Clinical Cancer Research
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Phase I Study of the Novel Enhancer of Zeste Homolog 2 (EZH2) Inhibitor GSK2816126 in Patients with Advanced Hematologic and Solid Tumors Abstract
Purpose:
Enhancer of zeste homolog 2 (EZH2) activity is dysregulated in many cancers.
Patients and Methods:
This phase I study determined the safety, maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of the intravenously administered, highly selective EZH2 inhibitor, GSK2816126, (NCT02082977). Doses of GSK2816126 ranged from 50 to 3,000 mg twice weekly, and GSK2816126 was given 3-weeks-on/1-week-off in 28-day cycles. Eligible patients had solid tumors or B-cell lymphomas with no available standard treatment regimen.
Results:
Forty-one patients (21 solid tumors, 20 lymphoma) received treatment. All patients experienced ≥1 adverse event (AE). Fatigue [22 of 41 (53.7%)] and nausea [20 of 41 (48.8%)] were the most common toxicity. Twelve (32%) patients experienced a serious AE. Dose-limiting elevated liver transaminases occurred in 2 of 7 patients receiving 3,000 mg of GSK2816126; 2,400 mg was therefore established as the MTD. Following intravenous administration of 50 to 3,000 mg twice weekly, plasma GSK2816126 levels decreased biexponentially, with a mean terminal elimination half-life of approximately 27 hours. GSK2816126 exposure (maximum observed plasma concentration and area under the plasma-time curve) increased in a dose-proportional manner. No change from baseline in H3K27me3 was seen in peripheral blood mononuclear cells. Fourteen of 41 (34%) patients had radiological best response of stable disease, 1 patient with lymphoma achieved a partial response, 21 of 41 (51%) patients had progressive disease, and 5 patients were unevaluable for antitumor response.
Conclusions:
The MTD of GSK2816126 was established at 2,400 mg, but the dosing method and relatively short half-life limited effective exposure, and modest anticancer activity was observed at tolerable doses.
Clinical Cancer Research - Tập 25 Số 24 - Trang 7331-7339 - 2019
Mutational Landscape of Aggressive Cutaneous Squamous Cell Carcinoma Abstract
Purpose: Aggressive cutaneous squamous cell carcinoma (cSCC) is often a disfiguring and lethal disease. Very little is currently known about the mutations that drive aggressive cSCC.
Experimental Design: Whole-exome sequencing was performed on 39 cases of aggressive cSCC to identify driver genes and novel therapeutic targets. Significantly, mutated genes were identified with MutSig or complementary methods developed to specifically identify candidate tumor suppressors based upon their inactivating mutation bias.
Results: Despite the very high-mutational background caused by UV exposure, 23 candidate drivers were identified, including the well-known cancer-associated genes TP53, CDKN2A, NOTCH1, AJUBA, HRAS, CASP8, FAT1, and KMT2C (MLL3). Three novel candidate tumor suppressors with putative links to cancer or differentiation, NOTCH2, PARD3, and RASA1, were also identified as possible drivers in cSCC. KMT2C mutations were associated with poor outcome and increased bone invasion.
Conclusions: The mutational spectrum of cSCC is similar to that of head and neck squamous cell carcinoma and dominated by tumor-suppressor genes. These results improve the foundation for understanding this disease and should aid in identifying and treating aggressive cSCC. Clin Cancer Res; 20(24); 6582–92. ©2014 AACR.
Clinical Cancer Research - Tập 20 Số 24 - Trang 6582-6592 - 2014
Antitumor Activity of Lurbinectedin, a Selective Inhibitor of Oncogene Transcription, in Patients with Relapsed Ewing Sarcoma: Results of a Basket Phase II Study Abstract
Purpose:
Lurbinectedin suppresses the oncogenic transcription factor EWS-FLI1 through relocalization to the nucleolus, and delays tumor growth in mice bearing Ewing sarcoma xenografts. On the basis of this rationale, lurbinectedin was evaluated in patients with relapsed Ewing sarcoma.
Patients and Methods:
This open-label, single-arm, Basket phase II trial included a cohort of 28 treated adult patients with confirmed Ewing sarcoma, measurable disease as per Response Evaluation Criteria In Solid Tumors (RECIST) v.1.1, Eastern Cooperative Oncology Group performance status ≤2, adequate organ function, no central nervous system metastasis, and pretreated with ≤2 chemotherapy lines for metastatic/recurrent disease. Patients received lurbinectedin 3.2 mg/m2 as a 1-hour infusion every 3 weeks. Primary endpoint was overall response rate (ORR) as per RECIST v.1.1. Secondary endpoints included time-to-event parameters and safety profile.
Results:
ORR was 14.3% [95% confidence interval (CI), 4.0%–32.7%], with median duration of response of 4.2 months (95% CI, 2.9–5.5 months). Median progression-free survival was 2.7 months (95% CI, 1.4–4.3 months), clinical benefit rate was 39.3%, and disease control rate was 57.1%. With 39% censoring, median overall survival was 12.0 months (95% CI, 8.5–18.5 months). Most common grade 3/4 adverse events were neutropenia (57%), anemia, thrombocytopenia, and treatment-related febrile neutropenia (14% each). No deaths or discontinuations were due to toxicity.
Conclusions:
Lurbinectedin was active in the treatment of relapsed Ewing sarcoma and had a manageable safety profile. Lurbinectedin could represent a valuable addition to therapies for Ewing sarcoma, and is currently being evaluated in combination with irinotecan in advanced Ewing sarcoma in a phase Ib/II trial.
Clinical Cancer Research - Tập 28 Số 13 - Trang 2762-2770 - 2022
The Double-Edged Sword of Autophagy Modulation in Cancer Abstract
Macroautophagy (autophagy) is a lysosomal degradation pathway for the breakdown of intracellular proteins and organelles. Although constitutive autophagy is a homeostatic mechanism for intracellular recycling and metabolic regulation, autophagy is also stress responsive, in which it is important for the removal of damaged proteins and organelles. Autophagy thereby confers stress tolerance, limits damage, and sustains viability under adverse conditions. Autophagy is a tumor-suppression mechanism, yet it enables tumor cell survival in stress. Reconciling how loss of a prosurvival function can promote tumorigenesis, emerging evidence suggests that preservation of cellular fitness by autophagy may be key to tumor suppression. As autophagy is such a fundamental process, establishing how the functional status of autophagy influences tumorigenesis and treatment response is important. This is especially critical as many current cancer therapeutics activate autophagy. Therefore, efforts to understand and modulate the autophagy pathway will provide new approaches to cancer therapy and prevention. (Clin Cancer Res 2009;15(17):5308–16)
Clinical Cancer Research - Tập 15 Số 17 - Trang 5308-5316 - 2009
Boron Neutron Capture Therapy of Cancer: Current Status and Future Prospects Abstract
Background: Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when boron-10 is irradiated with low-energy thermal neutrons to yield high linear energy transfer α particles and recoiling lithium-7 nuclei. Clinical interest in BNCT has focused primarily on the treatment of high-grade gliomas and either cutaneous primaries or cerebral metastases of melanoma, most recently, head and neck and liver cancer. Neutron sources for BNCT currently are limited to nuclear reactors and these are available in the United States, Japan, several European countries, and Argentina. Accelerators also can be used to produce epithermal neutrons and these are being developed in several countries, but none are currently being used for BNCT.
Boron Delivery Agents: Two boron drugs have been used clinically, sodium borocaptate (Na2B12H11SH) and a dihydroxyboryl derivative of phenylalanine called boronophenylalanine. The major challenge in the development of boron delivery agents has been the requirement for selective tumor targeting to achieve boron concentrations (∼20 μg/g tumor) sufficient to deliver therapeutic doses of radiation to the tumor with minimal normal tissue toxicity. Over the past 20 years, other classes of boron-containing compounds have been designed and synthesized that include boron-containing amino acids, biochemical precursors of nucleic acids, DNA-binding molecules, and porphyrin derivatives. High molecular weight delivery agents include monoclonal antibodies and their fragments, which can recognize a tumor-associated epitope, such as epidermal growth factor, and liposomes. However, it is unlikely that any single agent will target all or even most of the tumor cells, and most likely, combinations of agents will be required and their delivery will have to be optimized.
Clinical Trials: Current or recently completed clinical trials have been carried out in Japan, Europe, and the United States. The vast majority of patients have had high-grade gliomas. Treatment has consisted first of “debulking” surgery to remove as much of the tumor as possible, followed by BNCT at varying times after surgery. Sodium borocaptate and boronophenylalanine administered i.v. have been used as the boron delivery agents. The best survival data from these studies are at least comparable with those obtained by current standard therapy for glioblastoma multiforme, and the safety of the procedure has been established.
Conclusions: Critical issues that must be addressed include the need for more selective and effective boron delivery agents, the development of methods to provide semiquantitative estimates of tumor boron content before treatment, improvements in clinical implementation of BNCT, and a need for randomized clinical trials with an unequivocal demonstration of therapeutic efficacy. If these issues are adequately addressed, then BNCT could move forward as a treatment modality.
Clinical Cancer Research - Tập 11 Số 11 - Trang 3987-4002 - 2005
Identification of Necrosis-Associated Genes in Glioblastoma by cDNA Microarray Analysis Abstract
Purpose: In the field of cancer research, there has been a paucity of interest in necrosis, whereas studies focusing on apoptosis abound. In neuro-oncology, this is particularly surprising because of the importance of necrosis as a hallmark of glioblastoma (GBM), the most malignant and most common primary brain tumor, and the fact that the degree of necrosis has been shown to be inversely related to patient survival. It is therefore of considerable interest and importance to identify genes and gene products related to necrosis formation.
Experimental Design: We used a nylon cDNA microarray to analyze mRNA expression of 588 universal cellular genes in 15 surgically resected human GBM samples with varying degrees of necrosis. Gene expression was correlated with the degree of necrosis using rank correlation coefficients. The expression of identified genes was compared with their expression in tissue samples from 5 anaplastic astrocytomas (AAs). Immunostaining was used to determine whether genes showing the most positive correlation with necrosis were increasingly expressed in tumor tissues, as grade of necrosis increased.
Results: The hybridization results indicated that 26 genes showed significant correlation with the amount of necrosis. All 26 genes had functions associated with either Ras, Akt, tumor necrosis factor α, nuclear factor κB, apoptosis, procoagulation, or hypoxia. Nine genes were positively correlated with necrosis grade, and 17 genes were negatively correlated with necrosis grade. There were significant differences in the median expression levels of 3 of the 26 genes between grade III necrosis GBM and anaplastic astrocytoma (AA) samples; all but 1 of the genes had elevated expression when comparing necrosis grade III with AA samples. Two factors, the ephrin type A receptor 1 and the prostaglandin E2 receptor EP4 subtype, not previously considered in this context, were highlighted because of their particularly high (positive) correlation coefficients; immunostaining showed the products of these two genes to be localized in perinecrotic and necrotic regions and to be overexpressed in grade III GBMs, but not AAs. These two molecules also showed significant correlation with survival of GBM patients (P = 0.0034) in a combined model.
Conclusions: The application of cDNA expression microarray analysis has identified specific genes and patterns of gene expression that may help elucidate the molecular basis of necrogenesis in GBM. Additional studies will be required to further investigate and confirm these findings.
Clinical Cancer Research - Tập 10 Số 1 - Trang 212-221 - 2004
Intrinsic Breast Tumor Subtypes, Race, and Long-Term Survival in the Carolina Breast Cancer Study Abstract
Purpose: Previous research identified differences in breast cancer–specific mortality across 4 intrinsic tumor subtypes: luminal A, luminal B, basal-like, and human epidermal growth factor receptor 2 positive/estrogen receptor negative (HER2+/ER−).
Experimental Design: We used immunohistochemical markers to subtype 1,149 invasive breast cancer patients (518 African American, 631 white) in the Carolina Breast Cancer Study, a population-based study of women diagnosed with breast cancer. Vital status was determined through 2006 using the National Death Index, with median follow-up of 9 years.
Results: Cancer subtypes luminal A, luminal B, basal-like, and HER2+/ER− were distributed as 64%, 11%, 11%, and 5% for whites, and 48%, 8%, 22%, and 7% for African Americans, respectively. Breast cancer mortality was higher for participants with HER2+/ER− and basal-like breast cancer compared with luminal A and B. African Americans had higher breast cancer–specific mortality than whites, but the effect of race was statistically significant only among women with luminal A breast cancer. However, when compared with the luminal A subtype within racial categories, mortality for participants with basal-like breast cancer was higher among whites (HR = 2.0, 95% CI: 1.2–3.4) than African Americans (HR = 1.5, 95% CI: 1.0–2.4), with the strongest effect seen in postmenopausal white women (HR = 3.9, 95% CI: 1.5–10.0).
Conclusions: Our results confirm the association of basal-like breast cancer with poor prognosis and suggest that basal-like breast cancer is not an inherently more aggressive disease in African American women compared with whites. Additional analyses are needed in populations with known treatment profiles to understand the role of tumor subtypes and race in breast cancer mortality, and in particular our finding that among women with luminal A breast cancer, African Americans have higher mortality than whites. Clin Cancer Res; 16(24); 6100–10. ©2010 AACR.
Clinical Cancer Research - Tập 16 Số 24 - Trang 6100-6110 - 2010
Curcumin Suppresses the Paclitaxel-Induced Nuclear Factor-κB Pathway in Breast Cancer Cells and Inhibits Lung Metastasis of Human Breast Cancer in Nude Mice Abstract Currently, there is no effective therapy for metastatic breast cancer after surgery, radiation, and chemotherapy have been used against the primary tumor. Because curcumin suppresses nuclear factor-κB (NF-κB) activation and most chemotherapeutic agents activate NF-κB that mediates cell survival, proliferation, invasion, and metastasis, we hypothesized that curcumin would potentiate the effect of chemotherapy in advanced breast cancer and inhibit lung metastasis. We tested this hypothesis using paclitaxel (Taxol)-resistant breast cancer cells and a human breast cancer xenograft model. As examined by electrophoretic mobility gel shift assay, paclitaxel activated NF-κB in breast cancer cells and curcumin inhibited it; this inhibition was mediated through inhibition of IκBα kinase activation and IκBα phosphorylation and degradation. Curcumin also suppressed the paclitaxel-induced expression of antiapoptotic (XIAP, IAP-1, IAP-2, Bcl-2, and Bcl-xL), proliferative (cyclooxygenase 2, c-Myc, and cyclin D1), and metastatic proteins (vascular endothelial growth factor, matrix metalloproteinase-9, and intercellular adhesion molecule-1). It also enhanced apoptosis. In a human breast cancer xenograft model, dietary administration of curcumin significantly decreased the incidence of breast cancer metastasis to the lung and suppressed the expression of NF-κB, cyclooxygenase 2, and matrix metalloproteinase-9. Overall, our results indicate that curcumin, which is a pharmacologically safe compound, has a therapeutic potential in preventing breast cancer metastasis possibly through suppression of NF-κB and NF-κB–regulated gene products.
Clinical Cancer Research - Tập 11 Số 20 - Trang 7490-7498 - 2005
Mutations and Deletions of the <i>CBP</i> Gene in Human Lung Cancer Abstract
Purpose: Microarray-based comparative genomic hybridization analysis led us to detect a homozygous deletion at the cyclic AMP response element binding protein-binding protein (CBP) locus in a lung cancer cell line. Oncogenic roles of CBP had been suggested by functional and genetic studies; thus, involvement of CBP gene alterations in lung carcinogenesis was investigated by undertaking comprehensive analysis of genetic CBP alterations in human lung cancer.
Experimental Design: Fifty-nine cell lines and 95 surgical specimens of lung cancer were analyzed for mutations, homozygous and hemizygous deletions, and expression of the CBP gene.
Results: Homozygous CBP deletions, including two intragenic deletions, were detected in three (5.1%) lung cancer cell lines. CBP mutations, including missense, nonsense, and frame-shift mutations, were detected in six (10.2 %) cell lines and five (5.3%) surgical specimens of lung cancer. The wild-type CBP allele was retained in 9 of 11 cases with CBP mutations, and both the wild-type and mutant alleles were expressed in all the six cases with heterozygous CBP mutations examined. Three mutations with amino acid substitutions in the histone acetyltransferase domain caused significant reduction in transcription activation activity of CBP protein in vivo.
Conclusions: A fraction of lung cancers carried mutations and/or deletions of the CBP gene, suggesting that genetic CBP alterations are involved in the genesis and/or progression of a subset of lung cancers.
Clinical Cancer Research - Tập 11 Số 2 - Trang 512-519 - 2005
REM (Risk of Endometrial Malignancy): A Proposal for a New Scoring System to Evaluate Risk of Endometrial Malignancy Abstract
Purpose: It is often difficult to distinguish a benign endometrial disease from a malignancy and tools to help the physician are needed to triage patients into high and low risk of endometrial cancer. The purpose of this study was to obtain a predictive model to assess the risk of endometrial malignancy (REM) in women with ultrasound endometrial abnormalities.
Experimental Design: Women, between ages 45 to 80 years, diagnosed through ultrasound with endometrial abnormalities and scheduled to have surgery were enrolled on a prospective study at the Department of Gynaecologic Oncology of Campus Bio-Medico, University of Rome. Preoperative clinical, ultrasound and laboratory characteristics were taken into account. Logistic regression algorithm was used to categorize patients into low- and high-risk groups for endometrial cancer.
Results: A total of 675 patients were considered for the analysis: 88 with endometrial cancer and 587 with benign endometrial disease. We divided the patients into two groups: training set (TS) and verification set (VS). Preoperative age, symptom, HE4 levels, and ultrasound endometrial thickness were found statistically significant, and were included into a multivariate logistic regression model to determine the probability to have endometrial cancer. In the TS, REM reported 93.3% sensitivity and 97.1% specificity [positive predictive value (PPV), 0.83; negative predictive value (NPV), 0.98; AUC, 0.957; 95% confidence interval (CI), 0.908–0.984]. In the VS, REM reported 89.3% sensitivity and 95.4% specificity (PPV, 0.73; NPV, 0.98; AUC, 0.919; 95% CI, 0.829–0.970).
Conclusions: Our data support the use of REM to triage patients into low- and high-risk groups for endometrial cancer, even if an external validation of the model is needed. Clin Cancer Res; 19(20); 5733–9. ©2013 AACR.
Clinical Cancer Research - Tập 19 Số 20 - Trang 5733-5739 - 2013
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