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  • American Association for Cancer Research (AACR)  (13)
  • Medicine  (13)
  • 1
    Online Resource
    Online Resource
    A Meta-analysis of Individual Participant Data Reveals an Association between Circulating Levels of IGF-I and Prostate Cancer Risk
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 8 ( 2016-04-15), p. 2288-2300
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 8 ( 2016-04-15), p. 2288-2300
    Abstract: The role of insulin-like growth factors (IGF) in prostate cancer development is not fully understood. To investigate the association between circulating concentrations of IGFs (IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3) and prostate cancer risk, we pooled individual participant data from 17 prospective and two cross-sectional studies, including up to 10,554 prostate cancer cases and 13,618 control participants. Conditional logistic regression was used to estimate the ORs for prostate cancer based on the study-specific fifth of each analyte. Overall, IGF-I, IGF-II, IGFBP-2, and IGFBP-3 concentrations were positively associated with prostate cancer risk (Ptrend all ≤ 0.005), and IGFBP-1 was inversely associated weakly with risk (Ptrend = 0.05). However, heterogeneity between the prospective and cross-sectional studies was evident (Pheterogeneity = 0.03), unless the analyses were restricted to prospective studies (with the exception of IGF-II, Pheterogeneity = 0.02). For prospective studies, the OR for men in the highest versus the lowest fifth of each analyte was 1.29 (95% confidence interval, 1.16–1.43) for IGF-I, 0.81 (0.68–0.96) for IGFBP-1, and 1.25 (1.12–1.40) for IGFBP-3. These associations did not differ significantly by time-to-diagnosis or tumor stage or grade. After mutual adjustment for each of the other analytes, only IGF-I remained associated with risk. Our collaborative study represents the largest pooled analysis of the relationship between prostate cancer risk and circulating concentrations of IGF-I, providing strong evidence that IGF-I is highly likely to be involved in prostate cancer development. Cancer Res; 76(8); 2288–300. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-15-1551
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 2
    Online Resource
    Online Resource
    Fc-γ Receptor Polymorphisms, Cetuximab Therapy, and Survival in the NCIC CTG CO.17 Trial of Colorectal Cancer
    American Association for Cancer Research (AACR) ; 2016
    In:  Clinical Cancer Research Vol. 22, No. 10 ( 2016-05-15), p. 2435-2444
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 22, No. 10 ( 2016-05-15), p. 2435-2444
    Abstract: Purpose: Two germline Fc-γ receptor (FCGR) polymorphisms, rs1801274 [FCGR2A;His(H)131Arg(R)] and rs396991 [FCGR3A;Phe(F)158Val(V)] produce altered proteins through amino acid substitutions; both are reported to be associated with cetuximab-related outcomes. We performed a validation of these polymorphisms in NCIC CTG CO.17, a randomized trial of cetuximab monotherapy in refractory, metastatic colorectal cancer expressing EGFR. Experimental Design: DNA extracted from formalin-fixed paraffin-embedded tissue was genotyped. In addition to log-rank tests, Cox proportional hazard models assessed their relationships with overall (OS) and progression-free survival (PFS), adjusting for clinically important prognostic factors, along with a polymorphism–treatment arm interaction term. Results: Somatic KRAS status was wild-type for exon 2 in 153 (52%) of 293 patients, from whom tumor DNA was available. For FCGR2A H/H, a genotype–treatment interaction for KRAS wild-type patients was observed for OS (P = 0.03). In KRAS wild-type patients carrying FCGR2A H/H, cetuximab (vs. no cetuximab) improved survival substantially, with adjusted HRs (aHR) of 0.36 (OS) and 0.19 (PFS) and absolute benefits of 5.5 months (OS; P = 0.003) and 3.7 months (PFS; P = 0.02). In contrast, patients carrying FCGR2A R alleles (H/R or R/R) had aHRs of only 0.78 (OS; 2.8-month benefit) and 0.53 (PFS; 1.6-month benefit). No relationships were found for rs396991 (FCGR3A). Conclusions: In the CO.17 trial, cetuximab worked best for patients with KRAS wild-type colorectal cancers carrying FCGR2A H/H genotypes. Significantly lower benefits were observed in patients carrying germline FCGR2A R alleles. Clin Cancer Res; 22(10); 2435–44. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-15-0414
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 3
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    Abstract LB-015: XIAP induction by the MAPK-eIF4G1 pathway drives NFκB activation in inflammatory breast cancer growth and therapeutic resistance
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. LB-015-LB-015
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. LB-015-LB-015
    Abstract: Inflammatory breast cancer (IBC) is the most lethal, distinct form of breast cancer, however, the basis for its aggressiveness and rapid acquisition of drug resistance is not fully understood. Using immunohistochemical analysis, we identified a strong correlation between high grade, high stage, and triple-negative status and elevated expression of the X-linked inhibitor of apoptosis protein (XIAP) in IBC. Molecular profiling of multiple IBC cell lines revealed that modulating XIAP expression can significantly alter the expression pattern of a 79-gene, characteristic IBC profile that was previously obtained from clinical samples. Using specific antagonists and RNAi, we determined that the mitogen activated protein kinase (MAPK) pathway and its interaction with the protein synthesis initiation factor eIF4G1, both of which are elevated in IBC, cooperate to drive XIAP induction and resistance to therapeutic apoptosis. Further, we found that XIAP expression directly correlates with activation of the transcription factor NFκB, a molecular component defining IBC. Mutational analysis revealed that the BIR1 domain of XIAP is essential for subsequent TAB1:IKKβ-dependent NFκB activation. After determining this association between XIAP and TAB1, we tested a peptide-mediated strategy used to block the BIR1:TAB1 interaction antagonized NFκB activity which led to decreased anchorage independent growth and reversed resistance to an EGFR tyrosine kinase inhibitor. Most significantly, orthotopic implantation of XIAP silenced IBC cells revealed the necessity of expression for IBC tumor growth, while overexpression of XIAP enhanced tumor growth. Our findings establish that XIAP augments the malignant properties in IBC by enhancing NFκB function, identify a druggable pathway with multiple targets, and provide feasibility for the development of novel therapeutics targeting the BIR1 domain of XIAP in IBC. Grant Support: Supported by American Cancer Society, the Duke Cancer Institute as part of the P30 Cancer Center Support Grant NIH CA014236, the Duke Department of Surgery, and DOD grant W81XWH-13-1-0047. Citation Format: Myron K. Evans, Joseph Geradts, Courtney Edwards, Arianna Price, Arjun J. Arora, Amy J. Aldrich, Adrian Ramirez, Timothy J. Robinson, Peter B. Vermeulen, Steven van Laere, Gayathri R. Devi. XIAP induction by the MAPK-eIF4G1 pathway drives NFκB activation in inflammatory breast cancer growth and therapeutic resistance. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-015.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-LB-015
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 4
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    PIK3CA, BRAF , and PTEN Status and Benefit from Cetuximab in the Treatment of Advanced Colorectal Cancer—Results from NCIC CTG/AGITG CO.17
    American Association for Cancer Research (AACR) ; 2014
    In:  Clinical Cancer Research Vol. 20, No. 3 ( 2014-02-01), p. 744-753
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 20, No. 3 ( 2014-02-01), p. 744-753
    Abstract: Purpose: Cetuximab improves survival in patients with K-ras wild-type advanced colorectal cancer. We examined the predictive and prognostic significance of additional biomarkers in this setting, in particular BRAF, PIK3CA, and PTEN. Experimental Design: Available colorectal tumor samples were analyzed from the CO.17 study. BRAF mutations were identified in tumor-derived DNA by direct sequencing and PIK3CA mutations were identified using a high-resolution melting screen with confirmation by sequencing. PTEN expression by immunohistochemistry (IHC) was performed on tissue microarrays. For each biomarker, prognostic and predictive effects were examined using a Cox model with tests for treatment–biomarker interaction. Results: A total of 572 patients with pretreated colorectal cancer were randomly assigned to receive cetuximab or best supportive care (BSC). Of 401 patients assessed for BRAF status, 13 (3.2%) had mutations. Of 407 patients assessed for PIK3CA status, 61 (15%) had mutations. Of 205 patients assessed for PTEN, 148 (72%) were negative for IHC expression. None of BRAF, PIK3CA, or PTEN was prognostic for overall or progression-free survival in the BSC arm. None was predictive of benefit from cetuximab, either in the whole study population or the K-ras wild-type subset. In the K-ras wild-type subgroup, the overall survival adjusted HR according to BRAF mutation status was 1.39 (interaction P = 0.69), PIK3CA mutation status HR = 0.79 (interaction P = 0.63), and PTEN expression HR = 0.75 (interaction P = 0.61). Conclusions: In chemotherapy-refractory colorectal cancer, neither PIK3CA mutation status nor PTEN expression were prognostic, nor were they predictive of benefit from cetuximab. Evaluation of predictive significance of BRAF mutations requires a larger sample size. Clin Cancer Res; 20(3); 744–53. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-13-0606
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 5
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    Abstract P1-10-12: Menstrual cycling critically affects the Oncotype DX 21-gene signature: Implications for predictive biomarker assays in premenopausal women
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 4_Supplement ( 2020-02-15), p. P1-10-12-P1-10-12
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 4_Supplement ( 2020-02-15), p. P1-10-12-P1-10-12
    Abstract: Introduction: The 21-gene Oncotype DX Recurrence Score is predictive of adjuvant chemotherapy benefit for women with early stage, hormone receptor (HR)-positive, HER2-negative breast cancer. In premenopausal women, fluctuations in estrogen and progesterone during the menstrual cycle can impact gene expression in these hormone-responsive cancers. However, the extent to which hormonal fluctuations affect Oncotype DX Recurrence Scores remains unclear. Aim: To determine the extent to which ovarian cycling affects the Oncotype DX 21-gene signature using paired premenopausal breast cancer samples and mouse models. Methods: To investigate menstrual variation in the Oncotype DX 21-gene signature within the same tumour, paired formalin-fixed paraffin-embedded, HR-positive invasive breast cancer samples were collected on different days of the menstrual cycle from women & lt;50 years old (n=18), and compared to women & gt;50 years old (n=11). Samples were collected an average of 18 days apart and were neoadjuvant therapy naive. To determine the effect of progesterone on gene expression, HR-positive T47D breast cancer cells were xenografted into the mammary fat pad of BALB/c nude mice, treated with exogenous estrogen±progesterone (n=12, 11 respectively). Additionally, HR-positive mammary tumours were collected from naturally cycling Mmtv-Pymt mice at the estrus or diestrus phase of the ovarian cycle (n=25, 28 respectively). The 21-gene Oncotype DX signature was assessed through quantitative RT-PCR and an experimental recurrence score (RS) was calculated using the Oncotype DX Recurrence Score algorithm. Results: Increased discordance in RS was observed between paired samples collected from younger women (3.2±2.5; mean±stdev), compared to older women (2.0±1.7; p=0.04). In young women, discordance was primarily driven by variable expression of proliferative genes, compared to older women, where discordances were a result of variable expression of invasive genes. Variable concentrations of progesterone at the time of tissue collection may influence proliferative gene expression and contribute to discordant RS. In support of this, in HR-positive xenograft tumours, expression of proliferative genes Ki67 (p=0.03) and STK15 (p=0.04), and Ki67 protein expression (p=0.02), were reduced following progesterone treatment. Furthermore, in naturally cycling Mmtv-Pymt mice, mammary tumours collected at diestrus, analogous to the luteal phase of the menstrual cycle in humans, show significant differences in expression of 6 Oncotype DX signature genes (Ki67, Ccnb1, Esr1, Her2, Grb7, Bag1; p≤0.05) and a significant increase in RS (21.1±2.4; mean±SEM) compared to tumours dissected at estrus (15.5±1.9; p=0.03). Clustering analysis revealed a subgroup of Mmtv-Pymt mammary tumours collected at diestrus characterised by increased expression of proliferative (p & lt;0.001) and invasive (p=0.01) genes and a significant increase in RS (p=0.01). These tumours also exhibited higher expression of estrogen regulated genes (p=0.005) suggesting increased sensitivity to hormonal fluctuations during the ovarian cycle, and possibly greater variability in RS. Conclusion: Our results suggest that menstrual cycling affects the expression of genes included in the Oncotype DX 21-gene signature and influences experimental recurrence scores. Oncotype DX may be less effective for guiding chemotherapy treatment decisions for cycling premenopausal women compared to older postmenopausal women. Citation Format: Sarah M Bernhardt, Pallave Dasari, Danielle J Glynn, Lucy Woolford, Wendy Raymond, Lachlan M Moldenhauer, David Walsh, Amanda R Townsend, Timothy J Price, Wendy V Ingman. Menstrual cycling critically affects the Oncotype DX 21-gene signature: Implications for predictive biomarker assays in premenopausal women [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-10-12.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS19-P1-10-12
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 6
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    Dual Antiangiogenesis Agents Bevacizumab Plus Trebananib, without Chemotherapy, in First-line Treatment of Metastatic Colorectal Cancer: Results of a Phase II Study
    American Association for Cancer Research (AACR) ; 2021
    In:  Clinical Cancer Research Vol. 27, No. 8 ( 2021-04-15), p. 2159-2167
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 8 ( 2021-04-15), p. 2159-2167
    Abstract: To assess the efficacy and safety of dual antiangiogenesis agents, bevacizumab plus trebananib, without chemotherapy, in first-line treatment of metastatic colorectal cancer (mCRC). Patients and Methods: This open-label phase II study enrolled patients with unresectable mCRC with no prior systemic treatment. All patients received bevacizumab 7.5 mg/kg 3-weekly and trebananib 15 mg/kg weekly. The primary endpoint was disease control [stable disease, partial response (PR), or complete response (CR)] at 6 months (DC6m). Secondary endpoints included toxicity, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Exploratory biomarkers in plasma angiogenesis–related proteins, tumor gene expression, and plasma antibodies to tumor antigens were examined. Results: Forty-five patients were enrolled from four Australian sites. DC6m was 63% [95% confidence interval (CI), 47–77]. ORR was 17% (95% CI, 7–32), comprising of seven PRs. Median duration of response was 20 months (range, 10–48 months). Median PFS was 8.4 months and median OS 31.4 months. Grade 1–2 peripheral edema and joint-related symptoms were common. Overall incidence of grade 3–4 adverse events (AE) of any type was 33% (n = 15). Expected AEs of bevacizumab treatment did not appear to be increased by the addition of trebananib. Conclusions: In a first-line mCRC population, the dual antiangiogenic combination, bevacizumab plus trebananib, without chemotherapy, was efficacious with durable responses. The toxicity profile of the combination was manageable and did not exceed that expected with bevacizumab +/− chemotherapy. Exploratory biomarker results raise the hypothesis that the antiangiogenic combination may enable the antitumor immune response in immunotolerant colorectal cancer.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-20-2714
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 7
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    Analysis of KRAS / NRAS Mutations in a Phase III Study of Panitumumab with FOLFIRI Compared with FOLFIRI Alone as Second-line Treatment for Metastatic Colorectal Cancer
    American Association for Cancer Research (AACR) ; 2015
    In:  Clinical Cancer Research Vol. 21, No. 24 ( 2015-12-15), p. 5469-5479
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 21, No. 24 ( 2015-12-15), p. 5469-5479
    Abstract: Purpose: We evaluated the influence of RAS mutation status on the treatment effect of panitumumab in a prospective–retrospective analysis of a randomized, multicenter phase III study of panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) versus FOLFIRI alone as second-line therapy in patients with metastatic colorectal cancer (mCRC; ClinicalTrials.gov, NCT0039183). Experimental Design: Outcomes were from the study's primary analysis. RAS mutations beyond KRAS exon 2 (KRAS exons 3, 4; NRAS exons 2, 3, 4; BRAF exon 15) were detected by bidirectional Sanger sequencing in wild-type KRAS exon 2 tumor specimens. Progression-free survival (PFS) and overall survival (OS) were coprimary endpoints. Results: The RAS ascertainment rate was 85%; 18% of wild-type KRAS exon 2 tumors harbored other RAS mutations. For PFS and OS, the hazard ratio (HR) for panitumumab plus FOLFIRI versus FOLFIRI alone more strongly favored panitumumab in the wild-type RAS population than in the wild-type KRAS exon 2 population [PFS HR, 0.70 (95% confidence interval [CI], 0.54–0.91); P = 0.007 vs. 0.73 (95% CI, 0.59–0.90); P = 0.004; OS HR, 0.81 (95% CI, 0.63–1.03); P = 0.08 vs. 0.85 (95% CI, 0.70–1.04); P = 0.12] . Patients with RAS mutations were unlikely to benefit from panitumumab. Among RAS wild-type patients, the objective response rate was 41% in the panitumumab–FOLFIRI group versus 10% in the FOLFIRI group. Conclusions: Patients with RAS mutations were unlikely to benefit from panitumumab–FOLFIRI and the benefit–risk of panitumumab–FOLFIRI was improved in the wild-type RAS population compared with the wild-type KRAS exon 2 population. These findings support RAS testing for patients with mCRC. Clin Cancer Res; 21(24); 5469–79. ©2015 AACR. See related commentary by Salazar and Ciardiello, p. 5415
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-15-0526
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 8
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    Expanded Low Allele Frequency RAS and BRAF V600E Testing in Metastatic Colorectal Cancer as Predictive Biomarkers for Cetuximab in the Randomized CO.17 Trial
    American Association for Cancer Research (AACR) ; 2021
    In:  Clinical Cancer Research Vol. 27, No. 1 ( 2021-01-01), p. 52-59
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 1 ( 2021-01-01), p. 52-59
    Abstract: Expanded RAS/BRAF mutations have not been assessed as predictive for single-agent cetuximab in metastatic colorectal cancer (mCRC), and low mutant allele frequency (MAF) mutations are of unclear significance. We aimed to establish cetuximab efficacy in optimally selected patients using highly sensitive beads, emulsion, amplification, and magnetics (BEAMing) analysis, capable of detecting alterations below standard clinical assays. Patients and Methods: CO.17 trial compared cetuximab versus best supportive care (BSC) in RAS/BRAF-unselected mCRC. We performed RAS/BRAF analysis on microdissected tissue of 242 patients in CO.17 trial using BEAMing for KRAS/NRAS (codons 12/13/59/61/117/146) and BRAF V600E. Patients without BEAMing but with previous Sanger sequencing–detected mutations were included. Results: KRAS, NRAS, and BRAF mutations were present in 53%, 4%, and 3% of tumors, respectively. Cetuximab improved overall survival [OS; HR, 0.51; 95% confidence interval (CI), 0.32–0.81; P = 0.004] and progression-free survival (PFS; HR, 0.25; 95% CI, 0.15–0.41; P & lt; 0.0001) compared with BSC in RAS/BRAF wild-type patients. Cetuximab did not improve OS/PFS for KRAS-, NRAS-, or BRAF-mutated tumors, and tests of interaction confirmed expanded KRAS (P = 0.0002) and NRAS (P = 0.006) as predictive, while BRAF mutations were not (P = 0.089). BEAMing identified 14% more tumors as RAS mutant than Sanger sequencing, and cetuximab lacked activity in these patients. Mutations at MAF & lt; 5% were noted in 6 of 242 patients (2%). One patient with a KRAS A59T mutation (MAF = 2%) responded to cetuximab. More NRAS than KRAS mutations were low MAF (OR, 20.50; 95% CI, 3.88—96.85; P = 0.0038). Conclusions: We establish single-agent cetuximab efficacy in optimally selected patients and show that subclonal RAS/BRAF alterations are uncommon and remain of indeterminate significance.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-20-2710
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 9
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    Abstract 2084: Conformational activation and allosteric inhibition of SHP2 in RTK-driven cancers
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 2084-2084
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 2084-2084
    Abstract: The non-receptor protein tyrosine phosphatase (PTP) SHP2 is an important component of RTK signaling in response to growth factor stimulus and sits just upstream of the RAS-MAPK signaling cascade. The first oncogenic phosphatase to be identified, SHP2 is dysregulated in multiple human diseases including the developmental disorders Noonan and Leopard syndromes, as well as leukemia, lung cancer and neuroblastoma where aberrant activity of SHP2 leads to uncontrolled MAPK signaling. Cancer-associated activating mutations in SHP2 impart an “auto-on” state of the enzyme, boosting basal activity by shifting the equilibrium away from the auto-inhibited state. Reduction of SHP2 activity through genetic knockdown suppresses tumor growth, validating SHP2 as a target for cancer therapy. SHP099, a recently reported potent and selective allosteric inhibitor of SHP2, stabilizes the auto-inhibited form of SHP2 through interactions with the N-terminal SH2 and C-terminal PTP domains of the protein. SHP099 suppresses MAPK signaling in RTK amplified cancers resulting in suppressed proliferation in vitro and inhibition of tumor growth in mouse tumor xenograft models. Together, these data demonstrate the therapeutic potential of SHP2 inhibition in the treatment of cancer and other RAS/MAPK-linked diseases. Citation Format: Michael G. Acker, Ying-Nan P. Chen, Matthew J. LaMarche, Ho Man Chan, Peter Fekkes, Jorge Garcia-Fortanet, Jonathan R. LaRochelle, Brandon Antonakos, Christine Hiu-Tung Chen, Zhuoliang Chen, Vesselina G. Cooke, Jason R. Dobson, Zhan Deng, Fei Feng, Brant Firestone, Michelle Fodor, Cary Fridrich, Hui Gao, Huai-Xiang Hao, Jaison Jacob, Samuel Ho, Kathy Hsiao, Zhao B. Kang, Rajesh Karki, Mitsunori Kato, Jay Larrow, Laura R. La Bonte, Gang Liu, Shumei Liu, Dyuti Majumdar, Matthew J. Meyer, Mark Palermo, Minying Pu, Edmund Price, Subarna Shakya, Michael D. Shultz, Kavitha Venkatesan, Ping Wang, Markus Warmuth, Sarah Williams, Guizhi Yang, Jing Yuan, Ji-Hu Zhang, Ping Zhu, Stephen C. Blacklow, Timothy Ramsey, Nicholas J. Keen, William R. Sellers, Travis Stams, Pascal D. Fortin. Conformational activation and allosteric inhibition of SHP2 in RTK-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2084. doi:10.1158/1538-7445.AM2017-2084
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-2084
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 10
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    Phase I Clinical Trial of Marizomib (NPI-0052) in Patients with Advanced Malignancies Including Multiple Myeloma: Study NPI-0052-102 Final Results
    American Association for Cancer Research (AACR) ; 2016
    In:  Clinical Cancer Research Vol. 22, No. 18 ( 2016-09-15), p. 4559-4566
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 22, No. 18 ( 2016-09-15), p. 4559-4566
    Abstract: Purpose: Marizomib (NPI-0052) is an irreversible proteasome inhibitor, derived from a marine actinomycete, with activity and specificity that is distinct from other proteasome inhibitors. Experimental Design: Phase I study (NPI-0052-102) evaluated the MTD, pharmacokinetics, and pharmacodynamics of marizomib intravenously on two dosing schedules. Results: Forty-two patients with advanced malignancies received Schedule A (0.1–0.9 mg/m2 over 1–10 minutes on days 1, 8, 15 in 4-week cycles); 44 patients with relapsed and/or refractory multiple myeloma (RRMM) and other hematologic malignancies received Schedule B (0.075–0.6 mg/m2 over 1 minute to 2 hours on days 1, 4, 8, 11, in 3-week cycles). The Schedule A recommended phase II dose was 0.7 mg/m2 over 10 minutes; Schedule B was 0.5 mg/m2 over 2 hours. The most common ( & gt;25% of patients) related adverse events were fatigue, nausea, diarrhea, and infusion site pain (Schedule A); and fatigue (Schedule B). Overall response rate of 11% was seen in 27 efficacy-evaluable RRMM Schedule B patients (1 very good partial response, 3 partial responses, 4 minimal responses, and 12 stable disease). One Schedule A patient with transformed marginal zone lymphoma had complete response. Marizomib has a short half-life ( & lt;30 minutes), with high volume of distribution (∼15–416 L) and clearance (∼0.9–22 L/minutes). Conclusions: Marizomib does not exhibit the severe peripheral neuropathy or hematologic toxicity observed with other proteasome inhibitors. Marizomib was generally well tolerated with low-dose dexamethasone, demonstrated activity in heavily pretreated RRMM patients, and warrants further evaluation. Clin Cancer Res; 22(18); 4559–66. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-15-2616
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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