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mTOR inhibition as an adjuvant therapy in a metastatic model of HPV+ HNSCC.

Identifieur interne : 000959 ( Main/Exploration ); précédent : 000958; suivant : 000960

mTOR inhibition as an adjuvant therapy in a metastatic model of HPV+ HNSCC.

Auteurs : Joseph D. Coppock [États-Unis] ; Paola D. Vermeer [États-Unis] ; Daniel W. Vermeer [États-Unis] ; Kimberly M. Lee [États-Unis] ; W Keith Miskimins [États-Unis] ; William C. Spanos [États-Unis] ; John H. Lee [États-Unis]

Source :

RBID : pubmed:27015118

Descripteurs français

English descriptors

Abstract

Effective treatments for recurrent/metastatic human papillomavirus-positive (HPV+) head and neck squamous cell cancer (HNSCC) are limited. To aid treatment development, we characterized a novel murine model of recurrent/metastatic HPV+ HNSCC. Further analysis of the parental tumor cell line and its four recurrent/metastatic derivatives led to preclinical testing of an effective treatment option for this otherwise fatal disease. Reverse phase protein arrays identified key signaling cascades in the parental and recurrent/metastatic cell lines. While protein expression profiles differed among the recurrent/metastatic cell lines, activated proteins associated with the mTOR signaling cascade were a commonality. Based on these data, mTOR inhibition was evaluated as an adjuvant treatment for recurrent/metastatic disease. mTOR activity and treatment response were assessed in vitro by western blot, Seahorse, proliferation, clonogenic, and migration assays. Standard-of-care cisplatin/radiation therapy (CRT) versus CRT/rapamycin were compared in vivo. Low-dose rapamycin inhibited mTOR signaling, decreasing proliferation (43%) and migration (62%) while it enhanced CRT-induced cytotoxicity (3.3 fold) in clonogenic assays. Furthermore, rapamycin re-sensitized CRT-resistant, metastatic tumors to treatment in vivo, improving long-term cures (0-30% improved to 78-100%, depending on the recurrent/metastatic cell line) and limiting lymph node metastasis (32%) and lung metastatic burden (30 fold). Studies using immune compromised mice suggested rapamycin's effect on metastasis is independent of the adaptive immune response. These data suggest a role of mTOR activation in HPV+ HNSCC recurrent/metastatic disease and that adjuvant mTOR inhibition may enhance treatment of resistant, metastatic cell populations at the primary site and limit distant metastasis.

DOI: 10.18632/oncotarget.8286
PubMed: 27015118
PubMed Central: PMC5029697


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Le document en format XML

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<term>Apoptosis (drug effects)</term>
<term>Biomarkers, Tumor (metabolism)</term>
<term>Carcinoma, Squamous Cell (drug therapy)</term>
<term>Carcinoma, Squamous Cell (secondary)</term>
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<term>Cisplatin (administration & dosage)</term>
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<term>Mice (MeSH)</term>
<term>Mice, Inbred C57BL (MeSH)</term>
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<term>Neoplasm Recurrence, Local (virology)</term>
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<term>Carcinome épidermoïde (virologie)</term>
<term>Cellules cancéreuses en culture (MeSH)</term>
<term>Cisplatine (administration et posologie)</term>
<term>Humains (MeSH)</term>
<term>Infections à papillomavirus (anatomopathologie)</term>
<term>Infections à papillomavirus (traitement médicamenteux)</term>
<term>Infections à papillomavirus (virologie)</term>
<term>Invasion tumorale (MeSH)</term>
<term>Marqueurs biologiques tumoraux (métabolisme)</term>
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<term>Récidive tumorale locale (traitement médicamenteux)</term>
<term>Récidive tumorale locale (virologie)</term>
<term>Sirolimus (administration et posologie)</term>
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<term>Souris de lignée C57BL (MeSH)</term>
<term>Sérine-thréonine kinases TOR (antagonistes et inhibiteurs)</term>
<term>Tests d'activité antitumorale sur modèle de xénogreffe (MeSH)</term>
<term>Traitement médicamenteux adjuvant (MeSH)</term>
<term>Tumeurs de la tête et du cou (anatomopathologie)</term>
<term>Tumeurs de la tête et du cou (traitement médicamenteux)</term>
<term>Tumeurs de la tête et du cou (virologie)</term>
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<term>Infections à papillomavirus</term>
<term>Récidive tumorale locale</term>
<term>Tumeurs de la tête et du cou</term>
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<term>Sérine-thréonine kinases TOR</term>
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<term>Apoptosis</term>
<term>Cell Proliferation</term>
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<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en">
<term>Carcinoma, Squamous Cell</term>
<term>Head and Neck Neoplasms</term>
<term>Neoplasm Recurrence, Local</term>
<term>Papillomavirus Infections</term>
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<keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr">
<term>Apoptose</term>
<term>Prolifération cellulaire</term>
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<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr">
<term>Marqueurs biologiques tumoraux</term>
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<term>Papillomaviridae</term>
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<term>Papillomaviridae</term>
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<term>Head and Neck Neoplasms</term>
<term>Neoplasm Recurrence, Local</term>
<term>Papillomavirus Infections</term>
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<term>Carcinome épidermoïde</term>
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<term>Carcinoma, Squamous Cell</term>
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<term>Antineoplastic Combined Chemotherapy Protocols</term>
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<term>Carcinome épidermoïde</term>
<term>Infections à papillomavirus</term>
<term>Récidive tumorale locale</term>
<term>Tumeurs de la tête et du cou</term>
</keywords>
<keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr">
<term>Protocoles de polychimiothérapie antinéoplasique</term>
</keywords>
<keywords scheme="MESH" qualifier="virologie" xml:lang="fr">
<term>Carcinome épidermoïde</term>
<term>Infections à papillomavirus</term>
<term>Récidive tumorale locale</term>
<term>Tumeurs de la tête et du cou</term>
</keywords>
<keywords scheme="MESH" qualifier="virology" xml:lang="en">
<term>Carcinoma, Squamous Cell</term>
<term>Head and Neck Neoplasms</term>
<term>Neoplasm Recurrence, Local</term>
<term>Papillomavirus Infections</term>
</keywords>
<keywords scheme="MESH" xml:lang="en">
<term>Animals</term>
<term>Chemotherapy, Adjuvant</term>
<term>Humans</term>
<term>Lymphatic Metastasis</term>
<term>Male</term>
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<term>Souris</term>
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<div type="abstract" xml:lang="en">Effective treatments for recurrent/metastatic human papillomavirus-positive (HPV+) head and neck squamous cell cancer (HNSCC) are limited. To aid treatment development, we characterized a novel murine model of recurrent/metastatic HPV+ HNSCC. Further analysis of the parental tumor cell line and its four recurrent/metastatic derivatives led to preclinical testing of an effective treatment option for this otherwise fatal disease. Reverse phase protein arrays identified key signaling cascades in the parental and recurrent/metastatic cell lines. While protein expression profiles differed among the recurrent/metastatic cell lines, activated proteins associated with the mTOR signaling cascade were a commonality. Based on these data, mTOR inhibition was evaluated as an adjuvant treatment for recurrent/metastatic disease. mTOR activity and treatment response were assessed in vitro by western blot, Seahorse, proliferation, clonogenic, and migration assays. Standard-of-care cisplatin/radiation therapy (CRT) versus CRT/rapamycin were compared in vivo. Low-dose rapamycin inhibited mTOR signaling, decreasing proliferation (43%) and migration (62%) while it enhanced CRT-induced cytotoxicity (3.3 fold) in clonogenic assays. Furthermore, rapamycin re-sensitized CRT-resistant, metastatic tumors to treatment in vivo, improving long-term cures (0-30% improved to 78-100%, depending on the recurrent/metastatic cell line) and limiting lymph node metastasis (32%) and lung metastatic burden (30 fold). Studies using immune compromised mice suggested rapamycin's effect on metastasis is independent of the adaptive immune response. These data suggest a role of mTOR activation in HPV+ HNSCC recurrent/metastatic disease and that adjuvant mTOR inhibition may enhance treatment of resistant, metastatic cell populations at the primary site and limit distant metastasis. </div>
</front>
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<Title>Oncotarget</Title>
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<AbstractText>Effective treatments for recurrent/metastatic human papillomavirus-positive (HPV+) head and neck squamous cell cancer (HNSCC) are limited. To aid treatment development, we characterized a novel murine model of recurrent/metastatic HPV+ HNSCC. Further analysis of the parental tumor cell line and its four recurrent/metastatic derivatives led to preclinical testing of an effective treatment option for this otherwise fatal disease. Reverse phase protein arrays identified key signaling cascades in the parental and recurrent/metastatic cell lines. While protein expression profiles differed among the recurrent/metastatic cell lines, activated proteins associated with the mTOR signaling cascade were a commonality. Based on these data, mTOR inhibition was evaluated as an adjuvant treatment for recurrent/metastatic disease. mTOR activity and treatment response were assessed in vitro by western blot, Seahorse, proliferation, clonogenic, and migration assays. Standard-of-care cisplatin/radiation therapy (CRT) versus CRT/rapamycin were compared in vivo. Low-dose rapamycin inhibited mTOR signaling, decreasing proliferation (43%) and migration (62%) while it enhanced CRT-induced cytotoxicity (3.3 fold) in clonogenic assays. Furthermore, rapamycin re-sensitized CRT-resistant, metastatic tumors to treatment in vivo, improving long-term cures (0-30% improved to 78-100%, depending on the recurrent/metastatic cell line) and limiting lymph node metastasis (32%) and lung metastatic burden (30 fold). Studies using immune compromised mice suggested rapamycin's effect on metastasis is independent of the adaptive immune response. These data suggest a role of mTOR activation in HPV+ HNSCC recurrent/metastatic disease and that adjuvant mTOR inhibition may enhance treatment of resistant, metastatic cell populations at the primary site and limit distant metastasis. </AbstractText>
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