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  • American Association for Cancer Research (AACR)  (15)
  • 1
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    Abstract 3989: DSTYK inhibition sensitizes lung cancer cells to immunotherapy by collapsing cytoprotective autophagy and destroying mitochondrial wellness
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 3989-3989
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 3989-3989
    Abstract: Lung cancer is the leading cause of cancer-related death worldwide. The incidence and mortality associated to lung cancer is a major challenge of the Public Health Policy in advanced societies. Although the great effort has been done in NSCLC therapeutic strategies, there are still many NSCLC patients who cannot benefit either from molecular targeted or immune related therapies. Here, we identified DSTYK, a dual serine/threonine and tyrosine non-receptor protein kinase, as a novel candidate with a crucial role in NSCLC. According to data obtained from the TCGA, genomic alterations (mainly copy number alterations and mutations) of DSTYK are present in 40% of lung cancer patients, from which 4.7% LUAD and 3.4% LUSC correspond to copy number (CN) amplification (more than 3 genomic copies). Besides, DSTYK amplification is found to be a poor prognostic factor in lung cancer patients. Accordingly, high expression of DSTYK predicted both, a lower overall survival (OS) and poorer progression free survival (PFS). We next depleted DSTYK expression in both murine and human NSCLC cell lines. DSTYK abrogation prevented cytoprotective autophagy via mTOR regulation, accumulating LC3 and p-P62. In addition, DSTYK inhibition impaired lysosomal biogenesis and maturation, which contributed to dysfunctional autophagy. Furthermore, DSTYK depleted cells showed increased ROS levels caused by depolarized and damaged mitochondria. All together, these results demonstrate that knockdown of DSTYK promoted a dramatic reduction of mitophagy.As it has been shown that autophagy in cancer cells can limit antitumor immunity, we evaluated the role of immune-mediated tumor cell killing in an altered DSTYK context. We found that inhibition of DSTYK sensitized lung cancer cells to T cell–mediated cytotoxicity, via TNF-ɑ. More importantly, immunocompetent mouse models transplanted with DSTYK-inhibited tumors were sensitized to ɑnti-PD1 treatment.Finally, in a cohort of NSCLC patients that underwent immunotherapy (n=40), DSTYK amplification predicted resistance to the treatment, showing poorer PFS rates. The time to progression for DSTYK amplified patients was on average, around 50% faster than that for non-DSTYK altered patients, diminishing from 232 to 114 months.In conclusion, our results support that DSTYK is a new target and that its inhibition could be the base of new therapies, which could benefit a subgroup of NSCLC patients showing genetic amplification, both at early (adjuvant) or late (single or combined treatment) stages of the disease. Citation Format: Karmele Valencia, Mirari Echepare, Andrea Pasquier, Alvaro Teijeira, Cristina Bertolo, Cristina Sainz, Graziella Bosco, Roman K. Thomas, Jackeline Agorreta, Jose Maria Lopez-Picazo, Joan Frigola, Ramon Amat, Alfonso Calvo, Enriqueta Felip, Luis M. Montuenga. DSTYK inhibition sensitizes lung cancer cells to immunotherapy by collapsing cytoprotective autophagy and destroying mitochondrial wellness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3989.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-3989
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 2
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    BCR-ABL Induces the Expression of Skp2 through the PI3K Pathway to Promote p27Kip1 Degradation and Proliferation of Chronic Myelogenous Leukemia Cells
    American Association for Cancer Research (AACR) ; 2005
    In:  Cancer Research Vol. 65, No. 8 ( 2005-04-15), p. 3264-3272
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 65, No. 8 ( 2005-04-15), p. 3264-3272
    Abstract: Chronic myelogenous leukemia (CML) is characterized by the expression of the BCR-ABL tyrosine kinase, which results in increased cell proliferation and inhibition of apoptosis. In this study, we show in both BCR-ABL cells (Mo7e-p210 and BaF/3-p210) and primary CML CD34+ cells that STI571 inhibition of BCR-ABL tyrosine kinase activity results in a G1 cell cycle arrest mediated by the PI3K pathway. This arrest is associated with a nuclear accumulation of p27Kip1 and down-regulation of cyclins D and E. As a result, there is a reduction of the cyclin E/Cdk2 kinase activity and of the retinoblastoma protein phosphorylation. By quantitative reverse transcription-PCR we show that BCR-ABL/PI3K regulates the expression of p27Kip1 at the level of transcription. We further show that BCR-ABL also regulates p27Kip1 protein levels by increasing its degradation by the proteasome. This degradation depends on the ubiquitinylation of p27Kip1 by Skp2-containing SFC complexes: silencing the expression of Skp2 with a small interfering RNA results in the accumulation of p27Kip1. We also demonstrate that BCR-ABL cells show transcriptional up-regulation of Skp2. Finally, expression of a p27Kip1 mutant unable of being recognized by Skp2 results in inhibition of proliferation of BCR-ABL cells, indicating that the degradation of p27Kip1 contributes to the pathogenesis of CML. In conclusion, these results suggest that BCR-ABL regulates cell cycle in CML cells at least in part by inducing proteasome-mediated degradation of the cell cycle inhibitor p27Kip1 and provide a rationale for the use of inhibitors of the proteasome in patients with BCR-ABL leukemias.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-04-1357
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2005
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  • 3
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    Targeted Sequencing Reveals Low-Frequency Variants in EPHA Genes as Markers of Paclitaxel-Induced Peripheral Neuropathy
    American Association for Cancer Research (AACR) ; 2017
    In:  Clinical Cancer Research Vol. 23, No. 5 ( 2017-03-01), p. 1227-1235
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 23, No. 5 ( 2017-03-01), p. 1227-1235
    Abstract: Purpose: Neuropathy is the dose-limiting toxicity of paclitaxel and a major cause for decreased quality of life. Genetic factors have been shown to contribute to paclitaxel neuropathy susceptibility; however, the major causes for interindividual differences remain unexplained. In this study, we identified genetic markers associated with paclitaxel-induced neuropathy through massive sequencing of candidate genes. Experimental Design: We sequenced the coding region of 4 EPHA genes, 5 genes involved in paclitaxel pharmacokinetics, and 30 Charcot–Marie–Tooth genes, in 228 cancer patients with no/low neuropathy or high-grade neuropathy during paclitaxel treatment. An independent validation series included 202 paclitaxel-treated patients. Variation-/gene-based analyses were used to compare variant frequencies among neuropathy groups, and Cox regression models were used to analyze neuropathy along treatment. Results: Gene-based analysis identified EPHA6 as the gene most significantly associated with paclitaxel-induced neuropathy. Low-frequency nonsynonymous variants in EPHA6 were present exclusively in patients with high neuropathy, and all affected the ligand-binding domain of the protein. Accumulated dose analysis in the discovery series showed a significantly higher neuropathy risk for EPHA5/6/8 low-frequency nonsynonymous variant carriers [HR, 14.60; 95% confidence interval (CI), 2.33–91.62; P = 0.0042], and an independent cohort confirmed an increased neuropathy risk (HR, 2.07; 95% CI, 1.14–3.77; P = 0.017). Combining the series gave an estimated 2.5-fold higher risk of neuropathy (95% CI, 1.46–4.31; P = 9.1 × 10−4). Conclusions: This first study sequencing EPHA genes revealed that low-frequency variants in EPHA6, EPHA5, and EPHA8 contribute to the susceptibility to paclitaxel-induced neuropathy. Furthermore, EPHA's neuronal injury repair function suggests that these genes might constitute important neuropathy markers for many neurotoxic drugs. Clin Cancer Res; 23(5); 1227–35. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-16-0694
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 4
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    Abstract P1-18-28: Myocet or carboplatin as part of chemotherapy in HER2-positive operable breast cancer treated with trastuzumab and pertuzumab in the neoadjuvant setting: Efficacy data and cardiotoxicity in 60 patients diagnosed from 2016-2019 at a single institution
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 4_Supplement ( 2020-02-15), p. P1-18-28-P1-18-28
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 4_Supplement ( 2020-02-15), p. P1-18-28-P1-18-28
    Abstract: Objectives: To evaluate the efficacy and cardiotoxicity profile of liposomal anthracycline or Carboplatin as part of neoadjuvant therapy added to taxanes and dual blockade in HER2-positive operable breast cancer patients. Methods: A total of 60 patients diagnosed from August 2016 to May 2019 were included in the study. The treatment consisted of a sequential regimen of taxanes and non- pegilated liposomal anthracycline (Myocet) plus trastuzumab and pertuzumab, or taxanes in combination with carboplatin plus trastuzumab and pertuzumab. The clinical and pathologic responses were evaluated and correlated with clinical and biological factors. Pathologic complete response was defined as the total absence of invasive tumor in both breast and axillary nodes (ypT0/is ypN0).The cardiotoxicity profile was also analyzed. Results: The median age was 52(26-77) years and 5%, 62% and 33% of patients had stage I, II and III breast cancer, respectively, while 7% had inflammatory breast cancer at diagnosis. Hormone receptor (HR) status was negative in 48%, and 65% and 50% had grade III and ki-67 value up to 35%, respectively breast cancer. 65% of patients received weekly paclitaxelx12-trastuzumab-pertuzumab followed by Myocet-cyclophosphamide with -trastuzumab x 4 cycles or this sequence but beginning with the anthracycline, 23% of patients the same regimen but with pertuzumab concurrently with all chemotherapy treatment. The remaining 12% received docetaxel-carboplatin x6 cycles plus trastuzumab and pertuzumab. All treatment was administered previous surgery. The clinical complete response rate, was 57% and 63%, as assessed using ultrasound and MRI, respectively, and this allowed a high rate of conservative surgery (60%). The pathologic complete response (pCR) rate was 52%, and it was higher in HR-negative (61%) than in HR-positive (39%), in grade 3 (71%) than in grade 2(29%) tumors. There were not statistical significant differences in pCR between different chemotherapy treatments. Five patients showed a 10% decrease in left ventricular ejection fraction (LVEF) to below 50% at the end of neoadjuvant treatment. Asymptomatic drops in 2 patients and with heart failure symptoms in 3 of them. Myocet was part of chemotherapy in all of them. All patients recovered after discontinuation of adjuvant trastuzumab and heart medication. Two of these patients did not complete all preplanned adjuvant trastuzumab doses. Conclusion: A sequential regimen of taxanes and non-pegilated liposomal anthracycline or carboplatin plus trastuzumab and pertuzumab was effective, with high pCR rates and a good cardiotoxicity profile. Citation Format: Silvia Antolin, Cristina Reboredo, Rocío Lesta, Aurea Molina, Joaquin Mosquera, Patricia Cordeiro, Eva Pérez, Lourdes Calvo. Myocet or carboplatin as part of chemotherapy in HER2-positive operable breast cancer treated with trastuzumab and pertuzumab in the neoadjuvant setting: Efficacy data and cardiotoxicity in 60 patients diagnosed from 2016-2019 at a single institution [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 P1-18-28.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS19-P1-18-28
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 5
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    Abstract A38: A PERK inhibitor that blocks HER2-driven tumorigenesis and suppresses metastasis by targeting single disseminated tumor cells
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 7_Supplement ( 2016-04-01), p. A38-A38
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 7_Supplement ( 2016-04-01), p. A38-A38
    Abstract: The unfolded protein response (UPR) is a critical survival and adaptation pathway in cancer cells. The endoplasmic reticulum kinase PERK serves as a survival UPR factor for different tumor types, including those driven by the oncogene HER2, and it can also promote survival of dormant cancer cells. We wanted to evaluate the effect of a potent and selective new PERK inhibitor (LY4) on MMTV-HER2-driven tumorigenesis that, through genetic experiments, was shown to depend on a full complement of PERK for progression. Here we show that, from ductal carcinoma in situ (DCIS) through invasive cancer, MMTV-HER2-driven tumors and also HER2+ human cancer cell lines are exquisitely sensitive to this novel PERK inhibitor. We found that early MMTV-HER2+ lesions require PERK for HER2-driven alterations in ductal epithelial organization, and that LY4 impairs the expansion of established HER2+ tumor cells in 3D organotypic cultures and in vivo. Importantly, PERK inhibition blunted metastasis development. This effect was linked to the ability of the PERK inhibitor to eradicate solitary HER2+ disseminated tumor cells that, in their majority, are dormant or slow-cycling, but that represent the seeds for further metastases. Mechanism analyses revealed that PERK inhibition indirectly blocked the phosphorylation of HER2 and EGFR and their downstream signaling activation in response to EGF, possibly by altering receptor protein quality control. Our data suggest that in HER2-driven cancers PERK inhibition might be a novel therapeutic strategy to treat primary and metastatic lesions. Citation Format: Veronica Calvo, Kirk A. Staschke, Maria Cristina Garcia Paredes, Alvaro Avivar-Valderas, Julie Cheung, Robert Wild, Alan C. Rigby, Eduardo F. Farias, Julio Aguirre-Ghiso. A PERK inhibitor that blocks HER2-driven tumorigenesis and suppresses metastasis by targeting single disseminated tumor cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A38.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.TUMMET15-A38
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 6
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    Whole-Exome Sequencing Reveals Defective CYP3A4 Variants Predictive of Paclitaxel Dose-Limiting Neuropathy
    American Association for Cancer Research (AACR) ; 2015
    In:  Clinical Cancer Research Vol. 21, No. 2 ( 2015-01-15), p. 322-328
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 21, No. 2 ( 2015-01-15), p. 322-328
    Abstract: Purpose: Paclitaxel, a widely used chemotherapeutic drug, can cause peripheral neuropathies leading to dose reductions and treatment suspensions and decreasing the quality of life of patients. It has been suggested that genetic variants altering paclitaxel pharmacokinetics increase neuropathy risk, but the major causes of interindividual differences in susceptibility to paclitaxel toxicity remain unexplained. We carried out a whole-exome sequencing (WES) study to identify genetic susceptibility variants associated with paclitaxel neuropathy. Experimental Design: Blood samples from 8 patients with severe paclitaxel-induced peripheral neuropathy were selected for WES. An independent cohort of 228 cancer patients with complete paclitaxel neuropathy data was used for variant screening by DHPLC and association analysis. HEK293 cells were used for heterologous expression and characterization of two novel CYP3A4 enzymes. Results: WES revealed 2 patients with rare CYP3A4 variants, a premature stop codon (CYP3A4*20 allele) and a novel missense variant (CYP3A4*25, p.P389S) causing reduced enzyme expression. Screening for CYP3A4 variants in the independent cohort revealed three additional CYP3A4*20 carriers, and two patients with missense variants exhibiting diminished enzyme activity (CYP3A4*8 and the novel CYP3A4*27 allele, p.L475V). Relative to CYP3A4 wild-type patients, those carrying CYP3A4 defective variants had more severe neuropathy (2- and 1.3-fold higher risk of neuropathy for loss-of-function and missense variants, respectively, P = 0.045) and higher probability of neuropathy-induced paclitaxel treatment modifications (7- and 3-fold higher risk for loss-of-function and missense variants, respectively, P = 5.9 × 10−5). Conclusion: This is the first description of a genetic marker associated with paclitaxel treatment modifications caused by neuropathy. CYP3A4 defective variants may provide a basis for paclitaxel treatment individualization. Clin Cancer Res; 21(2); 322–8. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-14-1758
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 7
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    Abstract P3-07-28: SERENA-1: Updated analyses from a Phase 1 study of the next generation oral selective estrogen receptor degrader camizestrant (AZD9833) combined with abemaciclib, in women with ER-positive, HER2-negative advanced breast cancer
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 5_Supplement ( 2023-03-01), p. P3-07-28-P3-07-28
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. P3-07-28-P3-07-28
    Abstract: Background: SERENA-1 (NCT03616587) is a Phase 1, multi-part, open-label study of camizestrant in women with ER+/HER2− advanced breast cancer. Parts A/B and C/D (escalation/expansion) examined camizestrant as monotherapy and in combination with palbociclib respectively and have been presented previously.1,2 Here we present data from parts G/H which examined camizestrant in combination with abemaciclib. Methods: The primary objective was to determine the safety and tolerability of camizestrant 75 mg once daily (QD) in combination with abemaciclib 150 mg twice daily (BID). Secondary objectives included investigation of anti-tumor response and pharmacokinetics (PK). Participants were previously treated women of any menopausal status (pre-menopausal women received this combination alongside ongoing ovarian function suppressors). Prior treatment with ≤2 lines of chemotherapy in the advanced setting was permitted. There was no limit on the number of lines of prior endocrine treatment in the advanced setting; previous treatment with CDK4/6 inhibitors (CDK4/6i) and fulvestrant was permitted. Results: As of 1st June 2022, 24 patients had received camizestrant in combination with abemaciclib with a median 7.7 month follow up. Tolerability of the combination of camizestrant and abemaciclib was consistent with that of each drug individually. No patient required camizestrant dose reduction. All camizestrant-related heart rate decreases were Grade 1 (asymptomatic). PK data for camizestrant in combination with abemaciclib were consistent with camizestrant as monotherapy and published abemaciclib steady-state PK data, indicating no clinically relevant drug-drug interaction. In these heavily pre-treated patients (46% prior chemotherapy, 75% prior CDK4/6i, 54% prior fulvestrant; all in the advanced disease setting) and of whom 67% had visceral metastases, the objective response rate was 5/19 (26.3%), the clinical benefit rate at 24 weeks was 16/24 (66.7%) and the median progression-free survival had not been reached, with 8/24 patients experiencing a progression event. These data support the use of camizestrant 75 mg QD combined with the approved abemaciclib dose. Conclusions: Camizestrant 75 mg QD in combination with abemaciclib 150 mg BID was well tolerated with encouraging clinical activity. The inclusion of this regimen in the ongoing Phase 3, SERENA-6 trial 3, of camizestrant combined with CDK4/6i versus an aromatase inhibitor, will further clarify the role of this combination in the treatment of patients with ER+/HER2− advanced breast cancer with tumors expressing ESR1 mutations. References 1. Baird R, Oliveira M, Ciruelos Gil EM, et al. SABCS 2020 Virtual Meeting. Abstract PS11-05. 2. Oliveira M, Hamilton EP, Incorvati J, et al. J Clin Oncol 40, 2022 (suppl 16; abstr 1032). 3. SERENA-6 trial. Available at https://clinicaltrials.gov/ct2/show/NCT04964934 We acknowledge Helen Heffron, PhD, from InterComm International who provided medical writing support funded by AstraZeneca. Citation Format: Nicholas Turner, Christos Vaklavas, Emiliano Calvo, Javier Garcia-Corbacho, Jason Incorvati, Manuel Ruiz Borrego, Chris Twelves, Anne Armstrong, Begoña Bermejo, Erika Hamilton, Mafalda Oliveira, Eva Ciruelos, Peter Kabos, Manish R Patel, Maria Borrell, Howard Burris, Bruno de Paula, Alejandro Falcon, Cristina Hernando, Irene Moreno, Ciara S. O’Brien, Elena Shagisultanova, Ivan Victoria Ruiz, Judy S. Wang, Mei Wei, Tim Brier, Danielle Carroll, Carmela Ciardullo, Lisa Gibbons, itziar irurzun-Arana, Tony Jack, bistra kirova, Teresa Klinowska, Justin Lindemann, Julie Maidment, Alastair Mathewson, Rhiannon Maudsley, Robert McEwen, Christopher Morrow, Andy Sykes, Richard D. Baird. SERENA-1: Updated analyses from a Phase 1 study of the next generation oral selective estrogen receptor degrader camizestrant (AZD9833) combined with abemaciclib, in women with ER-positive, HER2-negative advanced breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-28.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS22-P3-07-28
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 8
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    A Phase I Pharmacokinetic and Pharmacodynamic Study of Dalotuzumab (MK-0646), an Anti-Insulin-like Growth Factor-1 Receptor Monoclonal Antibody, in Patients with Advanced Solid Tumors
    American Association for Cancer Research (AACR) ; 2011
    In:  Clinical Cancer Research Vol. 17, No. 19 ( 2011-10-01), p. 6304-6312
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 17, No. 19 ( 2011-10-01), p. 6304-6312
    Abstract: Purpose: Insulin-like growth factor-1 receptor (IGF-1R) mediates cellular processes in cancer and has been proposed as a therapeutic target. Dalotuzumab (MK-0646) is a humanized IgG1 monoclonal antibody that binds to IGF-1R preventing receptor activation. This study was designed to evaluate the safety and tolerability of dalotuzumab, determine the pharmacokinetic (PK) and pharmacodynamic (PD) profiles, and identify a recommended phase II dose. Experimental Design: Patients with tumors expressing IGF-1R protein were allocated to dose-escalating cohorts of three or more patients each and received intravenous dalotuzumab weekly, every 2 or 3 weeks. Plasma was collected for PK analysis. Paired baseline and on-treatment skin and tumor biopsy samples were collected for PD analyses. Results: Eighty patients with chemotherapy-refractory solid tumors were enrolled. One dose-limiting toxicity was noted, but a maximum-tolerated dose was not identified. Grade 1 to 3 hyperglycemia, responsive to metformin, occurred in 15 (19%) patients. At dose levels or more than 5 mg/kg, dalotuzumab mean terminal half-life was 95 hours or more, mean Cmin was more than 25 μg/mL, clearance was constant, and serum exposures were approximately dose proportional. Decreases in tumor IGF-1R, downstream receptor signaling, and Ki67 expression were observed. 18F-Fluorodeoxy-glucose positron emission tomography metabolic responses occurred in three patients. One patient with Ewing's sarcoma showed a mixed radiologic response. The recommended phase II doses were 10, 20, and 30 mg/kg for the weekly, every other week, and every third week schedules, respectively. Conclusions: Dalotuzumab was generally well-tolerated, exhibited dose-proportional PK, inhibited IGF-1R pathway signaling and cell proliferation in treated tumors, and showed clinical activity. The low clearance rate and long terminal half-life support more extended dosing intervals. Clin Cancer Res; 17(19); 6304–12. ©2011 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-10-3336
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 9
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    Abstract S12-04: COVID-19 disease in patients with lung cancer in Spain: GRAVID Lung Cancer Patients Disease (GRAVID study)
    American Association for Cancer Research (AACR) ; 2021
    In:  Clinical Cancer Research Vol. 27, No. 6_Supplement ( 2021-03-15), p. S12-04-S12-04
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 6_Supplement ( 2021-03-15), p. S12-04-S12-04
    Abstract: Background: Previous reports indicate that lung cancer patients are at an increased risk of severe COVID-19 disease and higher mortality rate compared to general population. However, prognostic factors are not yet clearly identified. The LunG canceR pAtients coVid19 Disease (GRAVID) study aimed to describe clinical characteristics, outcomes and predictors of poor prognosis in patients with lung cancer and COVID-19. Methods: In this large nationwide prospective study, medical records of lung cancer patients with COVID-19 diagnosis from 65 spanish hospitals were included. Clinical features, treatments and disease outcomes were collected. The primary endpoint was to determine any-cause mortality; secondary endpoints were hospitalization and admission at intensive care units (ICU). Risk factors of poor prognosis were identified by univariable and multivariable logistic regression models. Results: Overal, 447 patients were analysed. Mean age was 67.1 ± 9·8 years, and the majority were men (332, 74·3%) and current/former smokers (383 (85.7%). NSCLC was the most frequent cancer type (377, 84.5%), being adenocarcinoma (228, 51·0%) the predominant histology. 354 patients (79.2%) had unresectable stage III or metastatic disease, and 266 (59.5%) where receiving anticancer treatment, mostly first-line chemotherapy. 350 (78.3%) patients were hospitalized for a mean of 13·4 ± 11·4 days, 9 (2.0%) patients were admitted to ICU, and 146 (32.7%) patients died. Advanced disease and corticosteroid treatment at hospitalization were predictors of mortality. Non-terminal stage hospitalized patients with lymphocytopenia and high LDH showed an increased risk of death. Severity of COVID-19 correlated to mortality, admission at ICU and mechanical ventilation. Conclusion: With underlying comorbidities and immunocompromised status, patients with lung cancer and COVID-19 present high hospitalization and mortality rates. These outcomes, alongside the identification of prognostic factors, may inform physicians on risks and benefits for this population to provide individualized oncological care. Citation Format: Jose Maria Mazarico Gallego, Antonio Calles, Monica Antoñanzas, Cristina Pangua, Xabier Mielgo Rubio, Ernest Nadal, Rafael Lopez Castro, Ana Lopez-Martin, Edel del Barco, Manuel Domine, Virginia Calvo, Pilar Diz, Carmen Sandoval, Elia Sais Girona, Ivana Gabriela Sullivan, M. Angeles Sala, Gema Garcia Ledo, Jose Ramon Jarabo, Rosa Alvarez Alvarez, Javier Baena, Maria Gonzalez-Cao, Mariano Provencio. COVID-19 disease in patients with lung cancer in Spain: GRAVID Lung Cancer Patients Disease (GRAVID study) [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2021 Feb 3-5. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(6_Suppl):Abstract nr S12-04.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1557-3265.COVID-19-21-S12-04
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 10
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    Functional Mapping of AKT Signaling and Biomarkers of Response from the FAIRLANE Trial of Neoadjuvant Ipatasertib plus Paclitaxel for Triple-Negative Breast Cancer
    American Association for Cancer Research (AACR) ; 2022
    In:  Clinical Cancer Research Vol. 28, No. 5 ( 2022-03-01), p. 993-1003
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 28, No. 5 ( 2022-03-01), p. 993-1003
    Abstract: Despite extensive genomic and transcriptomic profiling, it remains unknown how signaling pathways are differentially activated and how tumors are differentially sensitized to certain perturbations. Here, we aim to characterize AKT signaling activity and its association with other genomic or IHC-based PI3K/AKT pathway biomarkers as well as the clinical activity of ipatasertib (AKT inhibitor) in the FAIRLANE trial. Experimental Design: In FAIRLANE, 151 patients with early triple-negative breast cancer (TNBC) were randomized 1:1 to receive paclitaxel with ipatasertib or placebo for 12 weeks prior to surgery. Adding ipatasertib did not increase pathologic complete response rate and numerically improved overall response rate by MRI. We used reverse-phase protein microarrays (RPPA) to examine the total level and/or phosphorylation states of over 100 proteins in various signaling or cell processes including PI3K/AKT and mTOR signaling. One hundred and twenty-five baseline and 127 on-treatment samples were evaluable by RPPA, with 110 paired samples at both time points. Results: Tumors with genomic/protein alterations in PIK3CA/AKT1/PTEN were associated with higher levels of AKT phosphorylation. In addition, phosphorylated AKT (pAKT) levels exhibited a significant association with enriched clinical benefit of ipatasertib, and identified patients who received benefit in the absence of PIK3CA/AKT1/PTEN alterations. Ipatasertib treatment led to a downregulation of AKT/mTORC1 signaling, which was more pronounced among the tumors with PIK3CA/AKT1/PTEN alterations or among the responders to the treatment. Conclusions: We showed that the high baseline pAKT levels are associated with the alterations of PI3K/AKT pathway components and enriched benefit of ipatasertib in TNBC.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-21-2498
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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