bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel selective therapeutic targeting heme oxygenase-1 revealed a potent antimetastatic activity in androgen-refractory human prostate cancer models
Authors: Alaoui-Jamali M. A. , Gupta A. , Szarek W. A. , Bismar T. A. , Gheorghe R. , Schipper H. M. 
Published: August 2020

e16090 Prostate cancer is a highly prevalent disease. Despite a significant improvement in the overall survival attributed in part to early detection and introduction of novel therapeutic modalities, many cancer patients at primary diagnosis present advanced disease or experience recurrence of the cancer. The progression of prostate cancer (PCA) to hormone-refractory phenotype (HRPCA) and to metastasis is an ominous event in patients with advanced PCA. Currently, clinically available drugs for hormone refractory PCA have only marginal efficacy. In this study, we identified heme oxygenase 1 (HO-1) to be significantly upregulated in epithelial PCA cells, but not in surrounding stromal cells, from hormone refractory prostate cancer cases compared to hormone-responsive prostate cancer and to benign tissues. We validated HO-1 as a novel therapeutic target for HRPCA. Specifically, inhibition of HO-1 gene in androgen-independent and highly invasive prostate cancer cells, PC3M, decreased HO-1 activity, oxidative stress, MAPKs activation, cell proliferation, and cell migration and invasion in vitro, as well as inhibition of prostate tumor growth and lymph nodes and lung metastases in vivo. The impact of HO-1 silencing on these oncogenic features was mimicked by exposure of cells to a novel selective small-molecule HO-1 inhibitor referred to as OB-24. OB-24 selectively downregulates HO-1 activity, oxidative stress, and significantly inhibits cell proliferation in vitro and tumor growth and lymph node/lung metastases in vivo. A potent synergistic activity in inhibiting HRPCA metastasis formation was observed when OB-24 was combined with the chemotherapy drug taxol. The molecular and potential clinical impact of OB-24 alone and in combination with taxanes on HRPCA will be discussed. [Table: see text]
Effects of sorafenib on proliferation of hormone-sensitive and hormone-insensitive prostate cancer cells
Authors: Culig Z. , Oh S. Jung , Santer F. R. , Puhr M. , Steiner H. , Hobisch A. 
Published: August 2020

e16092 Background: Sorafenib is a multi-targeted kinase inhibitor approved for treatment of renal and hepatocellular cancer. In patients with castration therapy-resistant prostate cancer sorafenib treatment is associated with discordant prostate-specific antigen (PSA) and clinical responses, possibly due to an effect on PSA expression. The mechanisms of its action in advanced prostate tumors are not investigated so far. The aim of the present study was to evaluate the effects of sorafenib in androgen-sensitive (LNCaP) and -insensitive (PC 3) prostate cancer cell lines. Methods: Proliferation was evaluated by measurement of cell number and protein. Expression of cell cycle and apoptosis regulatory proteins of the Bcl-2 family was determined by Western blot. Results: Treatment of those cells by sorafenib for 48 hours resulted in a concentration-dependent inhibition of proliferation. Maximal inhibition was achieved with 25 μM of the compound. Cell number was reduced by 50% in both cell lines. We observed inhibition of expression of cyclin-dependent kinase 2 in LNCaP and PC3 cells. In addition, Mcl-1 protein, that is frequently overexpressed in prostate cancer, was down-regulated by sorafenib in both cellular models. Conclusions: Sorafenib caused inhibition of growth of prostate cancer cells regardless of their androgen sensitivity. Its inhibitory effects on cyclin- dependent kinase 2 and Mcl-1 imply that sorafenib regulates cell cycle progression and apoptosis in prostate cancer. On the basis of these results experiments with chemotherapy-resistant prostate cells are being performed. [Table: see text]
Deleted in cancer 1: Search for a function in prostate cancer
Authors: Hirsch J. , Nelius T. , Pfarr C. , De Riese W. , Wieland I. , Filleur S. 
Published: August 2020

e16095 Background: Deleted In Cancer 1 (DICE1/INTS6) gene was recently identified to colocalize with the microsatellite marker D13S284 in 13q14.3, a region frequently affected by allelic deletion in many solid tumors including prostate cancer (PrCa). DICE1 missense mutations have been previously detected in PrCa cell line LNCap, and reduced DICE1 expression appears to be associated with CpG promoter hypermethylation in PrCa cells. DICE1 is a highly conserved nuclear protein suggesting its involvement in DNA repair, transcription, or RNA splicing. In mouse, the DICE1 homologue interferes with the response to insulin-like growth factor 1 and suppresses anchorage-independent growth of transformed mouse cells. The totality of these results suggests that DICE1 is a tumor suppressor gene and insist on the need to better characterize DICE1 function in PrCa. Methods: Expression of DICE1 was evaluated by Northern Blot in PrCa cell lines LNCap, DU145, PC3, PC3ml and CPTX1532 and compared to expression level in normal prostate cell line NPTX1532. DICE1 growth inhibitory effects were analyzed by colony formation assay on PC3 and DU145 cells transfected with DICE1 expression plasmid or control vector. Apoptosis was assessed by visualization of genomic DNA fragmentation on agarose gel. PCR arrays (SABiosciences) were used to identify specific signaling pathways modulated in response to DICE1 expression. Results: Markedly decreased DICE1 mRNA levels were detected in PrCa cell lines LNCap, DU145, PC3 and PC3ml as well as CPTX1532 as compared to NPTX1532, a cell line derived from normal prostate tissue. Ectopic expression of DICE1 cDNA in DU145 and PC3 cells substantially suppressed their ability to form colonies in vitro. This growth inhibition was not due to immediate induction of apoptosis suggesting growth suppression by other pathways. Expression profiling identified multiple pathways, such as Wnt, Hedgehog, PI-3 Kinase, NFκB and Insulin pathways, regulated in response to ectopic DICE1 expression. Furthermore, various transcription factors including Fos, Jun, CEBPA and PPAR-γ were up-regulated in response to DICE1. Conclusions: These results clearly illustrate the growth inhibitory ability of DICE1 in PrCa. Expression profiling links DICE1 function to growth factor signaling and cell-cell communication. No significant financial relationships to disclose.
Efficacy and thyroidal effects of sunitinib in Japanese patients with metastatic renal cell carcinoma: Hypothyroidism and thyroid atrophy as potential biomarkers for sunitinib?
Authors: Shinohara N. , Takahashi M. , Kamishima T. , Ikushima H. , Sazawa A. , Kanayama H. , Nonomura K. 
Published: August 2020

e16097 Background: Although hypothyroidism is a well-known adverse effect of sunitinib in western patients (pts) with metastatic renal cell carcinoma (MRCC), the effects on thyroid gland of sunitinib in Japanese pts still remain unclear. We therefore evaluated thyroid dysfunction and thyroid atrophy in Japanese RCC pts who received sunitinib. Methods: Fourteen (8 males, 6 females) of 51 pts who were treated in a phase II trial of sunitinib in Japanese pts with MRCC were included in this retrospective study. All 14 pts were euthyroid at baseline. The measurement of serum thyroid function test (fT3, fT4, TSH) was performed at the beginning of each sunitinib treatment cycle. A TSH concentration greater than 10 mU/L was considered as hypothyroidism regardless of subclinical or clinical. CT volumetry of the thyroid gland was performed utilizing the data obtained for tumor assessment in a phase II trial. Tumor response was evaluated based on the RECIST criteria. Results: 9 (64%) of 14 pts achieved RECIST-defined objective response (1 CR, 8 PRs). With regard to thyroid function, hypothyroidism was experienced by 11 (79%) pts. Three of 11 pts had Sunitinib-induced thyrotoxicosis before experiencing hypothyroidism. The mean time to development of hypothyroidism was 55 days (range 13–668). Six pts received typical doses of L-thyroxine. The response rate was 73% (8/11) in pts with hypothyroidism and 33% (1/3) in pts without. With regard to the volume of thyroid gland in 13 pts, 8 pts had more than 50% reduction comparing the volume at the baseline. Median reduction rate in volume of 13 pts was 57% (range 0–95%). Hypothyroidism was experienced by all 8 pts with more than 50% reduction in volume and 2 of 5 (40%) without. Furthermore, the response rate was 88% (7/8) in former pts and 40% (2/5) in latter pts. Conclusions: In addition to high anti-tumor efficacy, hypothyroidism and thyroid atrophy were commonly observed in Japanese MRCC pts who received sunitinib. Although further study should be required, these abnormal findings in thyroid gland following treatment with sunitinib may be potential biomarkers for tumor response to sunitinib. [Table: see text]
Phase I trial of sorafenib in combination with interferon-alpha in Japanese patients with unresectable or metastatic renal cell carcinoma
Authors: Sumiyoshi Y. , Hashine K. , Niwakawa M. , Yamaguchi R. , Fujii H. , Hamamoto Y. , Fukino K. 
Published: August 2020

e16107 Background: Sorafenib (SOR) is a multi-kinase inhibitor, targeting Raf kinase and the receptor tyrosine kinases VEGFR-2 and PDGFR-β. Interferon-α (IFN) is most commonly used for metastatic renal cell carcinoma (RCC) in Japan. In this phase I study, we investigated the safety profile, pharmacokinetics (PK), and tumor response of SOR/(recombinant)IFN combination in Japanese patients (pts) with RCC. Methods: After 2 weeks of IFN-alone treatment, a total of 18 pts (6 in each cohort) with unresectable/metastatic RCC received 28-day cycles of continuous SOR 200 (Cohort 1 [C1]) or (Cohorts 2 and 3 [C2 and C3]) 400 mg bid combined with intramuscular IFN 6 (C1 and C2) or 9 (C3) MIU three times a week (tiw). Objectives were safety/tolerability and recommended dose of SOR/IFN as primary, and tumor response and PK as secondary. Results: Pt characteristics were: median 64.5 y.o.; ECOG-PS 0:1, 14:4; prior anticancer therapy in 13 pts. All pts completed Cycle 1 and entered Cycle 2 or later cycles. At data cut-off (September 30, 2008), dose-limiting toxicities were reported in all cohorts, including G3 fatigue, G3 anorexia, and G3 skin disorders. Common drug-related grade 3/4 adverse events (AEs) included fatigue (50%), lipase increased (44%) and neutropenia (39%), all of which were reversible and manageable. AEs resulting in treatment discontinuation in Cycle 2 or later cycles were seen in 5 pts in Cohort 3. One death was reported in C1 at Cycle 18 due to gastrointestinal and intraabdominal hemorrhage. It seemed attributable to DIC accompanied by RCC. Five PR (1 in C1 and 4 in C3) and 11 SD (4 in C1, 5 in C2, and 2 in C3) were achieved as the best response. IFN had no relevant impact on PK of SOR. Conclusions: SOR/IFN combination has promise for clinical benefit in RCC, and its recommended dose was continuous SOR 400 mg bid and IFN 6 MIU tiw. [Table: see text]
Synergistic growth inhibition of RCC and NSCLC cell lines by sorafenib plus vorinostat and induction of angiogenic genes by ER stress
Authors: Drabkin H. A. , Sharma G. , Costa L. J. , Korch C. , Gemmill R. M. 
Published: August 2020

e16114 Sorafenib, vorinostat and the combination were examined in 34 RCC and NSCLC cell lines. In growth assays, sorafenib at 8 μM resulted in synergy with multiple vorinostat doses, whereas no synergy was seen with lower doses. Changes in phospho-ERK and AKT were not predictive of growth inhibition, whereas frequent inhibition of cyclin D1 and upregulation of p21Waf1 was observed. To anticipate resistance mechanisms to the anti-angiogenic effects of sorafenib, we studied the expression of 13 angiogenic factors in 10 selected lines. At baseline, bFGF, VEGF and IL-8 were highly expressed in RCCs, whereas Gro-α, VEGF, and IL-8 predominated in NSCLCs. Multiple angiogenic factors were upregulated by sorafenib and vorinostat, especially VEGF, IL-6, CTGF, EDN1, PDGFβ, and IL-8. Importantly, sorafenib at 8 μM, but not lower doses, induced ER stress in these cell lines and thapsigargin or tunicamycin treatment recapitulated many, but not all, of the observed angiogenic gene responses to sorafenib. In fact, CHOP induction by sorafenib plus vorinostat was the only parameter, other than growth inhibition, that changed in a synergistic manner. In summary, sorafenib plus vorinostat potently inhibits the in vitro growth of RCC and NSCLC cell lines. Upregulation of multiple angiogenic genes, in part by an ER-stress mechanism, may contribute to acquired resistance in vivo. No significant financial relationships to disclose.
A phase II trial of gefitinib and pegylated interferon alfa 2b (PEG-IFN) in previously-treated renal cell carcinoma (RCC)
Authors: Shek D. W. , Longmate J. , Quinn D. , Margolin K. , Twardowski P. , Gandara D. , Pan C. , Lara P. 
Published: August 2020

e16115 Background: Modulation of the epidermal growth factor receptor (EGFR) pathway is relevant to IFN activity in RCC. Cell lines sensitive to IFN's antiproliferative effects downregulate EGFR, while IFN treatment of resistant cells precludes such an effect. (Eisenkraft et al, Cancer Res. 1991) Lack of EGFR down-regulation may thus be responsible in part for IFN resistance. To explore this hypothesis, we conducted a trial of the EGFR tyrosine kinase inhibitor gefitinib plus PEG-IFN in RCC patients (pts). Methods: Unresectable or metastatic RCC pts (no limit on prior therapies; performance status 0–2, and adequate end-organ function) were eligible. Prior IFN was allowed. Dose schedule: PEG-IFN SQ weekly (6μg/kg/week or 4 μg/kg/week) × 12 weeks and gefitinib 250 mg po daily until progression. A 6-month progression free survival (PFS) rate of 50% was considered promising (vs. 30%) in a two-stage design incorporating the Green-Dahlberg rule. We accrued 21 patients in the first-stage of accrual. Results: Pt characteristics: Males -16; median age - 56 years; Prior nephrectomy - 12. All had > 1 prior systemic therapy . Accrual slowed with increased use of small molecule kinase inhibitors, bevacizumab, and temsirolimus for RCC. At 6 months, PFS was 26% (95% CI: 9%, 49%); 20% (4 pts) had died. Best responses by RECIST: complete (1), partial (4), stable (8); progression (4). Response duration: CR (35+ months) and PR (3, 5, 5, 38+ months). Median time to treatment failure was 18.4 weeks (95%CI: 7.4, 24.9). Median PFS and overall survival were 23 and 53 weeks, respectively. Most common treatment-related toxicities were leucopenia, thrombocytopenia, rash, nausea, diarrhea, and hyperglycemia. Conclusions: Although gefitinib plus PEG-IFN did not meet the pre-specified 6-month PFS of 50%, it appears to have activity similar to other first-line therapies even in this previously-treated setting. (Supported by Astra Zeneca) [Table: see text]
A dose-escalating phase I study of biweekly docetaxel in older men with hormone refractory prostate cancer (HRPC)
Authors: McDevitt J. , Hauser R. , Simon J. , Balducci L. 
Published: August 2020

e16117 Background: Docetaxel has been shown to be effective and is used in the treatment of HRPC. This phase I study is designed to investigate the maximum tolerated dose, tolerability and activity of docetaxel administered on a biweekly schedule in older patients with HRPC. This study will also explore the feasibility of a self-report geriatric assessment tool in this population. Methods: HRPC patients with progression of metastatic disease during hormonal therapy received docetaxel q 2 wks at dose levels of 40 (level 0), 45 (level 1), 50 (level 2), or 55 mg/m2 (level 3). The trial is a conventional phase I 3+3 dose-escalation design. Treatment was continued until progression, refused further treatment, or unacceptable toxicity. Patients were given the Vulnerable Elders Survey (VES-13) for completion every 4 weeks. Results: 16 patients were enrolled in the study. All are evaluable for toxicity, 10 for response. Pts had a median (range) age 76 (72–87). Median doses administered was 6 (range 3–19). The maximum tolerated dose (MTD) was not reached in the study. No dose limiting side effects were reported for any of the dosing levels in the 8 week assessment period. Five patients had a ≥50% decline in serum PSA on two consecutive measurements taken at least 2 weeks apart. Of the 10 patients with measureable disease, 2 patients (one at dose level 0 and one at dose level 3) achieved a complete response, 2 patients (one at dose level 1 and one at dose 2) achieved a partial response, and 3 patients had stable disease (one each at dose levels 1, 2, and 3). At the time of entry onto the study, 4 patients required narcotic analgesics for bone pain; after treatment, 1 (25%) discontinued their pain medications. The completion rate of the Vulnerable Elders Survey (VES-13) was 94.6%. Conclusions: Biweekly docetaxel can be safely administered in older metastatic HRPC patients and showed activity. For phase II evaluation, a bi-weekly dose of 55 mg/m2 appears to be suitable. The administration of the VES-13 was feasible in this population. [Table: see text]
Malignant transformation of teratoma to primitive neuroectodermal tumor (PNET): Outcome analysis with PNET based chemotherapy
Authors: Brames M. , Ehrlich Y. , Einhorn L. 
Published: August 2020

e16121 Background: Metastatic testis cancer is uniquely chemosensitive and highly curable. Residual teratoma can be surgically resected. However, testicular teratoma can differentiate along endodermal, ectodermal, or mesodermal elements (malignant transformation of teratoma), with capacity to metastasize and not be amenable to surgical resection. We report results of malignant transformation of teratoma to metastatic PNET treated with PNET based chemotherapy. Methods: Retrospective review of 42 patients with PNET in testis or at metastatic sites seen at Indiana University from 1999–2007. Of these 42 patients, 10 had inoperable or unresectable PNET treated with cyclophosphamide 1200 mg/M2, doxorubicin 75 mg/M2, and vincristine 2 mg IV alternating with ifosfamide 1.8 grams/M2 × 5 days plus etoposide 100 mg/M2 × 5 days. Courses were given every 3 weeks for 6 courses or until progression or undue toxicity. Results: 9 of 10 patients had at least 1 prior platinum based combination chemotherapy regimen for their germ cell tumor. Tumor markers (human chorionic gonadotropin and alphafetoprotein) were normal at start of chemotherapy for biopsy proven PNET. Eight of 10 achieved objective response. Two of 10 are currently disease-free for 16 and 33 months from initiation of PNET specific chemotherapy and 3 other patients are alive with disease at 73, 34, and 30 months. These 5 patients all had subsequent surgery. Conclusions: PNET specific chemotherapy has a high objective response rate for malignant transformation of teratoma to PNET, with some patients capable of long-term survival with chemotherapy followed by surgical resection. [Table: see text]
Impact of nail toxicity on survival of patients with hormone-refractory prostate cancer (HRPC) treated with docetaxel
Authors: Scotte F. , Banu E. , Medioni J. , Boudraoui M. , Tourani J. M. , Banu A. , Oudard S. 
Published: August 2020

e16122 Background: Docetaxel is the standard first-line treatment for patients (pts) with metastatic HRPC. Taxanes are a well known cause of nail toxicity but docetaxel-related nail toxicity is rarely explored. Methods: Eligible HRPC pts included in the current analysis were from a phase II, multicentre, case-control study (Scotte F et al, J Clin Oncol 2005). Pts were treated with docetaxel 75 mg/m2 every 3 weeks and oral prednisone 10 mg daily. Nail toxicity was graded according to NCI CTC version 2 (0: absence of toxicity; 1: minor changes; 2: onycholisis). The endpoint of interest was the impact of nail toxicity on overall survival (OS) using Cox regression analysis as the main statistical method. OS was the time from the start of chemotherapy to death or last follow-up. Results: Data from 23 HRPC pts treated in two French centres were analyzed. The median age was 68 years, 91% of pts had bone metastases, 84% had a single metastatic site, 49% had a Gleason score of ≥ 8 and 91% had an ECOG performance status (PS) of 0 or 1. Median OS was 16.7 months [95% confidence interval (CI), 5.7–27.6 months], all pts died. There were differences in OS between nail toxicity categories (see Table). Median OS was 10.6 months (95% CI, 9.5–11.7) and 22.7 months (95% CI, 15.1–30.3) for pts without and with nail changes, respectively. Nail changes severity was significantly related to OS: hazard ratio (HR)=0.50 (95% CI, 0.28–0.92), P=0.027 (univariate analysis). The multivariate analysis adjusted by ECOG PS (the second covariate associated with prognosis) showed a 63% reduction in the risk of death for pts with nail toxicities: HR=0.29 (95% CI, 0.09–0.82), P=0.049. Conclusions: Our results suggest that pts with docetaxel-related nail toxicity have a better OS than those with no nail toxicity. This demonstrates that nail changes in HRPC pts treated with docetaxel are predictive of OS; these findings should be validated in a large cohort of pts. [Table: see text] No significant financial relationships to disclose.
Alterations of natural killer cells in metastatic prostate cancer
Authors: Veuillen C. , Gravis G. , Marcy M. , Walz J. , Bladou F. , Salem N. , Brunelle S. , Olive D. 
Published: August 2020

e16131 Background: Recently, prostate cancer (PCa) has been considered as a potential target for antitumoral immunotherapy and cells such as Natural Killer (NK) cells, with antitumoral activity are a promising candidate. NK cells activity is regulated by opposite signals delivered by inhibitory (NKRi) and activating receptors (NKRa). Primary human PCa express ligands for NKRa but the HLA class I (ligands for NKRi) expression is downregulated. Recently, our group have reported that patients with acute myeloid leukaemia have defective interactions receptor -ligand in NK cells due to a decreasing expression of Natural Cytotoxicity Receptors and it could be used as a evasion mechanism by leukaemia cells. The aim of this work was to evaluate the activating receptors expression to know if it could be used as evasion mechanism of the immune response in PCa. Methods: Activating and inhibitory receptors were analysed by flow cytometry in peripheral NK cells from 8 patients with metastatic androgen dependent prostate cancer (ADPC), 10 with metastatic androgen independent prostate cancer (AIPC), 7 patients with localized prostate cancer (LPC ) and 15 healthy donors. Results: The expression of NKp30, NKp46, and NKG2D (as determined by MFI) was significantly lower on NK cells from patients with ADPC and AIPC than in healthy donors. In ADPC patients, the ratio MFI (MFI receptor/MFI control isotype) of NKP30 (4.73 ± 1.07, p = 0.0003), of NKp46 (16.62 ± 3.42, p = 0.036) and of NKG2D (19.61 ± 6.44, p = 0.026) significantly differed from healthy donors (NKp30 26.65 ± 6.12; NKp46 39.73 ± 9.66 and NKG2D 37.97 ± 6.77). It was similar for AIPC NK cells(NKp30 6.28 ± 1.27, p = 0.0002; NKp46 16.24 ± 2.34, p = 0.014; NKG2D 13.61 ± 2.29, p = 0.0003). In ADPC and AIPC NK cells, the expression of NKRi and other NKRa did not differ from healthy donors. In LPC NK cells, the expression of NKRi and NKRa did not differ from healthy donors. Conclusions: We observed a decreased expression of principal activating receptors only in metastatic form of PCa. This could affect the interactions receptor-ligand in NK cells. Is it hormonal therapy or extension of the disease that is responsible of NK cells alterations? Moreover, this could constitute a potential mechanism for cancer cells immune escape and a possible target for therapies improving NK functions. No significant financial relationships to disclose.