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PURPOSE - Because small cell carcinoma of the bladder is a relatively rare tumor type, literature about its treatment remains limited. We determined patterns of care and survival after treatment in what is to our knowledge the largest series to date of patients with locoregional small cell carcinoma of the bladder.
MATERIALS AND METHODS - We identified patients with localized/locally advanced (cTis-cT4, cN0 or cM0) bladder small cell carcinoma diagnosed between 1998 and 2010 from the National Cancer Database (NCDB). Treatment was categorized as bladder preservation therapy, radical cystectomy alone, bladder preservation therapy with multimodal treatment or radical cystectomy plus multimodal treatment. We performed Kaplan-Meier overall survival analysis to evaluate differential survival between treatment groups.
RESULTS - A total of 625 patients met study inclusion criteria. Median age at diagnosis was 73 years (range 36 to 90) and 65% of patients presented with cT2 disease. Patients were treated with bladder preservation therapy (174 or 27.8%), bladder preservation therapy plus multimodal treatment (333 or 53.3%), radical cystectomy alone (46 or 7.4%) and radical cystectomy plus multimodal treatment (72 or 11.5%) with a 3-year overall survival rate of 23% (95% CI 15-32), 35% (95% CI 30-45), 38% (95% CI 17-60) and 30.1% (95% CI 16-47), respectively. Overall survival was most favorable for radical cystectomy alone plus neoadjuvant chemotherapy with a 3-year rate of 53% (95% CI 19-79).
CONCLUSIONS - In the United States locoregional small cell carcinoma of the bladder develops predominantly in white males, in whom treatment is performed at metropolitan, comprehensive community cancer centers. Most patients were treated with bladder preservation therapy and most received multimodal therapy. Patients who received neoadjuvant chemotherapy followed by radical cystectomy had the most favorable survival.
Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
Neuroendocrine (NE) prostate tumors and neuroendocrine differentiation (NED) in prostatic adenocarcinomas have been associated with poor prognosis. In this study, we used the TRAMP mouse model that develops NE prostate tumors to identify key factors that can lead to NED. We have previously reported that NE tumors express the forkhead transcription factor, Foxa2, Mash1 (mouse achaete scute homolog-1), as well as Synaptophysin. In TRAMP, the prostatic intraepithelial neoplasia (PIN) first expresses Foxa2 and Synaptophysin, which then progresses to NE cancer. In order to determine if Foxa2 is dispensable for development or maintenance of NE cancer, a conditional knock-out of Foxa2 in TRAMP mice was generated by breeding mice with two floxed alleles of Foxa2 and one copy of Nkx3.1-Cre. Nkx3.1-Cre/Foxa2(loxP/loxP) mice showed loss of Foxa2 expression in embryonic prostatic buds. No expression of Foxa2 was seen in the adult prostate in either conditional null or control mice. Foxa2 is universally expressed in all wild type TRAMP NE tumors, but Mash1 expression is seen only in a few samples in a few cells. With the loss of Foxa2 in the NE tumors of the TRAMP/Nkx3.1-Cre/Foxa2(loxP/loxP) mice, the expression of the pro-neuronal gene Mash1 is upregulated. NE tumors from both the TRAMP control and Foxa2-deficient TRAMP prostate express Synaptophysin and SV40 Large T-antigen, and both show a loss of androgen receptor expression in NE cells. These studies suggest that the TRAMP NE tumors can form in the absence of Foxa2 by an up regulation of Mash1.
Copyright © 2012 Wiley Periodicals, Inc.
Small-cell lung cancer (SCLC) is the most aggressive subtype of lung cancer in its clinical behavior, with a 5-year overall survival as low as 5%. Despite years of research in the field, molecular determinants of SCLC behavior are still poorly understood, and this deficiency has translated into an absence of specific diagnostics and targeted therapeutics. We hypothesized that tumor DNA copy number alterations would allow the identification of molecular pathways involved in SCLC progression. Array comparative genomic hybridization was performed on DNA extracted from 46 formalin-fixed paraffin-embedded SCLC tissue specimens. Genomic profiling of tumor and sex-matched control DNA allowed the identification of 70 regions of copy number gain and 55 regions of copy number loss. Using molecular pathway analysis, we found a strong enrichment in these regions of copy number alterations for 11 genes associated with the focal adhesion pathway. We verified these findings at the genomic, gene expression and protein level. Focal Adhesion Kinase (FAK), one of the central genes represented in this pathway, was commonly expressed in SCLC tumors and constitutively phosphorylated in SCLC cell lines. Those were poorly adherent to most substrates but not to laminin-322. Inhibition of FAK phosphorylation at Tyr(397) by a small-molecule inhibitor, PF-573,228, induced a dose-dependent decrease of adhesion and an increase of spreading in SCLC cell lines on laminin-322. Cells that tended to spread also showed a decrease in focal adhesions, as demonstrated by a decreased vinculin expression. These results support the concept that pathway analysis of genes in regions of copy number alterations may uncover molecular mechanisms of disease progression and demonstrate a new role of FAK and associated adhesion pathways in SCLC. Further investigations of FAK at the functional level may lead to a better understanding of SCLC progression and may have therapeutic implications.
PURPOSE - The purpose of this study was to characterize the activity of the Bcl-2 protein family inhibitor ABT-263 in a panel of small cell lung cancer (SCLC) xenograft models.
EXPERIMENTAL DESIGN - A panel of 11 SCLC xenograft models was established to evaluate the efficacy of ABT-263. Single agent activity was examined on a continuous dosing schedule in each of these models. The H146 model was used to further evaluate dose and schedule, comparison to standard cytotoxic agents, and induction of apoptosis.
RESULTS - ABT-263 exhibited a range of antitumor activity, leading to complete tumor regression in several models. Significant regressions of tumors as large as 1 cc were also observed. The efficacy of ABT-263 was also quite durable; in several cases, minimal tumor regrowth was noted several weeks after the cessation of treatment. Antitumor effects were equal or superior to that of several clinically approved cytotoxic agents. Regression of large established tumors was observed through several cycles of therapy and efficacy was retained in a Pgp-1 overexpressing line. Significant efficacy was observed on several dose and therapeutic schedules and was associated with significant induction of apoptosis.
CONCLUSIONS - ABT-263 is a potent, orally bioavailable inhibitor of Bcl-2 family proteins that has recently entered clinical trials. The efficacy data reported here suggest that SCLC is a promising area of clinical investigation with this agent.
Overexpression of the prosurvival Bcl-2 family members (Bcl-2, Bcl-xL, and Mcl-1) is commonly associated with tumor maintenance, progression, and chemoresistance. We previously reported the discovery of ABT-737, a potent, small-molecule Bcl-2 family protein inhibitor. A major limitation of ABT-737 is that it is not orally bioavailable, which would limit chronic single agent therapy and flexibility to dose in combination regimens. Here we report the biological properties of ABT-263, a potent, orally bioavailable Bad-like BH3 mimetic (K(i)'s of <1 nmol/L for Bcl-2, Bcl-xL, and Bcl-w). The oral bioavailability of ABT-263 in preclinical animal models is 20% to 50%, depending on formulation. ABT-263 disrupts Bcl-2/Bcl-xL interactions with pro-death proteins (e.g., Bim), leading to the initiation of apoptosis within 2 hours posttreatment. In human tumor cells, ABT-263 induces Bax translocation, cytochrome c release, and subsequent apoptosis. Oral administration of ABT-263 alone induces complete tumor regressions in xenograft models of small-cell lung cancer and acute lymphoblastic leukemia. In xenograft models of aggressive B-cell lymphoma and multiple myeloma where ABT-263 exhibits modest or no single agent activity, it significantly enhances the efficacy of clinically relevant therapeutic regimens. These data provide the rationale for clinical trials evaluating ABT-263 in small-cell lung cancer and B-cell malignancies. The oral efficacy of ABT-263 should provide dosing flexibility to maximize clinical utility both as a single agent and in combination regimens.
BACKGROUND - Neuroendocrine (NE) prostate cancer develops as an aggressive disease that does not respond to androgen ablation therapy. It has been demonstrated that the paracrine action of NE cells facilitates the progression of androgen dependent adenocarcinoma to an androgen independent state, suggesting a significant role for NE cells during failure of androgen ablation therapy.
METHODS - To investigate the pathways that are involved in NE differentiation of prostate cancer, we have looked at the expression of genes known to be involved in endocrine differentiation of beta-cells in the pancreas. This study has been performed using the NE prostate cancer mouse model (12T-10) and the derivative allograft model (NE-10).
RESULTS - Immunohistochemical studies have shown that the neuroendocrine prostate tumors express the transcription factors Foxa2, mouse achaete-scute homolog-1 (mash-1), neurogenin3 (Ngn3) and Nkx2.2. These tumors show a loss of hairy/enhancer of split (Hes-1), a gene that inhibits NE differentiation. Human NE prostate cancers also express Foxa2 and human achaete-scute homolog-1 (HASH-1). These genes are expressed in NE prostate tumors in the similar sequential manner as they appear in a pancreatic beta-cell endocrine differentiation. Foxa2 expression is detected in early prostatic intraepithelial neoplasia (PIN). Mash-1 expression is detected in a few clusters within low grade PIN lesions and Nkx2.2 expression is rarely detected in individual scattered cells within the PIN lesion. Ngn3 and Nkx2.2 frequently appear in the invasive NE cancer. Subsequent NE metastasis to lung and liver show a distinct gene expression pattern. The lung metastasis expresses Ngn3 but does not express Nkx2.2 whereas liver metastases do not express Ngn3 but express Nkx2.2.
CONCLUSIONS - These results suggest that Ngn3 and Nkx2.2 expression are markers for site-specific metastasis and/or transcriptionally regulated genes that are required for organ-specific metastasis. This study indicates that a pathway similar to pancreatic beta-cell differentiation is involved in NE differentiation of prostate cancer.
(c) 2007 Wiley-Liss, Inc.
PURPOSE - There is a critical need for improvements in the noninvasive diagnosis of lung cancer. We hypothesized that matrix-assisted laser desorption ionization mass spectrometry (MALDI MS) analysis of the most abundant peptides in the serum may distinguish lung cancer cases from matched controls.
PATIENTS AND METHODS - We used MALDI MS to analyze unfractionated serum from a total of 288 cases and matched controls split into training (n = 182) and test sets (n = 106). We used a training-testing paradigm with application of the model profile defined in a training set to a blinded test cohort.
RESULTS - Reproducibility and lack of analytical bias was confirmed in quality-control studies. A serum proteomic signature of seven features in the training set reached an overall accuracy of 78%, a sensitivity of 67.4%, and a specificity of 88.9%. In the blinded test set, this signature reached an overall accuracy of 72.6 %, a sensitivity of 58%, and a specificity of 85.7%. The serum signature was associated with the diagnosis of lung cancer independently of gender, smoking status, smoking pack-years, and C-reactive protein levels. From this signature, we identified three discriminatory features as members of a cluster of truncated forms of serum amyloid A.
CONCLUSIONS - We found a serum proteomic profile that discriminates lung cancer from matched controls. Proteomic analysis of unfractionated serum may have a role in the noninvasive diagnosis of lung cancer and will require methodological refinements and prospective validation to achieve clinical utility.
ABT-737 is a novel and potent Bcl-2 antagonist with single-agent activity against small-cell lung cancer (SCLC) cell lines. Here, we evaluated the contribution of Bcl-2 family members to the in vitro cellular response of several SCLC cell lines to ABT-737. Relatively higher levels of Bcl-2, Bcl-X(L), Bim and Noxa, and lower levels of Mcl-1 characterized naïve SCLC cell lines that were sensitive to ABT-737. Conversely, a progressive decrease in the relative levels of Bcl-2 and Noxa and a progressive increase in Mcl-1 levels characterized the increased resistance of H146 cells following chronic exposure to ABT-737. Knockdown of Mcl-1 with small interfering RNA sensitized two resistant SCLC cell lines H196 and DMS114 to ABT-737 by enhancing the induction of apoptosis. Likewise, up-regulation of Noxa sensitized H196 cells to ABT-737. Combination treatment with DNA-damaging agents was extremely synergistic with ABT-737 and was associated with the down-regulation of Mcl-1 and the up-regulation of Noxa, Puma, and Bim in H196 cells. Thus, SCLC cells sensitive to ABT-737 expressed the target proteins Bcl-2 and Bcl-X(L), whereas Mcl-1 and factors regulating Mcl-1 function seem to contribute to the overall resistance of SCLC cells to ABT-737. Overall, these observations provide further insight as to the mechanistic bases for ABT-737 efficacy in SCLC and will be helpful for profiling patients and aiding in the rational design of combination therapies.
BACKGROUND - Platelet derived growth factor (PDGF) and PDGFR-beta are expressed and have been found to have prognostic value in several human cancers. Data in non-small-cell cancer cell lines have suggested that PDGFR is a therapeutic target for drug development. In the current study PDGFR-beta expression and prognostic value in small cell lung cancer (SCLC) was investigated.
METHODS AND MATERIALS - Paraffin-embedded tissue blocks from 53 patients with limited and extensive stage SCLC were obtained for immunohistochemical staining. Tumors from each patient were sampled 3 times and stained with PDGFR-beta specific antibody. Patients were divided into low and high staining groups based on intensity.
RESULTS - There was high intensity PDGFR-beta staining in 20 patients with SCLC. Another 29 expressed low intensity PDGFR-beta staining, with only 4 patients showing no PDGFR-beta staining. There was no statistically significant difference in 5 year overall survival between patients with low levels of PDGFR-beta staining vs. those with high level staining SCLC tumors (p = 0.538).
CONCLUSIONS - The present study found that the majority of SCLC patients express, at least, a low level of PDGF-beta. However, the level of PDGFR-beta expression was not a statistically significant predictor of 5 year overall survival in SCLC.
ABT-737 is a subnanomolar inhibitor of the antiapoptotic proteins Bcl-2, Bcl-X(L) and Bcl-w. Although ABT-737 triggers extensive cell death in many small-cell lung carcinoma (SCLC) cell lines, some of the SCLC cell lines and the majority of the cancer cell lines derived from other solid tumors were found to be resistant to ABT-737. To better understand the mechanism of resistance to ABT-737, we screened a short interfering RNA library consisting of short interfering RNA against 4000 'druggable' targets in an SCLC-derived cell line, NCI-H196. By comparing the knockdowns with phenotypes, all of the three top 'hits' from the screen were found to result from off-target gene silencing. Interestingly, the three off-target siRNAs were found to knock down an antiapoptotic Bcl-2 family protein Mcl-1 owing to the complementation between their seed regions with the 3' untranslated region (3' UTR) of Mcl-1. Furthermore, reducing the level of Mcl-1 using siRNAs or the small-molecule compounds Bay43-9006 and Seliciclib was sufficient to overcome the resistance to ABT-737 in the resistant SCLC cell line and cancer cell lines derived from other solid tumors. These results provide further evidence that Mcl-1 is the major factor that causes resistance to ABT-737 in cancer cells derived from diverse solid tumors, and the combination of Mcl-1 downregulating agents with ABT-737 could be potent therapeutic regimens for patient with ABT-737-resistant SCLC and many other types of solid tumors.