Prostatic Neoplasms: Twardowski P

Mohler J, Babaian RJ, Bahnson RR, Boston B, D'Amico A, Eastham JA, Hauke RJ, Huben RP, Kantoff P, Kawachi M, Kuettel M, Lange PH, Logothetis C, MacVicar G, Pollack A, Pow-Sang JM, Roach M, Sandler H, Shrieve D, Srinivas S, Twardowski P, Urban DA, Walsh PC, Anonymous00332. · No affiliation provided · J Natl Compr Canc Netw. · Pubmed #17692170 No free full text.

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Lara PN, Twardowski P, Quinn DI. · University of California Davis Cancer Center, 4501 X St, Suite 3016, Sacramento, CA 95817, USA. · Clin Prostate Cancer. · Pubmed #15636683 No free full text.

Abstract: Most patients with metastatic prostate cancer will respond initially to ablation of gonadal androgen production. Eventually, all patients will develop progressive disease despite continued androgen suppression, a condition called androgen-independent or hormone-refractory prostate cancer. Hormone-refractory prostate cancer is characterized by virulent biologic and clinical behavior. Recently, docetaxel-based chemotherapy has been shown to improve survival and quality of life in this disease when compared with mitoxantrone-based therapy. However, results remain suboptimal. Recently, there have been remarkable advances in the delineation of the mechanisms of cancer growth, metastasis, and the intricate interactions between tumor cells and the surrounding normal tissues. The accumulated evidence has confirmed the importance of angiogenesis in these processes and validated the theory that inhibition of neovascularization is a promising therapeutic anticancer strategy. Currently, dozens of compounds that interfere with different steps of the angiogenic cascade are in preclinical and clinical development. Some of these agents have exhibited promising antitumor activity in hormone-refractory prostate cancer. This review summarizes the molecular mechanisms implicating angiogenesis in the development and progression of advanced-stage prostate cancer, as well as the drug development efforts that are targeting this process.

Lara PN, Longmate J, Evans CP, Quinn DI, Twardowski P, Chatta G, Posadas E, Stadler W, Gandara DR. · University of California Davis Cancer Center, Sacramento, California 95817, USA. · Anticancer Drugs. · Pubmed #19396016 No free full text.

Abstract: Prostate cancer cells undergo neuroendocrine differentiation during androgen deprivation and secrete neuropeptides, hence activating androgen receptor-regulated genes. Src-family protein kinases are involved in neuropeptide-induced prostate cancer growth and migration. A phase II trial of AZD0530, an oral Src-family kinase inhibitor, in patients with advanced castration resistant prostate cancer was conducted. The primary endpoint was prostate cancer-specific antigen (PSA) response rate, defined as a 30% or greater decrease. A two-stage Simon design was used. Eligibility criteria included documentation of castration resistance (including antiandrogen withdrawal), adequate end-organ function, and performance status, and not more than one prior taxane-based chemotherapy regimen. AZD0530 was given at 175 mg orally once daily continuously. Rapid accrual led to 28 patients registering in the first stage. Median age was 67 years. Sixteen patients had performance status (PS) 0, eight patients had PS 1, and four patients had PS 2. Nine patients (32%) had prior docetaxel-based chemotherapy. Five patients had transient PSA reductions not meeting PSA response criteria. Median progression-free survival time was 8 weeks. Treatment was generally well tolerated. AZD0530, a potent oral Src kinase inhibitor, is feasible and tolerable in this pretreated patient population but possessed little clinical efficacy as monotherapy. Strong preclinical evidence warrants further investigation of AZD0530 in earlier-stage prostate cancer or as combination therapy.

Cheung E, Pinski J, Dorff T, Groshen S, Quinn DI, Reynolds CP, Maurer BJ, Lara PN, Tsao-Wei DD, Twardowski P, Chatta G, McNamara M, Gandara DR. · University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, USA. · Clin Genitourin Cancer. · Pubmed #19213668 No free full text.

Abstract: BACKGROUND: Fenretinide is a synthetic retinoid that is cytotoxic to a variety of cancers. We conducted a phase II trial of oral fenretinide in patients with biochemically recurrent prostate cancer. PATIENTS AND METHODS: Eligible patients had histologically confirmed prostate cancer and a confirmed rising prostate-specific antigen (PSA) >or= 2 ng/mL following either radical prostatectomy and/or pelvic radiation therapy, without clinical or radiographic evidence of metastasis. The primary endpoint was PSA response, which was defined as a confirmed decrease by >or=50%, and >or=5 ng/mL, from the pretreatment value. Treatment comprised oral fenretinide 900 mg/m2 twice daily for 1 week, every 3 weeks, for 1 year. RESULTS: After a median follow-up of 17.7 months, out of 23 patients, 7 (30%) patients had PSA stable disease (SD), 11 (48%) patients had PSA progression within 3 months, 4 patients had minimal increases over 3 months that did not qualify as SD or progression (17%), and one patient (4%) was not evaluable. Median time to PSA progression was 4.6 months (95% CI, 3.2-8.2 months). Observed grade 3 toxicities included fatigue, pain, hypermagnesemia, a rise in lipase, and nyctalopia. CONCLUSION: Although well-tolerated, oral fenretinide did not meet prespecified PSA criteria for response in biochemically recurrent prostate cancer; however, 30% of patients had SD, which suggests modest single-agent clinical activity. The role of different formulations of fenretinide, which might allow for higher serum concentrations of the drug, is currently under investigation.

Chee KG, Longmate J, Quinn DI, Chatta G, Pinski J, Twardowski P, Pan CX, Cambio A, Evans CP, Gandara DR, Lara PN. · University of California Davis Cancer Center, Sacramento, CA 95817, USA. · Clin Genitourin Cancer. · Pubmed #18272025 No free full text.

Abstract: BACKGROUND: Perifosine is an oral alkylphospholipid that inhibits cancer cell growth through decreased Akt phosphorylation. We conducted a phase II trial of perifosine in patients with biochemically recurrent, hormone-sensitive prostate cancer. PATIENTS AND METHODS: Eligible patients had histologically confirmed prostate cancer, previous prostatectomy and/or radiation therapy, and rising prostate-specific antigen (PSA) without radiographic evidence of metastasis. Previous androgen deprivation therapy < 9 months in duration (completed >or= 1 year before registration) was allowed. The primary endpoint was PSA response, defined as a decrease by >or= 50% from the pretreatment value. Treatment was composed of a loading dose of perifosine 900 mg orally on day 1, then 100 mg daily starting 24 hours later. RESULTS: Of 25 patients, 24 were evaluable for response. After a median follow-up of 8 months, 5 patients (20%) had a reduction in serum PSA levels, but none met criteria for PSA response. Three patients immediately progressed with no response to therapy. Median progression-free survival was 6.64 months (range, 4.53-12.81 months). No change in the PSA doubling time (7 months) was observed before and after treatment initiation. Dose-limiting toxicities (all grade 3) included hyponatremia, arthritis, hyperuricemia, and photophobia. CONCLUSION: Although well tolerated, perifosine did not meet prespecified PSA criteria for response as a single agent in biochemically recurrent prostate cancer. However, 20% of patients had evidence of PSA reduction, suggesting modest single-agent clinical activity. The role of perifosine in combination with androgen deprivation or chemotherapy is currently under investigation.

Lara PN, Stadler WM, Longmate J, Quinn DI, Wexler J, Van Loan M, Twardowski P, Gumerlock PH, Vogelzang NJ, Vokes EE, Lenz HJ, Doroshow JH, Gandara DR. · University of California Davis Cancer Center and the University of California Davis School of Medicine, Sacramento, California 95817, USA. · Clin Cancer Res. · Pubmed #16533781 links to  free full text

Abstract: BACKGROUND: BMS-275291 is a selective matrix metalloproteinase inhibitor (MMPI) that does not inhibit sheddases implicated in the dose-limiting arthritis of older MMPIs. We conducted a randomized phase II trial of two doses of BMS-275291 (1,200 versus 2,400 mg) in hormone-refractory prostate cancer (HRPC) patients with bone metastases to probe for a dose-response relationship and to assess differential toxicities. Serial serum and urine specimens were collected to assess for markers of bone metabolism. METHODS: The primary end point was 4-month progression-free survival (PFS). Eligibility criteria included documentation of androgen-independent disease (including anti-androgen withdrawal), skeletal metastasis, adequate end-organ function and performance status, and no more than one prior chemotherapy regimen. Patients were randomized to 1,200 mg orally once daily (arm A) or 1,200 mg orally twice daily (arm B). Response was assessed every 56 days. RESULTS: Eighty patients were enrolled: 39 in arm A and 41 in arm B. There were no responders by prostate-specific antigen or measurable disease to treatment. Stable disease was noted at 8 weeks in 39% of patients in arm A and in 17% of patients in arm B. Progression of disease at 8 weeks was seen in 61% of patients in arm A versus 83% of patients in arm B. Median survival time was 21.6 months (95% confidence interval, 17.5; not reached), whereas median PFS time was 1.8 months (95% confidence interval 1.74; 2) for all patients. Patients in arm A had a median survival time that was not reached, whereas patients on arm B has a median survival time of 21 months (P = 0.2). PFS at 4 months favored arm A: 22% versus 10% (log-rank, P = 0.008). Grade 3 toxicities occurred in 5 (13%) patients in arm A and in 9 (22%) patients in arm B. Grade 4 toxicities were uncommon (only 4% of patients): one each of thrombosis, fatigue, and motor neuropathy was seen in the arm B. Bone marker studies showed that baseline serum levels of N-telopeptide, osteocalcin, procollagen I NH2-terminal propeptide, and PICP had prognostic significance for PFS and/or overall survival. CONCLUSIONS: Regardless of dose schedule, BMS-275291 was well tolerated in HRPC patients and had no dose-limiting arthritis. Toxicities differed modestly according to the dose schedule employed. As overall survival and PFS favored the once daily schedule, this dose schedule is recommended for future studies. Baseline markers of bone metabolism may have prognostic value in HRPC patients with bone metastases.

Lara PN, Chee KG, Longmate J, Ruel C, Meyers FJ, Gray CR, Edwards RG, Gumerlock PH, Twardowski P, Doroshow JH, Gandara DR. · Division of Hematology Oncology, Department of Internal Medicine, University of California-Davis Cancer Center, Sacramento, California 95817, USA. · Cancer. · Pubmed #15139054 links to  free full text

Abstract: BACKGROUND: Overexpression of the HER-2/neu oncoprotein has been reported to occur in </= 60% of patients with prostate carcinoma and to correlate with shortened survival. Trastuzumab is a humanized monoclonal antibody to the HER-2 receptor and has activity against HER-2-positive breast carcinoma, more so when combined with a taxane. The authors screened for HER-2 overexpression in patients developing hormone-refractory prostate carcinoma (HRPC) and conducted a Phase II trial of trastuzumab plus docetaxel in HER-2-positive patients. METHODS: Paraffin-embedded tumor specimens from potentially eligible patients were screened for HER-2 expression by immunohistochemistry (IHC) and/or amplification by fluorescent in situ hybridization (FISH). Shed HER-2 was also assessed by enzyme-linked immunoradsorbent assay (ELISA). Patients with HER-2-positive tumor specimens (IHC 2+ or 3+ or FISH ratio > 2) were initially randomized to receive either single-agent trastuzumab or docetaxel. After two treatment cycles, nonresponding patients received the trastuzumab/docetaxel combination. Treatment was comprised of 30 mg/m(2) of docetaxel weekly for 6 weeks followed by a 2-week break and 4 mg/kg of trastuzumab intravenously during Week 1 then 2 mg/kg per week thereafter. The cycle length was 8 weeks. RESULTS: One hundred patients with HPRC were screened. IHC results were as follows: 3+ (n = 1), 2+ (n = 6), 1+ (n = 26), 0 (n = 39), and insufficient tissue specimen/not tested (n = 28). Only 3 of 37 patients had elevated shed HER-2 by ELISA (> 15 mg/mL). None overexpressed HER-2 by IHC. FISH amplification was found in 0 of 34 tissue samples. Of seven patients with IHC 3+ or 2+, four were tested by ELISA and two by FISH. None were abnormal. Age and Gleason score did not correlate with IHC status. Of the seven patients eligible for the Phase II study, only four agreed to participate. The trial was thus closed for nonfeasibility (the overall HER-2 positivity rate was < 20%). No patient responded to trastuzumab alone. The median survival was not reached and the median progression-free survival was 7 months. CONCLUSIONS: HER-2 overexpression by IHC in archival prostate carcinoma specimens was infrequent. There was no apparent correlation among IHC, ELISA, and FISH, although the sample size was limited. Conclusions regarding the predictive value of HER-2 status on outcome after trastuzumab-based therapy were not reached and were only drawn after larger-scale screening efforts. The authors estimated that 1000 patients need to be screened to complete accrual to a 40-patient efficacy trial.

Liu G, Gandara DR, Lara PN, Raghavan D, Doroshow JH, Twardowski P, Kantoff P, Oh W, Kim K, Wilding G. · Medical Oncology Section, Department of Medicine, University of Wisconsin Comprehensive Cancer Center, 600 Highland Avenue, Madison, WI 53792, USA. · Clin Cancer Res. · Pubmed #14871968 links to  free full text

Abstract: PURPOSE: Flavopiridol is a cyclin-dependent kinase inhibitor with preclinical activity against prostate cancer cell lines. A Phase II trial was conducted to determine the activity of flavopiridol in patients with metastatic hormone-refractory prostate cancer. EXPERIMENTAL DESIGN: A total of 36 patients was enrolled from several institutions and treated with a 72-h continuous infusion of flavopiridol every 14 days at the eventual starting dose of 40 mg/m(2)/day. Dose escalation up to 60 mg/m(2)/day was permitted if no significant toxicity was observed. Responses were assessed every 12 weeks. Only those patients completing four courses of the 72-h infusion were considered evaluable for response because the primary objective was to determine progression-free survival at 6 months given the cytostatic nature of the agent. RESULTS: This study was conducted in a two-stage fashion. During the first stage, at least 20 evaluable patients needed to be enrolled to assess response. There were 22 of 36 patients evaluable for response. No objective responses were observed. Only 4 patients had stable disease for 16, 26, 29, and 48 weeks, respectively, stopping the trial by design as only 3 of 22 (14%) of the patients met the 6-month progression-free survival end point. The most common toxicities were diarrhea (grade 1 and 2) and nausea, although some grade 3 and 4 diarrhea (11 and 6%, respectively) were evident. CONCLUSIONS: Flavopiridol has disappointing single-agent activity in hormone-refractory prostate cancer when administered at this dose and schedule. Its use in prostate cancer should be reserved for evaluation in combination therapies or alternative schedules.

Lara PN, Meyers FJ, Gray CR, Edwards RG, Gumerlock PH, Kauderer C, Tichauer G, Twardowski P, Doroshow JH, Gandara DR. · University of California Davis Cancer Center, Division of Hematology-Oncology, 4501 X Street, Sacramento, CA 95817, USA. · Cancer. · Pubmed #12173324 No free full text.

Abstract: BACKGROUND: The overexpression of HER-2/neu is found in 20-30% of patients with breast carcinoma and is an adverse prognostic factor. HER-2 overexpression also has been reported in up to 60% of patients with hormone-refractory prostate carcinoma (HRPC) and was correlated with shortened survival. Trastuzumab (Herceptin) is a humanized monoclonal antibody that binds to the HER-2 receptor and has antitumor activity in patients with HER-2-overexpressing breast carcinoma. The authors report the results of HER-2 screening from a Phase II trial of chemotherapy with trastuzumab and docetaxel in patients with HER-2-overexpressing prostate carcinoma. METHODS: Archival paraffin embedded tumor tissue was obtained from potentially eligible patients and was screened for HER-2 expression by immunohistochemistry (IHC) using a specialized test kit. Shed HER-2 antigen in serum also was determined using an enzyme-linked immunosorbent assay (ELISA). HER-2 gene amplification was assessed by fluorescent in situ hybridization (FISH). Patients with IHC scores of 2+ or 3+ were considered to have HER-2 overexpression and were eligible for the trial. To date, 62 patients with HRPC have been screened. RESULTS: The median patient age was 72 years, and Gleason scores were < 5 in 1 patients, 5-7 in 24 patients, > 7 in 23 patients, and not specified in 14 patients. IHC HER-2 expression was 0 in 28 patients, 1+ in 14 patients, 2+ in 4 patients, and 3+ in 1 patients. Fifteen patients had either suboptimal tissue (13 patients) for interpretation or had pending results (2 patients). Therefore, 8% of all patients screened (5 of 62 patients) had HER-2 overexpression by IHC. Quantitative ELISA for shed HER-2 was available in 32 patients; this level was elevated (> 15 ng/mL) in only 2 patients, and neither had HER-2 expression by IHC. Of the 5 patients with 2+ or 3+ HER-2 expression by IHC, none had elevated shed HER-2 antigen levels by ELISA. FISH for HER-2 amplification was performed on 12 specimens; 5 of these specimens were uninterpretable due to specimen artifact, and none of the remaining 7 specimens had HER-2 amplification, defined as a ratio > 1. Patient age and Gleason score were not correlated with HER-2 status. CONCLUSIONS: Unlike breast carcinoma and contrary to prior reports, HER-2 overexpression by IHC in archival prostate tissue from patients who eventually developed hormone-refractory disease was infrequent. There did not appear to be any correlation between HER-2 overexpression by IHC and shed HER-2 antigen levels in serum by ELISA in this tumor type. Whether trastuzumab possesses single-agent activity or modulates chemotherapy response in tumor types other than breast carcinoma remains to be determined.