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Vorinostat and hydroxychloroquine improve immunity and inhibit autophagy in metastatic colorectal cancer

Hydroxychloroquine (HCQ) enhances the anti-cancer activity of the histone deacetylase inhibitor, vorinostat (VOR), in pre-clinical models and early phase clinical studies of metastatic colorectal cancer (mCRC). Mechanisms could include autophagy inhibition, accumulation of ubiquitinated proteins, an...

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Autores principales: Patel, Sukeshi, Hurez, Vincent, Nawrocki, Steffan T., Goros, Martin, Michalek, Joel, Sarantopoulos, John, Curiel, Tyler, Mahalingam, Devalingam
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312297/
https://www.ncbi.nlm.nih.gov/pubmed/27463016
http://dx.doi.org/10.18632/oncotarget.10824
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author Patel, Sukeshi
Hurez, Vincent
Nawrocki, Steffan T.
Goros, Martin
Michalek, Joel
Sarantopoulos, John
Curiel, Tyler
Mahalingam, Devalingam
author_facet Patel, Sukeshi
Hurez, Vincent
Nawrocki, Steffan T.
Goros, Martin
Michalek, Joel
Sarantopoulos, John
Curiel, Tyler
Mahalingam, Devalingam
author_sort Patel, Sukeshi
collection PubMed
description Hydroxychloroquine (HCQ) enhances the anti-cancer activity of the histone deacetylase inhibitor, vorinostat (VOR), in pre-clinical models and early phase clinical studies of metastatic colorectal cancer (mCRC). Mechanisms could include autophagy inhibition, accumulation of ubiquitinated proteins, and subsequent tumor cell apoptosis. There is growing evidence that autophagy inhibition could lead to improved anti-cancer immunity. To date, effects of autophagy on immunity have not been reported in cancer patients. To address this, we expanded an ongoing clinical study to include patients with advanced, refractory mCRC to evaluate further the clinical efficacy and immune effects of VOR plus HCQ. Refractory mCRC patients received VOR 400 milligrams orally with HCQ 600 milligrams orally daily, in a 3-week cycle. The primary endpoint was median progression-free survival (mPFS). Secondary endpoints include median overall survival (mOS), adverse events (AE), pharmacodynamic of inhibition of autophagy in primary tumors, immune cell analyses, and cytokine levels. Twenty patients were enrolled (19 evaluable for survival) with a mPFS of 2.8 months and mOS of 6.7 months. Treatment-related grade 3–4 AEs occurred in 8 patients (40%), with fatigue, nausea/vomiting, and anemia being the most common. Treatment significantly reduced CD4(+)CD25(hi)Foxp3(+) regulatory and PD-1(+) (exhausted) CD4(+) and CD8(+) T cells and decreased CD45RO-CD62L(+) (naive) T cells, consistent with improved anti-tumor immunity. On-study tumor biopsies showed increases in lysosomal protease cathepsin D and p62 accumulation, consistent with autophagy inhibition. Taken together, VOR plus HCQ is active, safe and well tolerated in refractory CRC patients, resulting in potentially improved anti-tumor immunity and inhibition of autophagy.
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spelling pubmed-53122972017-03-06 Vorinostat and hydroxychloroquine improve immunity and inhibit autophagy in metastatic colorectal cancer Patel, Sukeshi Hurez, Vincent Nawrocki, Steffan T. Goros, Martin Michalek, Joel Sarantopoulos, John Curiel, Tyler Mahalingam, Devalingam Oncotarget Research Paper Hydroxychloroquine (HCQ) enhances the anti-cancer activity of the histone deacetylase inhibitor, vorinostat (VOR), in pre-clinical models and early phase clinical studies of metastatic colorectal cancer (mCRC). Mechanisms could include autophagy inhibition, accumulation of ubiquitinated proteins, and subsequent tumor cell apoptosis. There is growing evidence that autophagy inhibition could lead to improved anti-cancer immunity. To date, effects of autophagy on immunity have not been reported in cancer patients. To address this, we expanded an ongoing clinical study to include patients with advanced, refractory mCRC to evaluate further the clinical efficacy and immune effects of VOR plus HCQ. Refractory mCRC patients received VOR 400 milligrams orally with HCQ 600 milligrams orally daily, in a 3-week cycle. The primary endpoint was median progression-free survival (mPFS). Secondary endpoints include median overall survival (mOS), adverse events (AE), pharmacodynamic of inhibition of autophagy in primary tumors, immune cell analyses, and cytokine levels. Twenty patients were enrolled (19 evaluable for survival) with a mPFS of 2.8 months and mOS of 6.7 months. Treatment-related grade 3–4 AEs occurred in 8 patients (40%), with fatigue, nausea/vomiting, and anemia being the most common. Treatment significantly reduced CD4(+)CD25(hi)Foxp3(+) regulatory and PD-1(+) (exhausted) CD4(+) and CD8(+) T cells and decreased CD45RO-CD62L(+) (naive) T cells, consistent with improved anti-tumor immunity. On-study tumor biopsies showed increases in lysosomal protease cathepsin D and p62 accumulation, consistent with autophagy inhibition. Taken together, VOR plus HCQ is active, safe and well tolerated in refractory CRC patients, resulting in potentially improved anti-tumor immunity and inhibition of autophagy. Impact Journals LLC 2016-07-23 /pmc/articles/PMC5312297/ /pubmed/27463016 http://dx.doi.org/10.18632/oncotarget.10824 Text en Copyright: © 2016 Patel et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Patel, Sukeshi
Hurez, Vincent
Nawrocki, Steffan T.
Goros, Martin
Michalek, Joel
Sarantopoulos, John
Curiel, Tyler
Mahalingam, Devalingam
Vorinostat and hydroxychloroquine improve immunity and inhibit autophagy in metastatic colorectal cancer
title Vorinostat and hydroxychloroquine improve immunity and inhibit autophagy in metastatic colorectal cancer
title_full Vorinostat and hydroxychloroquine improve immunity and inhibit autophagy in metastatic colorectal cancer
title_fullStr Vorinostat and hydroxychloroquine improve immunity and inhibit autophagy in metastatic colorectal cancer
title_full_unstemmed Vorinostat and hydroxychloroquine improve immunity and inhibit autophagy in metastatic colorectal cancer
title_short Vorinostat and hydroxychloroquine improve immunity and inhibit autophagy in metastatic colorectal cancer
title_sort vorinostat and hydroxychloroquine improve immunity and inhibit autophagy in metastatic colorectal cancer
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312297/
https://www.ncbi.nlm.nih.gov/pubmed/27463016
http://dx.doi.org/10.18632/oncotarget.10824
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