS) in the 5'-UTR of AR. Strategies to regain control of increased AR transcription may overcome resistance of AI-cells and improve treatment outcomes. METHODS: MTT, real-time PCR, Western blot, ChIP, flow cytometry, and caspase 3/7 activation measured the effect on growth and targets of LBH589/bicalutamide treatment of AI-cells and androgen-dependent LNCaP cells (AD). RESULTS: Within 16 hr of treatment of AI-cells with low concentrations of the histone deacetylase inhibitor LBH589, a shift of cytoplasmic Puralpha restored the nuclear levels and the binding of Puralpha to the ARS. This was followed by a decline in AR-mRNA and protein reaching levels of parental AD-cells. The fraction of AI-cells in G1 increased and the cells in S phase decreased similar to AD-cells, and there was a modest caspase activation. Most notably, treatment of bicalutamide-resistant AI-cells with 10 nM LBH589 combined with 12.5 microM bicalutamide synergistically inhibited cell growth and induced a fivefold higher level of caspase 3/7 activation than observed in AD-cells. CONCLUSIONS: Low-dose LBH589 restores Puralpha binding to ARS and down-regulates AR transcription. Biologically, LBH589 reverses the resistance of AI-cells to bicalutamide and to apoptosis. The combination may restore the hormonal response of castration-resistant PC patients. Prostate 70: 179-189, 2010. (c)2009 Wiley-Liss, Inc
— id: 105961, year: 2010, vol: 70, page: 179, stat: Journal Article,

Sequential and intermittent docetaxel (D) and imatinib (Im) in hormone-refractory prostate cancer patients (NYU 04-47)
Gmez-Pinillos A.; Ballard H.; Shelton G.; Reilly M.M.; Chachoua A.; Taneja S.; Ferrari A.C.
2009 ;27(15 Suppl 1):?-? #e16108, Journal of clinical oncology
Background: Platelet-derived growth factor is frequently expressed in advanced prostate cancer (PC) lesions where it supports PC cell growth and neo-angiogenesis. Im. is a PDGF inhibitor that blocks cell cycle in G1-S due to MEK/erk inhibition. D blocks cell cycle progression in G2-M. Sequential block of the cell cycle progression in G2-M followed by G1-S may increase anti-tumor responses. The phase II study dose of sequential D on day 1 and Im started 24-36h later given daily for 14 d was established in a previous phase I. Methods: Eligibility: at least 2 prior hormone manipulations and up to one prior chemotherapy, PSA>5ng/ml, ECOG PS 0-2. Treatment schedule: D 70mg/m2 day 1 followed 24-36 hours later by Im 600mg PO daily x 14 days. Cycles were repeated every 21d until toxicity or progression. Pegfilgrastim was given each cycle for neutropenia prevention. A two steps design was planned to assess activity (PSA decline >50% and/or measurable or symptomatic response) and tolerance including interim analysis to determine if 37 patients (pts) should be enrolled. Results: Of 15 pts enrolled, 13 had metastasis and 5(33%) received prior chemotherapy. There were 98 cycles of trial therapy administered and 9 events (PSA or bone progression) registered at the time of analysis. Median baseline PSA 73,5ng/ml (2.1-1954.3). Median follow-up estimated by inverse Kaplan Meier: 308 days (CI95%, 133-482). Median of cycles administrated 6 (1-12). PSA decline >50% observed in 7/15pts (46.67%) of which 3 was >80% (20%). PSA decline <50%, observed in 6/15(40%). 2/15(15.3%) were non-responders. Pain scores improved in all symptomatic pts. Median duration of response was 162 days (42- 281). Estimated median progression free survival by Kaplan-Meier was 155 days (CI95%, 80-339). Toxicity: there was G1-2 fatigue, anorexia, weight change in 66% pts; nausea, vomiting, taste changes in 66% pts, anemia in 46% and neuropathy in 46% pts. G3 fatigue in 2 pts, neuropathy and CHF in 1 pt. No G4 toxicities were observed. Conclusions: Sequential and intermittent D every 21 days and Im for 14 days is tolerable and active by PSA decline and symptomatic improvement. Compared to previous report with weekly D and continuous Im, this alternative schedule appears to have similar activity with better tolerance
— id: 111804, year: 2009, vol: 27, page: ?, stat: Journal Article,

LEF1 in androgen-independent prostate cancer: regulation of androgen receptor expression, prostate cancer growth, and invasion
Li, Yirong; Wang, Longgui; Zhang, Miao; Melamed, Jonathan; Liu, Xiaomei; Reiter, Robert; Wei, Jianjun; Peng, Yi; Zou, Xuanyi; Pellicer, Angel; Garabedian, Michael J; Ferrari, Anna; Lee, Peng
2009 Apr 15;69(8):3332-3338, Cancer research
A major obstacle in treating prostate cancer is the development of androgen-independent disease. In this study, we examined LEF1 expression in androgen-independent cancer as well as its regulation of androgen receptor (AR) expression, prostate cancer growth, and invasion in androgen-independent prostate cancer cells. Affymetrix microarray analysis of LNCaP and LNCaP-AI (androgen-independent variant LNCaP) cells revealed 100-fold increases in LEF1 expression in LNCaP-AI cells. We showed that LEF1 overexpression in LNCaP cells resulted in increased AR expression and consequently enhanced growth and invasion ability, whereas LEF1 knockdown in LNCaP-AI cells decreased AR expression and, subsequently, growth and invasion capacity. Chromatin immunoprecipitation, gel shift, and luciferase assays confirmed LEF1 occupancy and regulation of the AR promoter. Thus, we identified LEF1 as a potential marker for androgen-independent disease and as a key regulator of AR expression and prostate cancer growth and invasion. LEF1 is highly expressed in androgen-independent prostate cancer, potentially serving as a marker for androgen-independent disease
— id: 99128, year: 2009, vol: 69, page: 3332, stat: Journal Article,

Lef1 Expression in Androgen-Independent Prostate Cancer
Zhang, M; Li, YR; Wang, LG; Melamed, J; Liu, XM; Wei, JJ; Peng, Y; Pellicer, A; Garabedian, MJ; Ferrari, A; Lee, P
2009 ;89:921-921, Laboratory investigation
— id: 104576, year: 2009, vol: 89, page: 921, stat: Journal Article,

Lef1 Expression in Androgen-Independent Prostate Cancer
Zhang, M; Li, YR; Wang, LG; Melamed, J; Liu, XM; Wei, JJ; Peng, Y; Pellicer, A; Garabedian, MJ; Ferrari, A; Lee, P
2009 ;22(Suppl 1):203A-203A 921, Modern pathology
— id: 104577, year: 2009, vol: 22, page: 203A, stat: Journal Article,

Androgen receptor overexpression in prostate cancer linked to Pur alpha loss from a novel repressor complex
Wang, Longgui G; Johnson, Edward M; Kinoshita, Yayoi; Babb, James S; Buckley, Michael T; Liebes, Leonard F; Melamed, Jonathan; Liu, Xiao-Mei; Kurek, Ralf; Ossowski, Liliana; Ferrari, Anna C
2008 Apr 15;68(8):2678-2688, Cancer research
Increased androgen receptor (AR) expression and activity are pivotal for androgen-independent (AI) prostate cancer (PC) progression and resistance to androgen-deprivation therapy. We show that a novel transcriptional repressor complex that binds a specific sequence (repressor element) in the AR gene 5'-untranslated region contains Pur alpha and hnRNP-K. Pur alpha expression, its nuclear localization, and its AR promoter association, as determined by chromatin immunoprecipitation analysis, were found to be significantly diminished in AI-LNCaP cells and in hormone-refractory human PCs. Transfection of AI cells with a plasmid that restored Pur alpha expression reduced AR at the transcription and protein levels. Pur alpha knockdown in androgen-dependent cells yielded higher AR and reduced p21, a gene previously shown to be under negative control of AR. These changes were linked to increased proliferation in androgen-depleted conditions. Treatment of AI cells with histone deacetylase and DNA methylation inhibitors restored Pur alpha protein and binding to the AR repressor element. This correlated with decreased AR mRNA and protein levels and inhibition of cell growth. Pur alpha is therefore a key repressor of AR transcription and its loss from the transcriptional repressor complex is a determinant of AR overexpression and AI progression of PC. The success in restoring Pur alpha and the repressor complex function by pharmacologic intervention opens a promising new therapeutic approach for advanced PC
— id: 95063, year: 2008, vol: 68, page: 2678, stat: Journal Article,

Dual action on promoter demethylation and chromatin by an isothiocyanate restored GSTP1 silenced in prostate cancer
Wang, L G; Beklemisheva, A; Liu, X M; Ferrari, A C; Feng, J; Chiao, J W
2007 Jan;46(1):24-31, Molecular carcinogenesis
Prostate carcinoma is characterized by the silencing of pi-class glutathione S-transferase gene (GSTP1), which encodes a detoxifying enzyme. The silencing of GSTP1, due to aberrant methylation at the CpG island in the promoter/5'-UTR, occurs in the vast majority of prostate tumors and precancerous lesions. It is a pathologic marker and probably an underlying cause of oxidative damage and inflammation at tumor initiation. Inhibition of the aberrant promoter methylation could therefore be an effective mean to prevent carcinogenesis. Several isothiocyanates, including phenethyl isothiocyanate (PEITC), found naturally in cruciferous vegetables, induced growth arrest and apoptosis in prostate cancer cells in culture and xenografts. The effects of PEITC to reactivate GSTP1 were investigated. Exposure of prostate cancer LNCaP cells to PEITC inhibited the activity and level of histone deacetylases (HDACs), and induced selective histone acetylation and methylation for chromatin unfolding. Concurrently PEITC demethylated the promoter and restored the unmethylated GSTP1 in both androgen-dependent and -independent LNCaP cancer cells to the level found in normal prostatic cells, as quantified by methylation-specific PCR and pyrosequencing. The dual action of PEITC on both the DNA and chromatin was more effective than 5'-Aza-2'-deoxycytidine, sodium butyrate, or trichostatin A (TSA), and may de-repress the methyl-binding domain (MBD) on gene transcription. The PEITC-mediated cross-talk between the DNA and chromatin in demethylating and reactivating GSTP1 genes, which is critically inactivated in prostate carcinogenesis, underlines a primary mechanism of cancer chemoprevention. Consequently, new approaches could be developed, with isothiocyanates to prevent and inhibit malignancies
— id: 70302, year: 2007, vol: 46, page: 24, stat: Journal Article,

Molecular load of pathologically occult metastases in pelvic lymph nodes is an independent prognostic marker of biochemical failure after localized prostate cancer treatment
Ferrari, Anna C; Stone, Nelson N; Kurek, Ralf; Mulligan, Elizabeth; McGregor, Roy; Stock, Richard; Unger, Pamela; Tunn, Ulf; Kaisary, Amir; Droller, Michael; Hall, Simon; Renneberg, Heiner; Livak, Kenneth J; Gallagher, Robert E; Mandeli, John
2006 Jul 1;24(19):3081-3088, Journal of clinical oncology
PURPOSE: Thirty percent of patients treated with curative intent for localized prostate cancer (PC) experience biochemical recurrence (BCR) with rising serum prostate-specific antigen (sPSA), and of these, approximately 50% succumb to progressive disease. More discriminatory staging procedures are needed to identify occult micrometastases that spawn BCR. PATIENTS AND METHODS: PSA mRNA copies in pathologically normal pelvic lymph nodes (N0-PLN) from 341 localized PC patients were quantified by real-time reverse-transcriptase polymerase chain reaction. Based on comparisons with normal lymph nodes and PLN with metastases and on normalization to 5 x 10(6) glyceraldehyde-3'-phosphate dehydrogenase mRNA copies, normalized PSA copies (PSA-N) and a threshold of PSA-N 100 or more were selected for continuous and categorical multivariate analyses of biochemical failure-free survival (BFFS) compared with established risk factors. RESULTS: At median follow-up of 4 years, the BFFS of patients with PSA-N 100 or more versus PSA-N less than 100 was 55% and 77% (P = .0002), respectively. The effect was greatest for sPSA greater than 20 ng/mL, 25% versus 60% (P = .014), Gleason score 8 or higher, 21% versus 66% (P = .0002), stage T3c, 18% versus 64% (P = .001), and high-risk group (50% v 72%; P = .05). By continuous analysis PSA-N was an independent prognostic marker for BCR (P = .049) with a hazard ratio of 1.25 (95% CI, 1.001 to 1.57). By categorical analysis, PSA-N 100 or more was an independent variable (P = .021) with a relative risk of 1.98 (95% CI, 1.11 to 3.55) for BCR compared with PSA-N less than 100. CONCLUSION: PSA-N 100 or more is a new, independent molecular staging criterion for localized PC that identifies high-risk group patients with clinically relevant occult micrometastases in N0-PLN, who may benefit from additional therapy to prevent BCR
— id: 65800, year: 2006, vol: 24, page: 3081, stat: Journal Article,

Mithramycin Targets Sp1 and The Androgen Receptor Transcription Level: Potential Therapeutic Role in Advanced Prostate Cancer
Wang LG; Ferrari AC
2006 ;1:19-31, Translational oncogenomics
— id: 109028, year: 2006, vol: 1, page: 19, stat: Journal Article,

Unique induction of p21(WAF1/CIP1) expression by vinorelbine in androgen-independent prostate cancer cells
Liu, XM; Jiang, JD; Ferrari, AC; Budman, DR; Wang, LG
2003 OCT 20 ;89(8):1566-1573, British journal of cancer
To study the mechanisms of the development of hormone refractory prostate cancer, we established an androgen-independent ( AI) prostate cancer cell line derived from hormone-dependent (AD) LNCaP cells. Our previous studies have demonstrated that AI cells are deficient in expression of p21(WAFl/CIP1) (p21) due to overexpressed AR and are resistant to apoptosis. In this study, the induction of p53 and p21 expression by vinorelbine ( Navelbine) was compared between AD and AI cells in an attempt to understand the difference(s) in apoptotic signalling pathways in these cells. Using a series of deletion of p21 reporter constructs, we found that vinorelbine mediated p21 induction in a p53-dependent manner in AD cells. In contrast, p21 expression restored by vinorelbine in AI cells was found to be through both p53-dependent and-independent pathways. In the absence of two p53 binding sites, Spl-3 and Spl-4 sites, in the promoter of human p21 gene, were found to be required for vinorelbine-mediated p21 activation. No p21 induction was observed by paclitaxel in AI cells. Exposure of AI cells to paciltaxel followed by vinorelbine produced synergism. Our data, thus, provide a basis for the synergistic combination of vinorelbine and paclitaxel for the treatment of advanced prostate cancer
— id: 55499, year: 2003, vol: 89, page: 1566, stat: Journal Article,

A Phase I/II study of weekly paclitaxel and 3 days of high dose oral estramustine in patients with hormone-refractory prostate carcinoma
Ferrari AC; Chachoua A; Singh H; Rosenthal M; Taneja S; Bednar M; Mandeli J; Muggia F
2001 Jun 1;91(11):2039-2045, Cancer
BACKGROUND: The maximum tolerated dose (MTD) and efficacy of weekly 1-hour paclitaxel with 3 days of high dose oral estramustine were evaluated in patients with hormone-refractory prostate carcinoma. METHODS: Patients enrolled in cohorts of three received two cycles of six weekly treatments with 1 week of rest: Cohort I received paclitaxel 40 mg/m2 and estramustine 600 mg/m2, and Cohorts II-IV received paclitaxel 60 mg/m2, 75 mg/m2, or 90 mg/m2, respectively, and estramustine 900 mg/m2. Toxicity was assessed weekly, and response was measured by serum prostate specific antigen (PSA), abdominal computed tomography scans, and bone scans at Week 13. RESULTS: Eighteen patients were enrolled, with 12 in Cohorts III and IV. Four patients did not complete treatment. Grade 3 toxicity included one patient with nausea and diarrhea in Cohort III and one patient each with neutropenia and edema followed by Grade 4 thromboembolism in Cohort IV. Grade 1-2 anemia or myelotoxicity were not observed; 3 patients had neuropathy, 5 patients had hair loss, and 8 patients had gastrointestinal symptoms. A decline in the serum PSA level > or = 50% occurred in none of three patients, one of three patients, four of six patients, and four of six patients in Cohorts I-IV, respectively. An intent-to-treat analysis showed responses in 9 of 18 patients (50%) in Cohorts I-IV, with 9 of 15 responders (60%) in Cohorts II-IV. Seven patients achieved declines in serum PSA levels > 75%. The median duration of PSA response was 16.7 weeks. Response was observed in one of three patients with measurable disease. CONCLUSIONS: The MTD for 1-hour weekly paclitaxel was 90 mg/m2 with 3 days of 900 mg/m2 estramustine. Hematologic and neurotoxicity were reduced markedly, and gastrointestinal symptoms were ameliorated, but thromboembolic events were unaffected. PSA response rates were within the expected 60% range for these agents
— id: 34610, year: 2001, vol: 91, page: 2039, stat: Journal Article,

The FGF-related oncogene, K-FGF, maps to human chromosome region 11q13, possibly near int-2
Huebner K; Ferrari AC; Delli Bovi P; Croce CM; Basilico C
1988 ;3(3):263-270, Oncogene research
The protein encoded in a novel human oncogene isolated by transfection of Kaposi's sarcoma DNA is a growth factor with significant homology to basic and acidic FGFs. The genomic structure of this oncogene (designated K-FGF), as originally isolated, carried DNA rearrangements upstream and downstream of the coding region. The normally discontinuous sequence upstream of the K-FGF coding region derived from the 3' end of the c-fms gene and thus originated from human chromosome 5. In order to determine the normal chromosomal location of the K-FGF gene and of the DNA sequences adjacent to its 3' end, we have correlated the presence of these sequences with retention of specific human chromosome regions in rodent-human somatic cell hybrids. These experiments mapped the K-FGF gene to human chromosome region 11q13----11q23, and in situ hybridization localized it more precisely to region 11q13 near int-2, which also belongs to the FGF family. The sequence downstream of the gene in transfectants and discontinuous with K-FGF in normal human DNA derives from chromosome region 12p12----12q13, possibly near the int-1 locus
— id: 14424, year: 1988, vol: 3, page: 263, stat: Journal Article,