Arif Hussain

A Phase II Trial of Gefitinib (Iressa, ZD1839) in Stage IV and Recurrent Renal Cell Carcinoma

Purpose: The epidermal growth factor receptor (EGFR) is overexpressed in 75 to 90% of renal cell carcinomas and may play a role in tumor initiation and progression. Gefitinib (Iressa, ZD1839) is a potent, selective EGFR-tyrosine kinase inhibitor. This trial was undertaken to assess the efficacy and toxicity of gefitinib in advanced renal cell carcinoma. Experimental Design: Oral gefitinib, 500 mg once daily, was given continuously. A single-dose reduction to 250 mg daily was allowed for toxicity. The primary end point was response rate (defined as complete remission + partial remission + stable disease). Secondary end points were progression-free survival, overall survival, toxicity, and correlation of response with EGFR status. Results: Twenty-one patients were enrolled on this study, and all are evaluable for response and toxicity. Patient characteristics were median age 61 (range, 35–78 years); 17 males, 4 females; median performance status 0 (range 0–2); median number of prior systemic therapies 1 (range, 0–3). The median and mean number of cycles of therapy received was 3 and 4.7 (range, 1–14+). The best response was stable disease in eight patients (38%). Median progression-free survival was 2.7 months. Median overall survival was 8.3 months. The difference in overall survival was significantly different between patients with progressive disease versus stable disease (6.1 months versus 16+ months; Log-Rank test P value < 0.0001). Three patients required a dose reduction, all for grade 3 diarrhea. There was no apparent correlation between EGFR status and stability of disease or progression of disease. Conclusions: Gefitinib is without significant conventional activity in renal cell carcinoma. The relation of “stable disease” to treatment or to disease-related prognostic heterogeneity remains to be defined.

Docetaxel Followed by Hormone Therapy in Men Experiencing Increasing Prostate-Specific Antigen After Primary Local Treatments for Prostate Cancer

PURPOSE Prostatectomy or radiation for localized prostate cancer (PC) can fail in up to 15% to 30% of patients. The purpose of this study was to determine feasibility, tolerability, and outcome of docetaxel followed by hormone therapy in men experiencing an increasing prostate-specific antigen (PSA) after their primary local treatments for PC. PATIENTS AND METHODS Men with increasing serum PSA after prostatectomy or/and radiation were eligible. Serum PSA had to be > or = 4 ng/mL and serum testosterone had to be in the noncastrate range. Treatment included docetaxel 70 mg/m2 every 3 weeks for up to six cycles, followed by total androgen suppression (luteinizing hormone-releasing hormone agonist plus bicalutamide) and peripheral androgen blockade (finasteride plus bicalutamide) for 12 to 20 months. RESULTS Thirty-nine men were enrolled; 32 had PSA-only failure, seven also had clinical metastasis. Baseline median PSA was 13.7 ng/mL. Serum PSA decreased > or = 50% in 17 of 35 patients (48.5%) and > or = 75% in seven of 35 patients (20%) with docetaxel. The PSA decreased to a median of 0.1 ng/mL with subsequent hormone therapy. In 28 of 33 patients the PSA increased (median, 0.41 ng/mL) at a median follow-up of 2.3 months after treatment. In contrast, in five of 33 men the PSA remains at 0.1 ng/mL at a median of 18.9 months after therapy; three of these five men had soft tissue metastasis at entry but remain in complete remission. The most common grade 3 to 4 toxicity was neutropenia (61.5%). CONCLUSION Docetaxel followed by hormone therapy of limited duration may provide disease control in subgroups of men experiencing failure after local treatments for PC.

Docetaxel followed by castration improves outcomes in LNCaP prostate cancer- bearing severe combined immunodeficient mice

Purpose: Androgen ablation is the standard initial treatment for advanced prostate cancer; however, tumors eventually develop androgen independence and become incurable. Chemotherapy is commonly used after hormone treatment fails but has not shown significant survival benefit. Studies suggest that androgen ablation can select for a population of hormone-independent cells that are also relatively chemotherapy resistant. Thus, it may be therapeutically advantageous to target prostate cancer with chemotherapy before hormone ablation. This study was undertaken to determine the relative efficacy of such an approach in a preclinical model of prostate cancer. Experimental Design: Severe combined immunodeficient mice bearing human LNCaP prostate tumors were treated with docetaxel and/or surgical castration applied singly, concurrently, or in different sequences. Treatment efficacy was determined by tumor volume and growth delay measurements. The extent of apoptosis in tumors in response to treatments was assessed via terminal deoxynucleotidyl transferase–mediated nick-end labeling (TUNEL) assays. In addition, Western blots were done to study the relative expression of Bcl-2 and Bax in the tumors. Results: Docetaxel followed by castration showed the most potent antitumor effects. In contrast, with the exception of castration alone, castration followed by docetaxel produced the least antitumor activity. TUNEL assays confirmed that the density of apoptotic tumor cells was significantly greater for docetaxel followed by castration than for any other treatment. In tumors of mice treated with single modality therapies, Bax to Bcl-2 ratios decreased significantly after castration, whereas this ratio remained high after docetaxel treatment. Conclusion: A treatment sequence of docetaxel followed by hormone ablation may be more effective in treating prostate cancer than concurrent docetaxel/hormone therapy or hormone ablation followed by docetaxel.

Health disparities in staging of SEER-Medicare prostate cancer patients in the United States

OBJECTIVES To examine whether race or age disparities affected the odds of being staged among prostate cancer (PC) patients. Accurate staging is critical for determining treatment for PC. METHODS Multivariable logistic regression models examined race and age disparities with respect to the odds of being staged among PC patients using Surveillance, Epidemiology, and End Results-Medicare data. Similar analyses were performed to estimate the adjusted odds of being staged with distant metastatic vs in situ or local/regional disease. RESULTS The proportion of patients without staging ranged between 3% and 16% by age and between 6% and 8% by race. Adjusted results demonstrated statistically significant lower odds ratios (P <.05) for 70-74, 75-79, and 80+-year-olds of 0.76, 0.52, and 0.23, respectively, relative to PC patients aged 65-69. The odds of being staged for African Americans are 0.78 times that of non-Hispanic Whites (95% confidence interval = 0.72-0.86). The adjusted probability of distant metastatic disease at initial diagnosis is higher for African Americans (odds ratio = 1.61; 95% confidence interval = 1.47-1.76) and older men with odds ratios of 1.25, 1.85, and 4.33 for ages 70-74, 75-79, and 80+, respectively, compared with 65-69-year-olds (all P <.05). CONCLUSIONS Even though the overall odds of being staged increased over time, race and age disparities persisted. When staging did occur, the probability of distant metastatic disease was high for African Americans, and there were increasing odds of metastatic disease for all men with advanced age.

Divergent Effects of Castration on Prostate Cancer in TRAMP Mice: Possible Implications for Therapy

Purpose: Divergent responses to androgen deprivation have been found in patients and in animal models of prostate cancer. The molecular basis for these different outcomes is unknown. Our aim was to identify the molecular responses of prostate cancer with divergent outcomes to androgen deprivation in TRAMP mice. Experimental Design: Castrated and noncastrated B6xFVB TRAMP mice were evaluated for survival, tumor development, pathology, and expressions of specific proteins at different time points. Results: TRAMP mice responded differentially to androgen deprivation. In the majority, primary tumors regressed after castration (positive response), whereas in others the tumors grew even more aggressively than in the noncastrated mice (negative response). Mice with regressed tumors had the highest survival rates. Androgen receptor was elevated in all tumors from castrated mice despite significant differences in tumor sizes. In positively responding tumors, expressions of Bcl-2 and Grp78 were greatly increased by 10 weeks after castration, whereas expressions of Bax, Bcl-xl, SV40 T antigen, and c-myc were lower. These tumors also showed a reduction in proliferating cells compared with noncastrates and negatively responding tumors. Most of these changes disappeared 20 weeks after castration, by which time there was an increase in the size of primary tumors as well as in distant metastasis. Conclusions: In TRAMP prostate cancer that responded positively to castration, different expression patterns of proteins involved in cellular apoptosis, stress, and proliferation occur ∼10 weeks after castration. This may be an optimal time for targeting Bcl-2, and perhaps Grp78, to enhance the antitumor effects of androgen deprivation.

Docetaxel followed by hormone therapy after failure of definitive treatments for clinically localized/locally advanced prostate cancer : preliminary results

An increasingly important issue in the management of prostate cancer is the occurrence of biochemical failure (ie, increasing serum prostate-specific antigen [PSA] levels) in patients with clinically localized prostate cancer who initially underwent definitive treatments with curative intent (prostatectomy and/or radiation therapy). This pilot trial evaluated chemotherapy followed by hormone therapy for a defined period in patients with biochemical (and possibly clinical) recurrence after initial local therapies for localized/locally advanced prostate cancer. Patients who developed increasing PSA > 4 ng/mL after initial prostatectomy and/or radiation therapy received docetaxel, 70 mg/m(2) every 3 weeks for up to 6 courses, followed by 4 months of total androgen suppression (using a luteinizing hormone-releasing hormone agonist plus bicalutamide, 50 mg/d) and 8 months of peripheral androgen blockade (using finasteride, 5 mg/d, plus bicalutamide, 50 mg/d). Twenty-seven patients have enrolled to date, 23 of whom received four or six cycles of docetaxel before hormonal therapies. Seventeen (74%) of 23 patients who completed four to six cycles of chemotherapy had a > or =40% decrease in PSA, and 16 (89%) of 18 patients who completed 4 months of total androgen suppression achieved PSA values of < or =0.1. The most common hematologic toxicity was grade (3/4) neutropenia; grade 3 nonhematologic toxicities were rare, and no grade 4 nonhematologic toxicities were reported. Thus, the preliminary results suggest that docetaxel before hormonal therapy includes a PSA response in many prostate cancer patients with biochemical failure after definitive local therapies.

The relationship of neuroendocrine carcinomas to anti-tumor therapies in TRAMP mice.

Neuroendocrine differentiation and neuroendocrine carcinoma (NEC) have been linked to androgen deprivation in prostate cancers. No previous study has directly connected neuroendocrine phenotypes to chemotherapy. The pathogenesis of prostatic NEC has not yet been determined.

Efficacy of peripheral androgen blockade in prostate cancer patients with biochemical failure after definitive local therapy: results of Cancer and Leukemia Group B (CALGB) 9782.

The treatment for prostate cancer patients with biochemical failure after local therapy remains controversial. Peripheral androgen blockade using a combination of a 5‐alpha reductase inhibitor and an antiandrogen may allow control of the prostate‐specific antigen (PSA). Because testosterone levels are not suppressed, this approach may be associated with less morbidity than conventional gonadal androgen suppression.

Telomere and Microtubule Targeting in Treatment-Sensitive and Treatment-Resistant Human Prostate Cancer Cells

Modulating telomere dynamics may be a useful strategy for targeting prostate cancer cells, because they generally have short telomeres. Because a plateau has been reached in the development of taxane-based treatments for prostate cancer, this study was undertaken to evaluate the relative efficacy of targeting telomeres and microtubules in taxane-sensitive, taxane-resistant, androgen-sensitive, and androgen-insensitive prostate cancer cells. Paclitaxel- and docetaxel-resistant DU145 cells were developed and their underlying adaptive responses were evaluated. Telomere dynamics and the effects of targeting telomeres with sodium meta-arsenite (KML001) (an agent undergoing early clinical trials), including combinations with paclitaxel and docetaxel, were evaluated in parental and drug-resistant cells. The studies were extended to androgen-sensitive LNCaP cells and androgen-insensitive LNCaP/C81 cells. Both P-glycoprotein (Pgp)-dependent and non–Pgp-dependent mechanisms of resistance were recruited within the same population of DU145 cells with selection for drug resistance. Wild-type DU145 cells have a small side population (SP) (0.4–1.2%). The SP fraction increased with increasing drug resistance, which was correlated with enhanced expression of Pgp but not breast cancer resistance protein. Telomere dynamics remained unchanged in taxane-resistant cells, which retained sensitivity to KML001. Furthermore, KML001 targeted SP and non-SP fractions, inducing DNA damage signaling in both fractions. KML001 induced telomere erosion, decreased telomerase gene expression, and was highly synergistic with the taxanes in wild-type and drug-resistant DU145 cells. This synergism extended to androgen-sensitive and androgen-insensitive LNCaP cells under basal and androgen-deprived conditions. These studies demonstrate that KML001 plus docetaxel and KML001 plus paclitaxel represent highly synergistic drug combinations that should be explored further in the different disease states of prostate cancer.

Abstract 4366: The telomere targeting agent sodium metaarsenite can eradicate the side population of hormone resistant prostate cancer cells

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Cancer stem cells share properties with normal stem cells such as self-renewal, protection from cytotoxic insult, and quiescence. Due to the latter, conventional chemotherapies are ineffective against cancer stem cells (CSCs) and drug resistant tumors have an even higher CSC fraction as a result of clonal selection. Activation of telomerase in more than 90 % of all cancers ensures endless self-renewal and enables the maintenance of telomeres at a stable length after their rapid shortening during early tumorigenesis. In this study we examined the potential of sodium metaarsenite which can target telomeres and the catalytic subunit of telomerase (hTERT), to eradicate the mature and the CSC population in drug sensitive and resistant prostate cancer cell lines. We have shown earlier, that prostate cancer cells are sensitive to sodium metaarsenite. We analyzed various prostate cancer cell lines reflecting hormone responsive (LnCaP and LAPC-4), hormone resistant (LAPC-4/CSS100 and LNCaP/C81) chemonaive (DU145) and taxane resistant (DU145/Pac200) lines for the existence of a CSC subpopulation by using the side population assay which is based on the property of stem cells to express drug efflux pumps such as Pgp (P-glycoprotein) and BCRP (Breast Cancer Resistant Protein) that are responsible for the resistance to standard chemotherapies. Fluorescence activated cell sorting (FACS) was used to separate the side population (SP) from the mature cell population. We have tested the effect of sodium metaarsenite on cell growth in a standard MTT. Cells were treated with IC50 and IC100 concentrations of the compound for 72 hrs and analyzed for its effect on the SP and telomerase activity by a PCR ELISA assay as well as hTERT expression level by real-time PCR. DNA damage induction was analyzed by γH2AX immunfluorescence staining. Cell growth curves showed that all tested cancer cell lines respond with similar sensitivity to sodium metaarsenite (IC50 = 2-7μM) but that the sorted SP respond better (IC50 = 1μM) to this compound. The taxane resistant cell line Du145/Pac200 had the highest percentage of a SP of about 65% which was reduced to 89% at IC50 and to 52% at IC100 concentrations of sodium metaarsenite to controls. The sorted side population showed higher telomerase activity as well as hTERT expression. The compound induced telomere-associated DNA damage signaling which was more intense in the sorted side population than in the mature cell population. Our data suggest that resulting from a reduction in telomerase activity and hTERT expression particularly in the CSC population, sodium metaarsenite treatment is responsible for the decrease of the prostate cancer stem cell fraction and that this agent may be useful in the treatment of drug as well as hormone resistant prostate cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4366. doi:10.1158/1538-7445.AM2011-4366