-
Abby B Siegel,
Rupa Narayan,
Rosa Rodriguez,
Abhishek Goyal,
Judith S Jacobson,
Kara Kelly,
Elena Ladas,
Paul J Lunghofer,
Ryan J Hansen,
Daniel L Gustafson, Thomas W Flaig,
Wei Yann Tsai,
David P H Wu,
Valerie Lee,
Heather Greenlee
[show abstract]
[hide abstract]
ABSTRACT: PURPOSE: To determine the maximum tolerated dose per day of silybin phosphatidylcholine (Siliphos) in patients with advanced hepatocellular carcinoma (HCC) and hepatic dysfunction. Experimental Design. Patients with advanced HCC not eligible for other therapies based on poor hepatic function were enrolled in a phase I study of silybin phosphatidylcholine. A standard phase I design was used with 4 planned cohorts, dose escalating from 2, 4, 8, to 12 g per day in divided doses for 12 weeks. RESULTS: Three participants enrolled in this single institution trial. All enrolled subjects consumed 2 g per day of study agent in divided doses. Serum concentrations of silibinin and silibinin glucuronide increased within 1 to 3 weeks. In all 3 patients, liver function abnormalities and tumor marker α-fetoprotein progressed, but after day 56 the third patient showed some improvement in liver function abnormalities and inflammatory biomarkers. All 3 participants died within 23 to 69 days of enrolling into the trial, likely from hepatic failure, but it could not be ruled out that deaths were possibly due to the study drug. CONCLUSION: Short-term administration of silybin phosphatidylcholine in patients with advanced HCC resulted in detectable increases in silibinin and its metabolite, silibinin glucuronide. The maximum tolerated dose could not be established. Since patients died soon after enrollment, this patient population may have been too ill to benefit from an intervention designed to improve liver function tests.
Integrative Cancer Therapies 06/2013; · 2.14 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: Several case series have reported an association between sorafenib and the development of skin cancer, but they differ in the reported rapidity of skin cancer onset and the frequency of recurrence with ongoing multikinase inhibitor (MKI) treatment. OBJECTIVE: To compare the presentation and incidence of skin cancer in patients with renal cell carcinoma (RCC) treated with sorafenib and sunitinib. MATERIALS AND METHODS: This retrospective study reviewed the records of 69 patients with RCC treated with sorafenib or sunitinib at the University of Colorado Hospital between January 2005 and July 2009. RESULTS: Seven patients treated with MKI developed skin cancer (5 (13.5%) with sorafenib, 2 (6.3%) with sunitinib; 5 squamous cell carcinomas (SCC), 3 basal cell carcinomas (BCC)); all developed in sun-exposed areas during first-line MKI therapy. The median time from the start of MKI therapy until observation of a skin cancer lesion was 13.5 months. CONCLUSION: We observed more cases of skin cancer during sorafenib treatment than during sunitinib treatment for advanced RCC; median MKI treatment duration before the identification of skin cancer was longer than 1 year.
Dermatologic Surgery 03/2013; · 1.80 Impact Factor
-
Xiaoping Yang,
Elizabeth Kessler,
Lih-Jen Su,
Andrew Thorburn,
Arthur E Frankel,
Yuan Li,
Francisco G La Rosa,
Jingping Shen,
Chuan-Yuan Li,
Marileila Varella-Garcia,
L Michael Glodé, Thomas W Flaig
[show abstract]
[hide abstract]
ABSTRACT: PURPOSE: The novel fusion protein, DAB(389)EGF, is composed of both the catalytic and the translocation domains of diphtheria toxin that are fused to the human EGF, providing a targeting and a toxicity component. We tested DAB(389)EGF for antitumor activity in both in vitro and in vivo urinary bladder cancer models.EXPERIMENTAL DESIGN: Human bladder cancer lines were treated with DAB(389)EGF and assessed for growth inhibition and clonogenic suppression. Using 6- to 8-week-old female athymic nude mice implanted orthotopically with HTB9 cells, DAB(389)EGF was administered intravesically twice weekly for 2 weeks. The response of the luciferase-expressing HTB9 cells was monitored via bioluminescence as the primary endpoint.RESULTS: Treatment response with DAB(389)EGF was specific and robust, with an IC(50) ranging from 0.5 to 15 ng/mL in eight tested bladder cancer cell lines, but greater than 50 ng/mL in the EGF receptor (EGFR)-negative H520 control cell line. Simulating short-duration intravesical therapy used clinically, a 2-hour treatment exposure of DAB(389)EGF (10 ng/mL) produced clonogenic suppression in three selected bladder cancer cell lines. In vivo, luciferase activity was suppressed in five of six mice treated with DAB(389)EGF [70 μL (1 ng/μL) per mouse], as compared with only one of six mice treated with a control diphtheria toxin (DT) fusion protein. Histologic assessment of tumor clearance correlated with the bioluminescent changes observed with DAB(389)EGF treatment. Immunocompetent mice treated with intravesical DAB(389)EGF did not show any nonspecific systemic toxicity.CONCLUSIONS: The intravesical delivery of targeted toxin fusion proteins is a novel treatment approach for non-muscle-invasive urinary bladder cancer. With appropriate targeting, the treatments are effective and well-tolerated in vivo. Clin Cancer Res; 1-10. ©2012 AACR.
Clinical Cancer Research 11/2012; · 7.74 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: INTRODUCTION: Sunitinib and sorafenib are tyrosine kinase inhibitors used in metastatic renal cell carcinoma and are known to cause hypothyroidism in a subset of patients. The goal of this study was to better characterize the development of hypothyroidism in patients and to examine its relationship to progression-free survival. PATIENTS AND METHODS: A retrospective chart review was performed on patients treated with sunitinib or sorafenib from January 1, 2005, to January 1, 2011. Data pertaining to the treatment course and development of hypothyroidism were extracted. Patients with hypothyroidism at the beginning of treatment were analyzed separately. RESULTS: A total of 73 treatment periods had sufficient data to analyze. Among patients with normal baseline thyroid function, 15 (44%) of 34 patients treated with sunitinib and 6 (27%) of 22 patients treated with sorafenib developed hypothyroidism. The hazard ratio for the development of hypothyroidism with sorafenib vs. sunitinib treatment was significant, at 0.38 (95% CI, 0.14-0.97). There was a statistically significant difference in the progression-free survival between patients who developed hypothyroidism while receiving treatment compared with those who did not, 18.2 vs. 10.1 months (P = .01). CONCLUSIONS: This study demonstrated a significant difference in the incidence of hypothyroidism during treatment with sunitinib and sorafenib, with a higher incidence of hypothyroidism in patients treated with sunitinib. The development of hypothyroidism was associated with a longer progression-free survival.
Clinical Genitourinary Cancer 09/2012; · 2.61 Impact Factor
-
Nature Reviews Urology 05/2012; 9(7):358-60. · 4.41 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Recognition of micro-RNA function and their contribution to the biology of disease has given a new insight into disease mechanisms, with these discoveries potentially improving clinical diagnostic and therapeutic options. miR-125b has been identified as an important regulator in various cancers, including prostate cancer, but the mechanism of this regulation remains incompletely understood. In these studies, the effect of castration on miR-125b serum expression was evaluated in mice, simulating androgen deprivation. Furthermore, miR-125b expression was measured by quantitative real-time polymerase chain reaction (qRT-PCR) in LNCaP prostate cancer cells treated with the antiandrogen bicalutamide. Using LNCaP cells, the effect of miR-125b modulation on apoptotic protein and NCOR2, a co-repressor of androgen receptor (AR), was examined by Western blot. A 3'-untranslated region (UTR) luciferase-binding assay was performed to confirm that miR-125b targets NCOR2. We found that surgical castration induced an initial increase in the expression of circulating miR-125b in mice, while sham surgery did not. In addition, AR blockade via bicalutamide was associated with the rapid release of miR-125b into the cell culture medium of prostate cancer cells. A previously studied target of miR-125b, a regulator in the apoptotic pathway, BAK1, could not completely account for the role of miR-125b in prostate cancer. Thus, we looked for additional targets of miR-125b and found that NCOR2, which is a repressor of AR, is a direct target of miR-125b. We found that NCOR2 protein expression was blocked by mimics of miR-125b, and a luciferase-binding assay confirmed that NCOR2 is a direct target of miR-125b. Our data provide novel evidence that miR-125b is an important regulator of the AR with specific ramification for the effectiveness of antiandrogens and other hormonal therapies in prostate cancer.
BioResearch open access. 04/2012; 1(2):55-62.
-
[show abstract]
[hide abstract]
ABSTRACT: The rapid approval of several novel agents has given prostate cancer patients and their treating physicians many new and effective therapeutic options. Three new medical therapies were recently approved on the basis of prolonged overall survival in castration-resistant prostate cancer patients: sipuleucel-T (Provenge), cabazitaxel (Jevtana), and abiraterone acetate (Zytiga). Additionally, there are several other promising prostate cancer agents in late-stage development, including MDV3100, PROSTVAC-VF (Prostvac), orteronel (TAK-700), and radium-223 chloride (Alpharadin), each with a novel mechanism of action. Taken together, we have entered a period of accelerated drug development and optimism in the care of advanced prostate cancer. The treatment paradigm for these patients is rapidly evolving, with future study needed to define the optimal sequencing and potential combinations of these new agents.
Oncology (Williston Park, N.Y.) 01/2012; 26(1):70-7. · 1.03 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To examine the incidence and prognostic value of circulating tumor cells (CTCs) in urothelial cancer (UC). The detection of CTCs is prognostic in several cancer types.
A total of 44 subjects with UC were assessed for CTCs using CellSearch Technology and 7.5 mL of peripheral blood, sorted by magnetic separation (epithelial cell adhesion molecule positive) and immunofluorescent staining (positive for cytokeratin 8, 18, or 19, negative for CD45, positive for 4',6-diamidino-2-phenylindole) to identify the CTCs.
Five (17%) of 30 subjects with clinically localized and 7 (50%) of 14 subjects with metastatic UC had ≥1 detectable CTC (range 1-177). Six subjects had ≥5 CTCs. Fluorescence in situ hybridization analysis was performed in 20 samples from 18 unique subjects using the UroVysion probe set. Copy number gains consistent with neoplasm were observed in those with measurable CTCs but not in any of the CTC-negative samples tested. With a median follow-up of 337 days, all 7 patients with metastasis and detectable CTCs had died compared with 3 (43%) of the 7 with metastasis but without detectable CTCs.
CTCs are commonly observed in metastatic UC. CTCs were observed in 50% of the patients with metastatic UC tested. Fluorescence in situ hybridization analysis confirmed the aneusomic chromosomal content in the CTCs. These findings suggest that measurable CTCs might be prognostic for shortened survival in patients with metastatic UC, although the optimal threshold for a "positive" finding is unknown. CTCs were also detected in a subset of patients with clinically localized disease, identifying a potential high-risk, preoperative group for future study.
Urology 08/2011; 78(4):863-7. · 2.43 Impact Factor
-
Oncology (Williston Park, N.Y.) 08/2011; 25(9):832-8. · 1.03 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: OBJECTIVES: The purpose of this study was to assess the efficacy and safety of low-dose (1 mg) daily diethylstilbestrol (DES) for the treatment of castrate-resistant prostate cancer (CRPC). MATERIALS AND METHODS: A retrospective chart review was performed on patients treated with low-dose DES who had CRPC despite anti-androgen withdrawal. The study population consists of 63 patients treated in the pre- and post-chemotherapy settings based on a database review; 58 had sufficient data for efficacy, all were analyzed for safety. RESULTS: A PSA decrease of ≥50% was observed in 19 of 49 pre-chemotherapy patients (39%) with a median time to progression (TTP) of 30 weeks (95% CI, 21.9, 68.7). A PSA decrease of <50% was seen in another 16 patients (33%) with a median TTP of 16.4 weeks (95% CI, 13.0, 37.6). Fourteen patients (29%) had progressive disease by PSA testing; their median TTP was 6.9 weeks (95% CI, 5.6, 12.9). Thromboembolic events included 2 patients with DVTs and 1 patient who developed primary fibrinolysis syndrome. Additional adverse events included gynecomastia in 37 of 63 patients (59%). Secondary observations included PSA responses in 3 of 9 patients treated with DES after chemotherapy progression and a high rate of PSA responses in patients re-treated with DES after a drug holiday. CONCLUSIONS: Low-dose DES is safe and effective in a modern cohort of men with CRPC despite anti-androgen treatment. Its potential role in the post-chemotherapy setting and the suggestion of efficacy on re-challenge merits additional consideration.
Urologic Oncology 07/2011; · 3.22 Impact Factor
-
Tanya B Dorff, Thomas W Flaig,
Catherine M Tangen,
Maha H A Hussain,
Gregory P Swanson,
David P Wood,
Wael A Sakr,
Nancy A Dawson,
Naomi B Haas,
E David Crawford,
Nicholas J Vogelzang,
Ian M Thompson,
L Michael Glode
[show abstract]
[hide abstract]
ABSTRACT: Men with high-risk features (extraprostatic extension or high Gleason grade) face a high risk of prostate cancer recurrence after radical prostatectomy. Clinical trials of adjuvant systemic therapy for such patients have been limited.
The SWOG (Southwest Oncology Group) S9921 study randomly assigned 983 men with high-risk features at prostatectomy to receive adjuvant therapy with androgen deprivation (ADT) alone or in combination with mitoxantrone chemotherapy. ADT consisted of goserelin and bicalutamide for 2 years.
Although the final primary treatment comparison results are not ready for publication, this article reports results in the ADT-alone control arm with a median follow-up of 4.4 years. For these 481 men, the estimated 5-year biochemical failure-free survival is 92.5% (95% CI, 90 to 95), and 5-year overall survival is 95.9% (95% CI, 93.9 to 97.9).
The results of this trial, taken in context, make a compelling argument for counseling all high-risk patients with prostate cancer about adjuvant ADT. This article discusses the challenges in the design and implementation of clinical trials to take the next step forward in adjuvant therapy for prostate cancer because of the excellent survival achieved with currently available therapies and highlights the need for better molecular markers to personalize care.
Journal of Clinical Oncology 05/2011; 29(15):2040-5. · 18.37 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To investigate the efficacy of pazopanib, both alone and in combination with docetaxel, in bladder cancer cells. Bladder cancer expresses many potential therapeutic targets of biological agents, including the vascular endothelial growth factor receptor (VEGFR). Pazopanib is a small molecule inhibitor of VEGFR-1, -2-3, platelet-derived growth factor receptor (PDGFR), and c-Kit.
Using human bladder cancer cells HTB3, HT1376, J82, RT4, CRL1749, T24, Sup, and HTB9, the treatment effect of pazopanib and cytotoxic chemotherapy was assessed using a tetrazolium-based assay. The combinatorial effect of these agents on clonogenic growth was further examined. Western blotting was used to assess changes in relevant downstream targets, including phospho-AKT, phospho-FAK, total AKT, and total FAK.
Single-agent pazopanib had modest activity. However, synergy was seen with the combination of docetaxel and pazopanib in these multiple cells lines. J82 and T24 cells were selected for additional clonogenic testing because of their resistance to single-agent docetaxel chemotherapy. 1.25 nM of docetaxel had little effect on clonogenic formation; however, in combination with pazopanib, significant inhibition of colony formation was observed. This combination treatment additionally decreased phospho-AKT, an important mediator of cell survival in all cell lines, whereas phospho-FAK expression was variably affected.
The present study demonstrates synergistic efficacy of pazopanib with docetaxel in docetaxel-resistant bladder cancer cells. This work supports future evaluation of pazopanib with docetaxel for the treatment of bladder cancer with the potential of improved efficacy and toxicity.
Urology 04/2011; 78(1):233.e7-13. · 2.43 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Prostate cancer is a common cancer and the role of adjuvant medical therapy continues to be investigated. An understanding of the use of adjuvant medical therapy is essential for the appropriate care of prostate cancer patients, especially for those with locally advanced or high-risk disease.
This article reviews the role of adjuvant treatment of non-metastatic prostate cancer. To identify all pertinent publications, a literature search of the National Library of Medicine (PubMed) from inception to 22 June 2010 was conducted for 'adjuvant prostate cancer', with these results filtered for clinical trials and systematic reviews.
This work reviews the uses of adjuvant androgen deprivation therapy and chemotherapy for prostate cancer. There is a clear benefit from the use of androgen deprivation therapy in conjunction with radiation therapy for selected patients, but the role of postoperative chemotherapy is poorly defined. Identifying appropriate patients for adjuvant therapy continues to be a challenge.
There is a complex literature describing the role of adjuvant medical therapy in prostate cancer, which is reviewed here. Continuing and future clinical trials will define the utility of adjuvant therapy in this setting and require the support of the clinical community.
Expert Opinion on Pharmacotherapy 01/2011; 12(1):73-84. · 3.20 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Prostate cancer will be diagnosed in one of six men during their lifetimes, and a small portion of these will progress after primary and salvage therapies. For many years, there were few treatment options for these patients after routine hormonal maneuvers, and standard of care since the early 2000s has consisted primarily of docetaxel, which improved survival over the previous first-line therapy mitoxantrone. In recent years, however, new therapies have begun to emerge to treat this devastating form of prostate cancer. This review examines the mechanisms behind these therapeutics and the key trials seeking to validate their clinical use.
Oncology (Williston Park, N.Y.) 12/2010; 24(14):1308-13, 1318. · 1.03 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The present study investigated the effect of VEGFR and EGFR inhibition via vandetanib (Zactima) on epithelial-mesenchymal transition (EMT) in bladder cancer. Markers of EMT (EGFR, VEGR, E-cadherin and vimentin) were interogated by Western blotting at baseline and after treatment with EGF, VEGF, vandetanib, cisplatin, or their combination using representative epithelial- and mesenchymal-type human bladder cancer cells. Morphological changes induced by these treatments were examined by microscopy over various time courses. The effect of these changes on cisplatin chemotherapy sensitivity was assessed by MTT assay. RT4 and HTB3 cells had epithelial features while CRL1749 and J82 cells had mesenchymal features. After treatment with EGF, the epithelial-type cells demonstrated increased intercellular separation and pseudopodia, with these changes blocked by vandetanib. In contrast, the mesenchymal cells did not exhibit any morphological changes with the EGF treatment but adopted a clustered/epithelial appearance after the administration of vandetanib. Western blotting shows that treatment of epithelial cells with vandetanib increased the expression of E-cadherin. In comparison, mesenchymal cells demonstrated decreased vimentin expression with the treatment of vandetanib in the presence of EGF and VEGF. Improved growth inhibition was seen in the epithelial cells but not in mesenchymal cells with the concurrent treatment of vandetanib and cisplatin. Sequential treatment of mesenchymal cells with vandetanib followed by cisplatin demonstrated synergy with improved cisplatin activity. The findings offer a novel role of vandetanib on the EMT in bladder cancer, providing insight into EMT in bladder cancer.
Oncology Reports 10/2010; 24(4):1019-28. · 1.84 Impact Factor
-
Thomas W Flaig,
Michael Glodé,
Daniel Gustafson,
Adrie van Bokhoven,
Yuzhen Tao,
Shandra Wilson,
Lih-Jen Su,
Yuan Li,
Gail Harrison,
Rajesh Agarwal,
E David Crawford,
M Scott Lucia,
Michael Pollak
[show abstract]
[hide abstract]
ABSTRACT: Silibinin is a polyphenolic flavonolignan derived from milk thistle (Silybum marianium) with anti-oxidant properties. The purpose of the current trial was to determine the tissue and blood effects of high-dose silybin-phytosome in prostate cancer patients.
Subjects with localized prostate cancer planning for a prostatectomy were eligible to enroll. Six patients received 13 g of silybin-phytosome daily with six additional participants serving as control subjects.
Patients in the treatment arm received silybin-phytosome for 14-31 days (mean was 20 days) prior to surgery. Silibinin blood levels were measured 1 hr after the first silybin-phytosome dose with a mean value of 19.7 microM. Trough silibinin levels were assessed at the end of the trial with an average concentration of 1.2 microM. In contrast to the high peak levels of silibinin observed in blood, the highest silibinin level observed in the harvested prostate tissue was 496.6 pmol/g. There were no significant differences noted in baseline and post-treatment blood levels of IGF-I and IGFBP-3. One of the treated patients developed a grade 4 post-operative thromboembolic event. The other observed toxicities in the treatment group were mild: four subjects had diarrhea and one had asymptomatic grade 2 hyperbilirubinemia which was transient.
High-dose oral silybin-phytosome achieves high blood concentrations transiently, but low levels of silibinin are seen in prostate tissue. Silibinin's lack of tissue penetration may be explained by its short half-life, the brief duration of therapy in this study or an active process removing silibinin from the prostate.
The Prostate 06/2010; 70(8):848-55. · 3.48 Impact Factor
-
Oncology (Williston Park, N.Y.) 03/2010; 24(3):282-6. · 1.03 Impact Factor
-
Oncology (Williston Park, N.Y.) 12/2009; 23(14):1301-4. · 1.03 Impact Factor
-
Thomas W Flaig
The Journal of urology 04/2009; · 4.02 Impact Factor
-
Oncology (Williston Park, N.Y.) 03/2009; 23(2):177-80. · 1.03 Impact Factor
