Objectives: Pneumatic compression garment therapy (PCGT) has been established as treatment for postradiotherapy lymphedema, and its use in head and neck patients is becoming more common. Although effects on interstitial edema of the cervical soft tissues have been studied, effects on internal laryngopharyngeal edema, as well as associated symptoms of dysphagia and dysphonia, have yet to be published. Methods: We surveyed 7 patients treated with radiation for head and neck cancer (HNC) who had also been prescribed PCGT for cervical lymphedema. Patients were asked about subjective experience with the device, and also administered the Eating Assessment Tool-10 (EAT-10) and Voice Handicap Index-10 (VHI-10) surveys regarding their symptoms after using PCGT. Laryngoscopy videos from these same periods were also reviewed and scored using a validated tool for assessing laryngopharyngeal edema. Results: 85% of patients reported at least some improvement in dysphagia and dysphonia following PCGT. Average EAT-10 score after PCGT was 11.4 and average VHI-10 score after PCGT was 8.7. These compare more favorably to historical scores for the same questionnaires in similar patient populations. Laryngeal edema scores on endoscopic examination were not significantly different after at least 3 months of therapy (pre: 20.15, post: 20.21, P = .975); however, the utility of this result is limited by a low inter-rater reliability (Krippendorff α = .513). Conclusions: While we are unable to show any difference in objective assessment of laryngopharyngeal edema on endoscopic examination in this small pilot study, patients report substantial subjective improvement in postradiotherapy dysphagia and dysphonia following cervical PCGT that warrants more formal investigation.
TP53 is the most frequently mutated gene in head and neck squamous cell carcinoma (HNSCC). Patients with HPV-negative TP53 mutant HNSCC have the worst prognosis, necessitating additional agents for treatment. Since mutant p53 causes sustained activation of the PI3K/AKT/mTOR signaling pathway, we investigated the effect of rapalogs RAD001 and CCI-779 on HPV-negative mutTP53 HNSCC cell lines and xenografts. Rapalogs significantly reduced cell viability and colony formation. Interestingly, rapalogs-induced autophagy with no effect on apoptosis.Pretreatment with autophagy inhibitors, 3-methyladenine (3-MA) and ULK-101 rescued the cell viability by inhibiting rapalog-induced autophagy, suggesting that both RAD001 and CCI-779 induce non-apoptotic autophagy-dependent cell death (ADCD). Moreover, rapalogs upregulated the levels of ULK1 and pULK1 S555 with concomitant downregulation of the mTORC1 pathway. However, pretreatment of cells with rapalogs prevented the ULK-101-mediated inhibition of ULK1 to sustained autophagy, suggesting that rapalogs induce ADCD through the activation of ULK1.To further translate our in vitro studies, we investigated the effect of RAD001 in HPV-negative mutTP53 (HN31 and FaDu) tumor cell xenograft model in nude mice.Mice treated with RAD001 exhibited a significant tumor volume reduction without induction of apoptosis, and with a concomitant increase in autophagy. Further, treatment with RAD001 was associated with a considerable increase in pULK1 S555 and ULK1 levels through the inhibition of mTORC1. 3-MA reversed the effect of RAD001 on FaDu tumor growth suggesting that RAD001 promotes ACDC in HPVnegative mutTP53 xenograft. This is the first report demonstrating that rapalogs promote non-apoptotic ADCD in HPV-negative mutTP53 HNSCC via the ULK1 pathway. Further studies are required to establish the promising role of rapalogs in preventing the regrowth of HPV-negative mutTP53 HNSCC.
TP53 is the most frequently mutated gene in Head and Neck Squamous Cell Carcinoma (HNSCC). Patients with HPV-negative TP53 mutant HNSCC have the worst prognosis. A phase II multi-institutional clinical trial, determined that, adjuvant therapy with an mTOR inhibitor significantly increased 2-year progression free survival (PFS) in patients with p53 mutant tumors. Previous studies have shown that mutant p53 causes sustained activation of PI3K/AKT/mTOR pathway in cancer. We investigated the mechanism by which the mTOR inhibitor CCI-779 inhibits cell growth of TP53 mutant HNSCC in vitro. HPV-negative HNSCC cell lines harboring TP53 mutations at different positions were treated with CCI-779.CCI-779 significantly reduced cell viability and colony forming ability of all the cell lines tested. CCI-779 did not induce apoptosis or cell cycle arrest in these cells. However, the reduction in cell viability was associated with increase in autophagy as demonstrated by increased levels of LC3-II. The autophagy inhibitors, 3-methyl adenine (3-MA) and ULK-101 restored the cell viability by inhibiting CCI-779 induced autophagy. Therefore, we postulate that CCI-779 induces nonapototic autophagy dependent cell death (ADCD) in HPV-negative TP53 mutant HNSCC cell lines. CCI-779 induced autophagy is accompanied by increased level of ULK1 and Beclin1 as well as increased phosphorylation of ULK1 at Serine 555. However, ULK101 (ULK1 inhibitor) and 3-MA (PI3K inhibitor) when combined with CCI-779 reduced the level of both total and phosphorylated levels of ULK1, which resulted in inhibition of autophagy and improved cell viability. However, combination of CCI-779 and bafilomycin A1 treatment showed increased level of LC3-II, ULK1 and phospho-ULK1 (S555) with concomitant decrease in cell viability. Our data suggests that rapalog induces ADCD by facilitating autophagy initiation through the stabilization and activation of ULK1. Moreover our data demonstrated that CCI-779 mediated activation of ULK1 is associated with down regulation of mTORC1 but not mTORC2 signaling. This is a novel mechanism of how rapalogues induce ADCD through the stabilization/activation of ULK1 in HPV-negative TP53 mutant HNSCC cells. Together these data highlight the importance of how mTORi can be used to accelerate tumor cell death in HPV-negative TP53 mutant HNSCC. Citation Format: Md Maksudul Alam, Janmaris Marin Fermin, Patrick T. Spiller, Channing Dorr, Xiaohua Rong, Tara-Moore Medlin, Alok R. Khandelwal, Cherie-Ann Nathan. mTOR inhibitor induces non-apoptotic, autophagy dependent cell death (ADCD) in TP53 mutant HNSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1015.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.