[Show abstract][Hide abstract] ABSTRACT: The goal of the current study is to examine the biological effects of epithelial-specific tumor suppressor maspin on tumor host immune response. Accumulated evidence demonstrates an anti-tumor effect of maspin on tumor growth, invasion and metastasis. The molecular mechanism underlying these biological functions of maspin is thought to be through histone deacetylase inhibition, key to the maintenance of differentiated epithelial phenotype. Since tumor-driven stromal reactivities co-evolve in tumor progression and metastasis, it is not surprising that maspin expression in tumor cells inhibits extracellular matrix degradation, increases fibrosis and blocks hypoxia-induced angiogenesis. Using the athymic nude mouse model capable of supporting the growth and progression of xenogeneic human prostate cancer cells, we further demonstrate that maspin expression in tumor cells elicits neutrophil- and B cells-dependent host tumor immunogenicity. Specifically, mice bearing maspin-expressing tumors exhibited increased systemic and intratumoral neutrophil maturation, activation and antibody-dependent cytotoxicity, and decreased peritumoral lymphangiogenesis. These results reveal a novel biological function of maspin in directing host immunity towards tumor elimination that helps explain the significant reduction of xenograft tumor incidence in vivo and the clinical correlation of maspin with better prognosis of several types of cancer. Taken together, our data raised the possibility for novel maspin-based cancer immunotherapies.
[Show abstract][Hide abstract] ABSTRACT: Despite the positive impact of targeted therapies on metastatic renal cell carcinoma (mRCC), durable responses are infrequent and an unmet need exists for novel therapies with distinct mechanisms of action. We investigated the combination of recombinant Interleukin 21 (IL-21), a cytokine with unique immunostimulatory properties, plus sorafenib, a VEGFR tyrosine kinase inhibitor.
In this phase 1/2 study, 52 mRCC patients received outpatient treatment with oral sorafenib 400 mg twice daily plus intravenous IL-21 (10-50 mcg/kg) on days 1-5 and 15-19 of each 7-week treatment course. The safety, antitumor activity, pharmacokinetic and pharmacodynamic effects of the combination were evaluated.
In phase 1 (n = 19), the maximum tolerated dose for IL-21 with the standard dose of sorafenib was determined to be 30 mcg/kg/day; grade 3 skin rash was the only dose-limiting toxicity. In phase 2, 33 previously-treated patients tolerated the combination therapy well with appropriate dose reductions; toxicities were mostly grade 1 or 2. The objective response rate was 21% and disease control rate was 82%. Two patients have durable responses that are ongoing, despite cessation of both IL-21 and sorafenib, at 41+ and 30+ months, respectively. The median progression-free survival in phase 2 was 5.6 months. The pharmacokinetic and pharmacodynamic properties of IL-21 appeared to be preserved in the presence of sorafenib.
IL-21 plus sorafenib has antitumor activity and acceptable safety in previously treated mRCC patients. IL-21 may represent a suitable immunotherapy in further exploration of combination strategies in mRCC.
ClinicalTrials.gov Identifier: NCT00389285.
Journal for immunotherapy of cancer. 01/2014; 2:2.
[Show abstract][Hide abstract] ABSTRACT: The prostate-specific antigen (PSA) test has served as a blood marker of prostate cancer (PCa), and for monitoring recurrence/metastasis in patients after therapeutic intervention. However, the applicability/reliability of the PSA test was recently questioned as it is not without challenges, in particular in men who have PCa without an elevated PSA (false negative), or in men who are disease-free with elevated levels of PSA (false positive). Galectin-3 is a tumor-associated protein; present in the seminal fluid and is a substrate for the PSA enzyme e.g., a chymotrypsin-like serine protease. We hypothesized that the cleavage status and level of galectin-3 in the prostate tissue and sera are associated with PCa. Thus, we compared galectin-3 levels obtained from sera of non-cancer urology patients to those of metastatic PCa patients. The data were confirmed by analyzing PCa tissue arrays. Here, we report that galectin-3 levels in the sera of patients with metastatic PCa were uniformly higher as compared to the non-cancer patient controls. The data suggest that galectin-3 serum level may be a useful serum complementary marker to the PSA blood test to be used for initial and follow-up PSA complimentary diagnostic/prognostic tool for recurrence in PCa patients.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Satraplatin is an oral platinum compound that has demonstrated efficacy and tolerability in prostate cancer. Preclinical synergy between bevacizumab and platinum has been noted. METHODS: Docetaxel-pretreated metastatic castrate-resistant prostate cancer patients with disease progression were eligible. Satraplatin 80mg/m(2) orally on days 1 to 5, prednisone 5mg twice daily, and bevacizumab 10mg/kg on day 1, and 15mg/kg on day 15 were administered in 35-day cycles. RESULTS: Thirty one patients were enrolled. Grade 3 or 4 toxicities were pulmonary embolism in 2 patients and thrombocytopenia in 1 patient. 31% of the patients had a≥30% decline in prostate-specific antigen. Median time to progression was 7.0 months (90% confidence interval [CI] 4.7-8.5mo) and median overall survival was 11.2 months (90% CI 9.1-16.4mo). Polymorphism in the excision repair cross-complementation-1 (ERCC-1) gene was associated with time to progression (hazard ratio = 1.91). A circulating tumor cell count≥5was moderately prognostic of overall survival (hazard ratio = 1.49) as compared with CTC <5. CONCLUSIONS: The combination was tolerable, and revealed promising efficacy in metastatic castrate-resistant prostate cancer. ERCC1 genotype maybe predictive of clinical benefit with platinum-based therapy in metastatic prostate cancer.
[Show abstract][Hide abstract] ABSTRACT: PURPOSE: As tyrosine kinase inhibitors have been associated with cardiotoxicity, we evaluated the effect of pazopanib, an inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, on electrocardiographic parameters in patients with cancer. METHODS: This double-blind, placebo-controlled, parallel-group study randomized patients (N = 96) to moxifloxacin (positive control) or placebo on Day 1 followed by pazopanib or placebo 800 mg/day (fasted) on Days 2-8 and 1,600 mg (with food) on Day 9. Treatment effects were evaluated by baseline-adjusted, time-matched, serial Holter electrocardiograms. RESULTS: Sixty-five patients were evaluable for preplanned analyses. On Day 1, the maximum mean difference in baseline-adjusted, time-matched Fridericia-corrected QT (QTcF) interval in moxifloxacin-treated patients versus placebo was 10.6 ms (90 % confidence interval [CI]: 4.2, 17.0). The administration scheme increased plasma pazopanib concentrations approximately 1.3- to 1.4-fold versus the recommended 800 mg once-daily dose. Pazopanib caused clinically significant increases from baseline in blood pressure, an anticipated class effect, and an unexpected reduction in heart rate from baseline that correlated with pazopanib exposure. On Day 9, the maximum mean difference in baseline-adjusted, time-matched QTcF interval in pazopanib-treated patients versus placebo was 4.4 ms (90 % CI: -2.4, 11.2). Mixed-effects modeling indicated no significant concentration-dependent effect of pazopanib or its metabolites on QTcF interval. CONCLUSIONS: Pazopanib as administered in this study achieved supratherapeutic concentrations, produced a concentration-dependent decrease in heart rate, and caused a small, concentration-independent prolongation of the QTcF interval.
Cancer Chemotherapy and Pharmacology 01/2013; · 2.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background. The antifungal drug itraconazole inhibits angiogenesis and Hedgehog signaling and delays tumor growth in murine prostate cancer xenograft models. We conducted a noncomparative, randomized, phase II study evaluating the antitumor efficacy of two doses of oral itraconazole in men with metastatic prostate cancer.Patients and Methods. We randomly assigned 46 men with chemotherapy-naïve metastatic castration-resistant prostate cancer (CRPC) to receive low-dose (200 mg/day) or high-dose (600 mg/day) itraconazole until disease progression or unacceptable toxicity. The primary endpoint was the prostate-specific antigen (PSA) progression-free survival (PPFS) rate at 24 weeks; a 45% success rate in either arm was prespecified as constituting clinical significance. Secondary endpoints included the progression-free survival (PFS) rate and PSA response rate (Prostate Cancer Working Group criteria). Exploratory outcomes included circulating tumor cell (CTC) enumeration, serum androgen measurements, as well as pharmacokinetic and pharmacodynamic analyses.Results. The high-dose arm enrolled to completion (n = 29), but the low-dose arm closed early (n = 17) because of a prespecified futility rule. The PPFS rates at 24 weeks were 11.8% in the low-dose arm and 48.0% in the high-dose arm. The median PFS times were 11.9 weeks and 35.9 weeks, respectively. PSA response rates were 0% and 14.3%, respectively. In addition, itraconazole had favorable effects on CTC counts, and it suppressed Hedgehog signaling in skin biopsy samples. Itraconazole did not reduce serum testosterone or dehydroepiandrostenedione sulfate levels. Common toxicities included fatigue, nausea, anorexia, rash, and a syndrome of hypokalemia, hypertension, and edema.Conclusion. High-dose itraconazole (600 mg/day) has modest antitumor activity in men with metastatic CRPC that is not mediated by testosterone suppression.
[Show abstract][Hide abstract] ABSTRACT: PURPOSE: KX2-391 is an oral non-ATP-competitive inhibitor of Src kinase and tubulin polymerization. In phase 1 trials, prostate-specific antigen (PSA) declines were seen in patients with advanced prostate cancer. We conducted a single-arm phase 2 study evaluating KX2-391 in men with chemotherapy-naïve bone-metastatic castration-resistant prostate cancer (CRPC). METHODS: We treated 31 patients with oral KX2-391 (40 mg twice-daily) until disease progression or unacceptable toxicity. The primary endpoint was 24-week progression-free survival (PFS); a 50 % success rate was pre-defined as clinically significant. Secondary endpoints included PSA progression-free survival (PPFS) and PSA response rates. Exploratory outcomes included pharmacokinetic studies, circulating tumor cell (CTC) enumeration, and analysis of markers of bone resorption [urinary N-telopeptide (uNTx); C-telopeptide (CTx)] and formation [bone alkaline phosphatase (BAP); osteocalcin]. RESULTS: The trial closed early after accrual of 31 patients, due to a pre-specified futility rule. PFS at 24 weeks was 8 %, and median PFS was 18.6 weeks. The PSA response rate (≥30 % decline) was 10 %, and median PPFS was 5.0 weeks. Additionally, 18 % of men with unfavorable (≥5) CTCs at baseline converted to favorable (<5) CTCs with treatment. The proportion of men with declines in bone turnover markers was 32 % for uNTx, 21 % for CTx, 10 % for BAP, and 25 % for osteocalcin. In pharmacokinetic studies, median C (max) was 61 (range 16-129) ng/mL, and median AUC was 156 (35-348) ng h/mL. Common toxicities included hepatic derangements, myelosuppression, fatigue, nausea, and constipation. CONCLUSION: KX2-391 dosed at 40 mg twice-daily lacks antitumor activity in men with CRPC, but has modest effects on bone turnover markers. Because a C (max) of ≥142 ng/mL is required for tubulin polymerization inhibition (defined from preclinical studies), higher once-daily dosing will be used in future trials.
Cancer Chemotherapy and Pharmacology 01/2013; · 2.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PURPOSEEC145 (vintafolide), a conjugate of folic acid and the vinca alkaloid desacetylvinblastine hydrazide (DAVLBH), is a ligand for the folate receptor (FR), with activity against FR-positive tumor xenografts in vivo. This phase I study determined the maximum-tolerated dose (MTD) of EC145 administered as a bolus intravenous injection or 1-hour infusion in patients with refractory solid tumors. PATIENTS AND METHODSEC145 was administered as a bolus injection or 1-hour infusion on days 1, 3, and 5 and days 15, 17, and 19 of each 28-day cycle with dose escalation in cohorts of three to six patients until the MTD was identified. Plasma pharmacokinetics were determined on days 1 and 3 of the first cycle.ResultsThe MTD of EC145 was 2.5 mg when administered as either a bolus injection or 1-hour infusion. Constipation was the dose-limiting toxicity with both routes. Constipation, nausea, fatigue, and vomiting were the most commonly reported adverse events. One partial response to therapy was observed in a patient with metastatic ovarian cancer. CONCLUSIONEC145 administered by bolus injection or as a 1-hour infusion at a dose of 2.5 mg on days 1, 3, and 5 and days 15, 17, and 19 of a 28-day cycle has an acceptable safety profile in patients with advanced cancer. On the basis of these findings, phase II studies of EC145 have been initiated in patients with advanced epithelial ovarian cancer and non-small-cell lung cancer.
Journal of Clinical Oncology 10/2012; · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: For cancer patients on Phase I trials, one of the most important physician decisions is whether or not patients are deriving benefit from therapy. With an increasing number of cytostatic treatment agents, the criteria to determine patient response to Phase I treatment has become harder to define. Physicians are increasingly looking to patient-reported outcomes (PROs) such as quality of life (QOL) to help evaluate treatment response. Electronic daily diary (EDD) devices can be used by patients to report their QOL over extended periods of time, thereby providing a more accurate picture of how patients are affected by treatment on a daily basis. However, questions remain about how to integrate this patient-reported information into decisions about Phase I treatment. This study investigated how physicians use patients' daily QOL reports to evaluate patient response to Phase I treatment. Data were collected over a 4-month period from Phase I patients (N = 30) and physicians (N = 3) in an NCI-designated comprehensive cancer center. Patients completed daily QOL reports using EDD devices and physicians were provided with a summary of patients' QOL before each visit. After the visit, doctors recorded their treatment decision and also rated the importance of four biomedical factors (Toxicity, Imaging, Labs, and Performance Status) and QOL in their treatment decision for that visit. Although physicians rated QOL as being very important in evaluating treatment response, in practice, when predictors of their decisions were analyzed, results showed they relied exclusively on biomedical data (Toxicity, Imaging) to make Phase I treatment decisions. Questions remain about the utility and effective integration of QOL and biomedical data in clinical decision-making processes in Phase I clinical trials.
[Show abstract][Hide abstract] ABSTRACT: GSK923295 is an inhibitor of CENP-E, a key cellular protein important in the alignment of chromosomes during mitosis. This was a Phase I, open-label, first-time-in-human, dose-escalation study, to determine the maximum-tolerated dose (MTD), safety, and pharmacokinetics of GSK923295.
Adult patients with previously treated solid tumors were enrolled in successive cohorts at GSK923295 doses ranging from 10 to 250 mg/m(2). GSK923295 was administered by a 1-h intravenous infusion, once weekly for three consecutive weeks, with treatment cycles repeated every 4 weeks.
A total of 39 patients were enrolled. The MTD for GSK923295 was determined to be 190 mg/m(2). Observed dose-limiting toxicities (all grade 3) were as follows: fatigue (n = 2, 5%), increased AST (n = 1, 2.5%), hypokalemia (n = 1, 2.5%), and hypoxia (n = 1, 2.5%). Across all doses, fatigue was the most commonly reported drug-related adverse event (n = 13; 33%). Gastrointestinal toxicities of diarrhea (n = 12, 31%), nausea (n = 8, 21%), and vomiting (n = 7, 18%) were generally mild. Frequency of neutropenia was low (13%). There were two reports of neuropathy and no reports of mucositis or alopecia. GSK923295 exhibited dose-proportional pharmacokinetics from 10 to 250 mg/m(2) and did not accumulate upon weekly administration. The mean terminal elimination half-life of GSK923295 was 9-11 h. One patient with urothelial carcinoma experienced a durable partial response at the 250 mg/m(2) dose level.
The novel CENP-E inhibitor, GSK923295, had dose-proportional pharmacokinetics and a low number of grade 3 or 4 adverse events. The observed incidence of myelosuppression and neuropathy was low. Further investigations may provide a more complete understanding of the potential for GSK923295 as an antiproliferative agent.
Cancer Chemotherapy and Pharmacology 03/2012; 69(3):733-41. · 2.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The emergence of castrate-resistant prostate cancer (CRPC) contributes to the high mortality of patients diagnosed with prostate cancer (PCa), which in part could be attributed to the existence and the emergence of cancer stem cells (CSCs). Recent studies have shown that deregulated expression of microRNAs (miRNAs) contributes to the initiation and progression of PCa. Among several known miRNAs, let-7 family appears to play a key role in the recurrence and progression of PCa by regulating CSCs; however, the mechanism by which let-7 family contributes to PCa aggressiveness is unclear. Enhancer of Zeste homolog 2 (EZH2), a putative target of let-7 family, was demonstrated to control stem cell function. In this study, we found loss of let-7 family with corresponding over-expression of EZH2 in human PCa tissue specimens, especially in higher Gleason grade tumors. Overexpression of let-7 by transfection of let-7 precursors decreased EZH2 expression and repressed clonogenic ability and sphere-forming capacity of PCa cells, which was consistent with inhibition of EZH2 3'UTR luciferase activity. We also found that the treatment of PCa cells with BR-DIM (formulated DIM: 3,3'-diindolylmethane by Bio Response, Boulder, CO, abbreviated as BR-DIM) up-regulated let-7 and down-regulated EZH2 expression, consistent with inhibition of self-renewal and clonogenic capacity. Moreover, BR-DIM intervention in our on-going phase II clinical trial in patients prior to radical prostatectomy showed upregulation of let-7 consistent with down-regulation of EZH2 expression in PCa tissue specimens after BR-DIM intervention. These results suggest that the loss of let-7 mediated increased expression of EZH2 contributes to PCa aggressiveness, which could be attenuated by BR-DIM treatment, and thus BR-DIM is likely to have clinical impact.
PLoS ONE 01/2012; 7(3):e33729. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Prostate cancer is the most common nonskin malignant neoplasm in men worldwide. In the United States, 241,740 new diagnoses of prostate cancer and 28,170 prostate cancer deaths have been estimated for 2012, representing 28% of new cancer cases and 10% of male cancer deaths.(1) Although metastatic prostate cancer remains an incurable disease, substantial advances have been made in therapeutic options available for men in the past several years. Development of novel agents that modulate the androgen receptor pathway, growth factor signaling pathways, and immune function and bone targeting pathways has been the focus of therapeutic strategies because of its significance in the biology of prostate cancer progression. Several of the agents have gained U.S. Food and Drug Administration (FDA) approval, whereas many are in late-stage clinical trials. With the growth of available treatment options, a major challenge as we move forward will be to determine the best sequence and/or combination of therapy that will result in maximum clinical efficacy with minimum toxicity. Highlighted in this publication are several of the exciting advances in prostate cancer therapy for patients with metastatic, castrate-resistant prostate cancer.
American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting. 01/2012; 32:309-313.
[Show abstract][Hide abstract] ABSTRACT: Introduction/Background. Nonmetastatic castrate resistant prostate cancer (CRPC) is a challenging disease state. The objective of this study was to evaluate the efficacy and tolerability of bevacizumab in nonmetastatic CRPC patients. Patients. Patients with prostate cancer who developed PSA recurrence after local therapy were included if they had absence of bone or visceral metastases and PSA progression despite androgen deprivation therapy. Methods. Bevacizumab 10 mg/kg intravenously was administered every 14 days until PSA progression, development of metastasis, or unacceptable toxicity. Results. 15 patients were enrolled and treated with bevacizumab for a median duration of 3.1 months. Median baseline PSA was 27 ng/mL, and seven patients had Gleason Score ≥8. Five patients had declined in PSA during the treatment. Median PSA doubling time was prolonged from 4.7 months pretreatment to 6.5 months. Median time to PSA progression and new metastasis were 2.8 and 7.9 months, respectively. There were three grade 3 adverse events (one proteinuria and two hypertension) and one pulmonary embolism. There was no treatment-related mortality. Conclusion. Bevacizumab therapy had minimal impact on the disease course of nonmetastatic CRPC, and investigation of novel strategies is needed.
[Show abstract][Hide abstract] ABSTRACT: Androgen Receptor (AR) signaling is critically important during the development and progression of prostate cancer (PCa). The AR signaling is also important in the development of castrate resistant prostate cancer (CRPC) where AR is functional even after androgen deprivation therapy (ADT); however, little is known regarding the transcriptional and functional regulation of AR in PCa. Moreover, treatment options for primary PCa for preventing the occurrence of CRPC is limited; therefore, novel strategy for direct inactivation of AR is urgently needed. In this study, we found loss of miR-34a, which targets AR, in PCa tissue specimens, especially in patients with higher Gleason grade tumors, consistent with increased expression of AR. Forced overexpression of miR-34a in PCa cell lines led to decreased expression of AR and prostate specific antigen (PSA) as well as the expression of Notch-1, another important target of miR-34a. Most importantly, BR-DIM intervention in PCa patients prior to radical prostatectomy showed re-expression of miR-34a, which was consistent with decreased expression of AR, PSA and Notch-1 in PCa tissue specimens. Moreover, BR-DIM intervention led to nuclear exclusion both in PCa cell lines and in tumor tissues. PCa cells treated with BR-DIM and 5-aza-dC resulted in the demethylation of miR-34a promoter concomitant with inhibition of AR and PSA expression in LNCaP and C4-2B cells. These results suggest, for the first time, epigenetic silencing of miR -34a in PCa, which could be reversed by BR-DIM treatment and, thus BR-DIM could be useful for the inactivation of AR in the treatment of PCa.
American Journal of Translational Research 01/2012; 4(1):14-23.
[Show abstract][Hide abstract] ABSTRACT: Introduction. Predicting the aggressiveness of prostate cancer at biopsy is invaluable in making treatment decisions. In this paper we review the differential expression of genes and microRNAs identified through microarray analysis as potentially useful markers for prostate cancer prognosis and discuss some of the challenges associated with their development. Methods. A review of the literature was conducted through Medline. Articles were identified through searches of the following terms: "prostate cancer AND differential expression", "prostate cancer prognosis", and "prostate cancer AND microRNAs". Results. Though numerous differentially expressed genes and microRNAs were identified as possible prognostic markers, the significance of several of these genes is either debated due to conflicting results or is not validated in other study populations. A few of the articles constructed predictive nomograms using a panel of biomarkers which require further validation. Challenges to the development of useful markers include different methodology, cancer heterogeneity, and sampling error. These can be overcome by categorizing prognostic factors into particular gene pathways or by supplementing biopsy information with blood or urine-based biomarkers. Conclusion. Though biomarkers based on differential expression offer the potential to improve decision making concerning prostate cancer, further validation of their utility and accuracy at the biopsy level is needed.