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IGF-1R/mTOR Targeted Therapy for Ewing Sarcoma: A Meta-Analysis of Five IGF-1R-Related Trials Matched to Proteomic and Radiologic Predictive Biomarkers
Background : Ten to fourteen percent of Ewing sarcoma (ES) study participants treated nationwide with IGF-1 receptor (IGF-1R)-targeted antibodies achieved tumor regression. Despite this success, low response rates and short response durations (approximately 7-weeks) have slowed the development of th...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408058/ https://www.ncbi.nlm.nih.gov/pubmed/32630797 http://dx.doi.org/10.3390/cancers12071768 |
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author | Amin, Hesham M. Morani, Ajaykumar C. Daw, Najat C. Lamhamedi-Cherradi, Salah-Eddine Subbiah, Vivek Menegaz, Brian A. Vishwamitra, Deeksha Eskandari, Ghazaleh George, Bhawana Benjamin, Robert S. Patel, Shreyaskumar Song, Juhee Lazar, Alexander J. Wang, Wei-Lien Kurzrock, Razelle Pappo, Alberto Anderson, Peter M. Schwartz, Gary K. Araujo, Dejka Cuglievan, Branko Ratan, Ravin McCall, David Mohiuddin, Sana Livingston, John A. Molina, Eric R. Naing, Aung Ludwig, Joseph A. |
author_facet | Amin, Hesham M. Morani, Ajaykumar C. Daw, Najat C. Lamhamedi-Cherradi, Salah-Eddine Subbiah, Vivek Menegaz, Brian A. Vishwamitra, Deeksha Eskandari, Ghazaleh George, Bhawana Benjamin, Robert S. Patel, Shreyaskumar Song, Juhee Lazar, Alexander J. Wang, Wei-Lien Kurzrock, Razelle Pappo, Alberto Anderson, Peter M. Schwartz, Gary K. Araujo, Dejka Cuglievan, Branko Ratan, Ravin McCall, David Mohiuddin, Sana Livingston, John A. Molina, Eric R. Naing, Aung Ludwig, Joseph A. |
author_sort | Amin, Hesham M. |
collection | PubMed |
description | Background : Ten to fourteen percent of Ewing sarcoma (ES) study participants treated nationwide with IGF-1 receptor (IGF-1R)-targeted antibodies achieved tumor regression. Despite this success, low response rates and short response durations (approximately 7-weeks) have slowed the development of this therapy. Methods: We performed a meta-analysis of five phase-1b/2 ES-oriented trials that evaluated the anticancer activity of IGF-1R antibodies +/− mTOR inhibitors (mTORi). Our meta-analysis provided a head-to-head comparison of the clinical benefits of IGF-1R antibodies vs. the IGF-1R/mTOR-targeted combination. Available pretreatment clinical samples were semi-quantitatively scored using immunohistochemistry to detect proteins in the IGF-1R/PI3K/AKT/mTOR pathway linked to clinical response. Early PET/CT imaging, obtained within the first 2 weeks (median 10 days), were examined to determine if reduced FDG avidity was predictive of progression-free survival (PFS). Results: Among 56 ES patients treated at MD Anderson Cancer Center (MDACC) with IGF-1R antibodies, our analysis revealed a significant ~two-fold improvement in PFS that favored a combination of IGF-1R/mTORi therapy (1.6 vs. 3.3-months, p = 0.042). Low pIGF-1R in the pretreatment specimens was associated with treatment response. Reduced total-lesion glycolysis more accurately predicted the IGF-1R response than other previously reported radiological biomarkers. Conclusion: Synergistic drug combinations, and newly identified proteomic or radiological biomarkers of IGF-1R response, may be incorporated into future IGF-1R-related trials to improve the response rate in ES patients. |
format | Online Article Text |
id | pubmed-7408058 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-74080582020-08-25 IGF-1R/mTOR Targeted Therapy for Ewing Sarcoma: A Meta-Analysis of Five IGF-1R-Related Trials Matched to Proteomic and Radiologic Predictive Biomarkers Amin, Hesham M. Morani, Ajaykumar C. Daw, Najat C. Lamhamedi-Cherradi, Salah-Eddine Subbiah, Vivek Menegaz, Brian A. Vishwamitra, Deeksha Eskandari, Ghazaleh George, Bhawana Benjamin, Robert S. Patel, Shreyaskumar Song, Juhee Lazar, Alexander J. Wang, Wei-Lien Kurzrock, Razelle Pappo, Alberto Anderson, Peter M. Schwartz, Gary K. Araujo, Dejka Cuglievan, Branko Ratan, Ravin McCall, David Mohiuddin, Sana Livingston, John A. Molina, Eric R. Naing, Aung Ludwig, Joseph A. Cancers (Basel) Article Background : Ten to fourteen percent of Ewing sarcoma (ES) study participants treated nationwide with IGF-1 receptor (IGF-1R)-targeted antibodies achieved tumor regression. Despite this success, low response rates and short response durations (approximately 7-weeks) have slowed the development of this therapy. Methods: We performed a meta-analysis of five phase-1b/2 ES-oriented trials that evaluated the anticancer activity of IGF-1R antibodies +/− mTOR inhibitors (mTORi). Our meta-analysis provided a head-to-head comparison of the clinical benefits of IGF-1R antibodies vs. the IGF-1R/mTOR-targeted combination. Available pretreatment clinical samples were semi-quantitatively scored using immunohistochemistry to detect proteins in the IGF-1R/PI3K/AKT/mTOR pathway linked to clinical response. Early PET/CT imaging, obtained within the first 2 weeks (median 10 days), were examined to determine if reduced FDG avidity was predictive of progression-free survival (PFS). Results: Among 56 ES patients treated at MD Anderson Cancer Center (MDACC) with IGF-1R antibodies, our analysis revealed a significant ~two-fold improvement in PFS that favored a combination of IGF-1R/mTORi therapy (1.6 vs. 3.3-months, p = 0.042). Low pIGF-1R in the pretreatment specimens was associated with treatment response. Reduced total-lesion glycolysis more accurately predicted the IGF-1R response than other previously reported radiological biomarkers. Conclusion: Synergistic drug combinations, and newly identified proteomic or radiological biomarkers of IGF-1R response, may be incorporated into future IGF-1R-related trials to improve the response rate in ES patients. MDPI 2020-07-02 /pmc/articles/PMC7408058/ /pubmed/32630797 http://dx.doi.org/10.3390/cancers12071768 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Amin, Hesham M. Morani, Ajaykumar C. Daw, Najat C. Lamhamedi-Cherradi, Salah-Eddine Subbiah, Vivek Menegaz, Brian A. Vishwamitra, Deeksha Eskandari, Ghazaleh George, Bhawana Benjamin, Robert S. Patel, Shreyaskumar Song, Juhee Lazar, Alexander J. Wang, Wei-Lien Kurzrock, Razelle Pappo, Alberto Anderson, Peter M. Schwartz, Gary K. Araujo, Dejka Cuglievan, Branko Ratan, Ravin McCall, David Mohiuddin, Sana Livingston, John A. Molina, Eric R. Naing, Aung Ludwig, Joseph A. IGF-1R/mTOR Targeted Therapy for Ewing Sarcoma: A Meta-Analysis of Five IGF-1R-Related Trials Matched to Proteomic and Radiologic Predictive Biomarkers |
title | IGF-1R/mTOR Targeted Therapy for Ewing Sarcoma: A Meta-Analysis of Five IGF-1R-Related Trials Matched to Proteomic and Radiologic Predictive Biomarkers |
title_full | IGF-1R/mTOR Targeted Therapy for Ewing Sarcoma: A Meta-Analysis of Five IGF-1R-Related Trials Matched to Proteomic and Radiologic Predictive Biomarkers |
title_fullStr | IGF-1R/mTOR Targeted Therapy for Ewing Sarcoma: A Meta-Analysis of Five IGF-1R-Related Trials Matched to Proteomic and Radiologic Predictive Biomarkers |
title_full_unstemmed | IGF-1R/mTOR Targeted Therapy for Ewing Sarcoma: A Meta-Analysis of Five IGF-1R-Related Trials Matched to Proteomic and Radiologic Predictive Biomarkers |
title_short | IGF-1R/mTOR Targeted Therapy for Ewing Sarcoma: A Meta-Analysis of Five IGF-1R-Related Trials Matched to Proteomic and Radiologic Predictive Biomarkers |
title_sort | igf-1r/mtor targeted therapy for ewing sarcoma: a meta-analysis of five igf-1r-related trials matched to proteomic and radiologic predictive biomarkers |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408058/ https://www.ncbi.nlm.nih.gov/pubmed/32630797 http://dx.doi.org/10.3390/cancers12071768 |
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