Prostate cancer (PCa) is the second-leading cause of cancer-related mortality, after lung cancer, in men from developed countries. In its early stages, primary tumor growth is dependent on androgens, ...thus generally can be controlled by androgen deprivation therapy (ADT). Eventually however, the disease progresses to castration-resistant prostate cancer (CRPC), a lethal form in need of more effective treatments. G-protein coupled receptors (GPCRs) comprise a large clan of cell surface proteins that have been implicated as therapeutic targets in PCa growth and progression. The findings reported here provide intriguing evidence of a role for the newly characterized glutamate family member GPR158 in PCa growth and progression. We found that GPR158 promotes PCa cell proliferation independent of androgen receptor (AR) functionality and that this requires its localization in the nucleus of the cell. This suggests that GPR158 acts by mechanisms different from other GPCRs. GPR158 expression is stimulated by androgens and GPR158 stimulates AR expression, implying a potential to sensitize tumors to low androgen conditions during ADT via a positive feedback loop. Further, we found GPR158 expression correlates with a neuroendocrine (NE) differentiation phenotype and promotes anchorage-independent colony formation implying a role for GPR158 in therapeutic progression and tumor formation. GPR158 expression was increased at the invading front of prostate tumors that formed in the genetically defined conditional Pten knockout mouse model, and co-localized with elevated AR expression in the cell nucleus. Kaplan-Meier analysis on a dataset from the Memorial Sloan Kettering cancer genome portal showed that increased GPR158 expression in tumors is associated with lower disease-free survival. Our findings strongly suggest that pharmaceuticals targeting GPR158 activities could represent a novel and innovative approach to the prevention and management of CRPC.
This study sought to determine if alterations in molecular pathways could supplement TNM staging to more accurately predict clinical outcome in patients with urothelial carcinoma (UC).
Expressions of ...69 genes involved in known cancer pathways were quantified on bladder specimens from 58 patients with UC (stages Ta-T4) and five normal urothelium controls. All tumor transcript values beyond two standard deviations from the normal mean expression were designated as over- or underexpressed. Univariate and multivariable analyses were conducted to obtain a predictive expression signature. A published external data set was used to confirm the potential of the prognostic gene panels.
In univariate analysis, six genes were significantly associated with time to recurrence, and 10 with overall survival. Recursive partitioning identified three genes as significant determinants for recurrence, and three for overall survival. Of all genes identified by either univariate or partitioning analysis, four were found to significantly predict both recurrence and survival (JUN, MAP2K6, STAT3, and ICAM1); overexpression was associated with worse outcome. Comparing the favorable (low or normal) expression of > or = three of four versus < or = two of four of these oncogenes showed 5-year recurrence probability of 41% versus 88%, respectively (P < .001), and 5-year overall survival probability of 61% versus 5%, respectively (P < .001). The prognostic potential of this four-gene panel was confirmed in a large independent external cohort (disease-specific survival, P = .039).
We have documented the generation of a concise, biologically relevant four-gene panel that significantly predicts recurrence and survival and may also identify potential therapeutic targets for UC.
ABSTRACT
Introduction
In surgical series of muscle‐invasive bladder cancer (MIBC), women have higher recurrence rates, disease progression, and mortality following radical cystectomy than men. ...Similar reports of oncologic differences between men and women following trimodality therapy (TMT) are rare. Our hypothesis was that there would be no difference in overall survival (OS) between sexes receiving TMT.
Methods
We queried the National Cancer Database (NCDB) for patients diagnosed with clinical stage T2‐T4aN0 M0 MIBC between 2004–2016. We considered patients to have received TMT if they received 55 Gy in 20 fractions or 59.4–70.2 Gy of radiotherapy with concurrent chemotherapy following a transurethral resection of bladder tumor (TURBT). We used multivariable Cox proportional hazard models to determine whether sex was associated with risk of mortality. In addition to OS, we calculated relative survival (RS) to adjust for the fact that females generally survive longer than males.
Results
Of the patients, 1960 underwent TMT and had survival data. Less than one quarter were female. In the first year following treatment, women had worse OS and RS than men (p = 0.093 and p = 0.030, respectively). However, overall and relative survival differences between sexes were not statistically significantly different in Years 2 and later. Unlike with OS, the RS between sexes remained significant at 9 years; in multivariable analysis based on RS, women were 43% more likely to die than men (p < 0.001).
Conclusions
Women had a higher initial risk of death than men in the first year following TMT. However, long‐term survival between sexes was similar. TMT is an important treatment option in both men and women seeking bladder preservation.
In surgical series of muscle invasive bladder cancer, females have higher recurrence rates, disease progression, and mortality following radical cystectomy than men. Trimodality therapy (TMT) is an important definitive treatment option in patients seeking bladder preservation. This study examines survival following TMT of women compared with men in a population‐based analysis.
The aim of this study was to determine the prognostic significance of PET/CT findings in women with cervical cancer and describe the normalization of lymph node SUVmax (nSUVmax).
A retrospective ...review was performed of 113 patients with cervical cancer who underwent a PET/CT before receiving definitive therapy. SUVmax measurements were normalized to the SUV of the pelvic blood pool. Patient, tumor, and PET/CT data were correlated to extracervical recurrence-free survival (ecRFS) and lymph node pathology.
Of 113 patients, there were 23 (20%) extracervical recurrences. On univariate analysis, stage, histology, nSUVmax, and radiographic size of the primary tumor, and nSUVmax of the most hypermetabolic lymph node were significantly associated with ecRFS. On multivariable analysis, nSUVmax and radiographic size of the primary tumor remained associated with ecRFS (both P < 0.001). Sixty-six patients underwent pelvic, common iliac, and/or para-aortic nodal sampling. The sensitivity, specificity, false-negative, and false-positive rates of PET/CT for lymph node metastases were 53%, 75%, 6%, and 82%, respectively. On univariate analysis, nSUVmax, and radiographic size of the primary tumor, and nSUVmax of the most hypermetabolic lymph node, and radiographic size of the largest lymph node, were associated with the presence of at least one pathologically positive lymph node. On multivariable analysis, only the radiographic size of the largest lymph node remained significantly associated with lymph node metastases (P < 0.001).
The size and nSUVmax of the primary tumor were associated with ecRFS. PET/CT has a low false-negative rate but high false-positive rate for lymph node metastases.
Iodine-131-metaiodobenzylguanidine ((131)I-MIBG) provides targeted radiotherapy with more than 30% response rate in refractory neuroblastoma, but activity infused is limited by radiation safety and ...hematologic toxicity. The goal was to determine the maximum-tolerated dose of (131)I-MIBG in two consecutive infusions at a 2-week interval, supported by autologous stem-cell rescue (ASCR) 2 weeks after the second dose.
The (131)I-MIBG dose was escalated using a 3 + 3 phase I trial design, with levels calculated by cumulative red marrow radiation index (RMI) from both infusions. Using dosimetry, the second infusion was adjusted to achieve the target RMI, except at level 4, where the second infusion was capped at 21 mCi/kg.
Twenty-one patients were enrolled onto the study at levels 1 to 4, with 18 patients assessable for toxicity and 20 patients assessable for response. Cumulative (131)I-MIBG given to achieve the target RMI ranged from 22 to 50 mCi/kg, with cumulative RMI of 3.2 to 8.92 Gy. No patient had a dose-limiting toxicity. Reversible grade 3 nonhematologic toxicity occurred in six patients at level 4, establishing the recommended cumulative dose as 36 mCi/kg. The median time to absolute neutrophil count more than 500/microL after ASCR was 13 days (4 to 27 days) and to platelet independence was 17 days (6 to 47 days). Responses included two partial responses, eight mixed responses, three stable disease, and seven progressive disease. Responses by semiquantitative MIBG score occurred in eight patients, soft tissue responses occurred in five of 11 patients, but bone marrow responses occurred in only two of 13 patients.
The lack of toxicity with this approach allowed dramatic dose intensification of (131)I-MIBG, with minimal toxicity and promising activity.
Summary Chemotherapy resistance is a significant contributor to treatment failure and death in men with hormone-refractory prostate cancer. One unexplored mechanism for drug resistance is the ...induction of stress response proteins referred to as the glucose-regulated proteins (GRPs). We sought to determine the level of expression of GRP78, the best characterized GRP in lymph node–positive prostate cancer. Archived, paraffin-embedded, radical prostatectomy specimens were obtained from 153 patients with lymph node–positive prostate cancer (stage D1). The level of GRP78 expression was determined by immunohistochemistry. We assessed the expression and specificity of GRP78 immunoreactivity in benign prostatic tissue, prostate cancer, and lymph node metastasis. We correlated the intensity of immunopositivity with prostate cancer recurrence and survival. Whereas immunohistochemical staining demonstrated that all prostate tissue was immunoreactive for GRP78, the intensity of expression was markedly higher in the primary tumor compared with areas of benign epithelium. GRP78 expression was also evident in lymph node metastases although less intensely than in the primary tumor. Patients with strong GRP78 immunoreactivity in the primary tumor are at higher risk for clinical recurrence (relative risk = 2.0, P = .019) and death (relative risk = 1.8, P = .024) than patients with weak GRP78 expression. This finding confirms that GRP78 protein expression is significantly higher in prostate cancer than in benign prostatic tissue. The intensity of expression is significantly associated with survival and clinical recurrence. GRP78 has considerable potential not only as a prognostic indicator but also as a potential therapeutic target.
Despite the significant progress made in colon cancer chemotherapy, advanced disease remains largely incurable and novel efficacious chemotherapies are urgently needed. Histone deacetylase inhibitors ...(HDACi) represent a novel class of agents which have demonstrated promising preclinical activity and are undergoing clinical evaluation in colon cancer. The goal of this study was to identify genes in colon cancer cells that are differentially regulated by two clinically advanced hydroxamic acid HDACi, vorinostat and LBH589 to provide rationale for novel drug combination partners and identify a core set of HDACi-regulated genes.
HCT116 and HT29 colon cancer cells were treated with LBH589 or vorinostat and growth inhibition, acetylation status and apoptosis were analyzed in response to treatment using MTS, Western blotting and flow cytometric analyses. In addition, gene expression was analyzed using the Illumina Human-6 V2 BeadChip array and Ingenuity Pathway Analysis.
Treatment with either vorinostat or LBH589 rapidly induced histone acetylation, cell cycle arrest and inhibited the growth of both HCT116 and HT29 cells. Bioinformatic analysis of the microarray profiling revealed significant similarity in the genes altered in expression following treatment with the two HDACi tested within each cell line. However, analysis of genes that were altered in expression in the HCT116 and HT29 cells revealed cell-line-specific responses to HDACi treatment. In addition a core cassette of 11 genes modulated by both vorinostat and LBH589 were identified in both colon cancer cell lines analyzed.
This study identified HDACi-induced alterations in critical genes involved in nucleotide metabolism, angiogenesis, mitosis and cell survival which may represent potential intervention points for novel therapeutic combinations in colon cancer. This information will assist in the identification of novel pathways and targets that are modulated by HDACi, providing much-needed information on HDACi mechanism of action and providing rationale for novel drug combination partners. We identified a core signature of 11 genes which were modulated by both vorinostat and LBH589 in a similar manner in both cell lines. These core genes will assist in the development and validation of a common gene set which may represent a molecular signature of HDAC inhibition in colon cancer.
Children with relapsed neuroblastoma have poor survival. It is crucial to have a reliable method for evaluating functional response to new therapies. In this study, we compared two functional imaging ...modalities for neuroblastoma: metaiodobenzylguanidine (MIBG) scan for uptake by the norepinephrine transporter and (18)Ffluorodeoxyglucose positron emission tomography (FDG-PET) uptake for glucose metabolic activity.
Patients enrolled onto a phase I study of sequential infusion of iodine-131 ((131)I) MIBG (NANT-2000-01) were eligible for inclusion if they had concomitant FDG-PET and MIBG scans. (131)I-MIBG therapy was administered on days 0 and 14. For each patient, we compared all lesions identified on concomitant FDG-PET and MIBG scans and gave scans a semiquantitative score.
The overall concordance of positive lesions on concomitant MIBG and FDG-PET scans was 39.6% when examining the 139 unique anatomic lesions. MIBG imaging was significantly more sensitive than FDG-PET overall and for the detection of bone lesions (P < .001). There was a trend for increased sensitivity of FDG-PET for detection of soft tissue lesions. Both modalities showed similar improvement in number of lesions identified from day 0 to day 56 scan and in semiquantitative scores that correlated with overall response. FDG-PET scans became completely negative more often than MIBG scans after treatment.
MIBG scan is significantly more sensitive for individual lesion detection in relapsed neuroblastoma than FDG-PET, though FDG-PET can sometimes play a complementary role, particularly in soft tissue lesions. Complete response by FDG-PET metabolic evaluation did not always correlate with complete response by MIBG uptake.
To determine the combined effects of p53, p21, and pRb alterations in predicting the progression of bladder transitional cell carcinoma.
p53, p21, and pRb expression was examined ...immunohistochemically on archival radical cystectomy samples from 164 patients with invasive or high-grade recurrent superficial transitional cell carcinoma (TCC; lymph node-negative, 117 patients; lymph node-positive, 47 patients). Median follow-up was 8.6 years. Based on percentage of nuclear reactivity, p53 was considered as wild-type (0% to 10%) or altered (>10%); p21 was scored as wild-type (>10%) or altered (<10%); and pRb status was considered wild-type (1% to 50%) or altered (0% or >50%).
As individual determinants, the p53, p21, and pRb status were independent predictors of time to recurrence (P<.001, P<.001, and P<.001, respectively), and overall survival (P<.001, P=.002, and P=.001, respectively). By examining these determinants in combination, patients were categorized as group I (no alteration in any determinant, 47 patients), group II (any one determinant altered, 51 patients), group III (any two determinants altered, 42 patients), and group IV (all three determinants altered, 24 patients). The 5-year recurrence rates in these groups were 23%, 32%, 57%, and 93%, respectively (log-rank P<.001), and the 5-year survival rates were 70%, 58%, 33%, and 8%, respectively (log-rank P<.001). After stratifying by stage, the number of altered proteins remained significantly associated with time to recurrence and overall survival.
This study suggests that alterations in p53, p21, and pRb act in cooperative or synergistic ways to promote bladder cancer progression. Examining these determinants in combination provides additional information above the use of a single determinant alone.
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