A Phase 1 Study of Everolimus + Weekly Cisplatin + Intensity Modulated Radiation Therapy in Head-and-Neck Cancer

Fury, Matthew G.; Lee, Nancy Y.; Sherman, Eric J.; Ho, Alan L.; Rao, Shyam; Heguy, Adriana; Shen, Ronglai; Korte, Susan; Lisa, Donna; Ganly, Ian; Patel, Snehal G.; Wong, Richard J.; Shaha, Ashok R.; Shah, Jatin P.; Haque, Sofia; Katabi, Nora; Pfister, David G.

doi:10.1016/j.ijrobp.2013.06.2043

Cited by 52 publications

(30 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, two Phase I clinical studies have been completed: the first in resected, locally advanced HNC patients combining everolimus, weekly cisplatin and radiation and the second, combining everolimus with docetaxel and cisplatin as part of an induction chemotherapy regimen. Both clinical studies have demonstrated tolerability and safety and are presumed to be progressing to Phase II (42, 43). It is enticing to consider that the combination of an mTOR inhibitor, cyclopamine, and RT in recurrent or locally-advanced HNC patients may be more efficacious since it targets both the tumor and stroma-mediated components involved with tumor repopulation.…”

Section: Discussionmentioning

confidence: 99%

Hedgehog Signaling Drives Radioresistance and Stroma-Driven Tumor Repopulation in Head and Neck Squamous Cancers

et al. 2014

View full text Add to dashboard Cite

Local control and overall survival in patients with advanced head and neck squamous cell cancer (HNSCC) remains dismal. Signaling through the Hedgehog (Hh) pathway is associated with epithelial-to-mesenchymal transition (EMT) and activation of the Hh effector transcription factor Gli1 is a poor prognostic factor in this disease setting. Here we report that increased GLI1 expression in the leading edge of HNSCC tumors is further increased by irradition where it contributes to therapy resistance. Hh pathway blockade with cyclopamine suppressed GLI1 activation and enhanced tumor sensitivity to radiotherapy. Further, radiotherapy-induced GLI1 expression was mediated in part by the mTOR/S6K1 pathway. Stroma exposed to radiotherapy promoted rapid tumor repopulation and this effect was suppressed by Hh inhibition. Our results demonstrate that GLI1 is upregulated at the tumor-stroma intersection in HNSCC is elevated by radiotherapy where it contributes to stromal-mediated resistance, and that Hh inhibitors offer a rational strategy to reverse this process to sensitize HNSCC to radiotherapy.

show abstract

Section: Discussionmentioning

confidence: 99%

Hedgehog Signaling Drives Radioresistance and Stroma-Driven Tumor Repopulation in Head and Neck Squamous Cancers

et al. 2014

View full text Add to dashboard Cite

show abstract

“…These results suggested that rapamycin can retard NPC growth and improve the radiosensitivity of NPC through inhibiting both the Akt/mTOR/S6 and Akt/GSK3β/cyclin D1 pro-survival signaling pathways. A recent phase I clinical trial documented the safety and tolerance of everolimus, another mTOR inhibitor, in the treatment of head and neck cancer when administered in combination with weekly cisplatin and intensity-modulated RT (29). As a widely used drug for suppressing autoimmune responses in organ transplantation, rapamycin is safe and may be used as a radiosensitizer in the RT of NPC.…”

Section: Discussionmentioning

confidence: 99%

Improved antitumor effect of ionizing radiation in combination with rapamycin for treating nasopharyngeal carcinoma

et al. 2017

View full text Add to dashboard Cite

Abstract. The aim of the present study is to investigate if rapamycin is a radiosensitizer of nasopharyngeal carcinoma (NPC), and to identify which pathways are involved in radiation sensitization. In vitro, using untreated cells as the control, NPC cells were treated with rapamycin, ionizing radiation (IR) or both. Differences in the phosphorylation of ribosomal protein S6 and glycogen synthase kinase (GSK) 3β, expression of cyclin D1, clonogenic survival, number of phosphorylated histone subunit 2AX (γH2AX) foci, and cell cycle status between the study groups were compared. The results indicated that rapamycin alone decreased the phosphorylation of S6 and GSK3β, as well as the expression of cyclin D1, in NPC cells. Thus, rapamycin-treated NPC cells had lower cell viability, and higher DNA damage and G1 arrest than control cells. In addition, the combination of rapamycin and IR caused the highest cell death, DNA damage and G1 arrest when compared with the effects caused by either treatment alone. In conclusion, rapamycin improves the anti-tumor effect of IR for treating NPC through inhibiting the Akt/mechanistic target of rapamycin/S6 and Akt/GSK3β/cyclin D1 signaling pathways.

show abstract

“…A larger phase 2 study of this induction chemotherapy regimen followed by definitive locoregional therapy to assess efficacy and explore candidate biomarkers is warranted. We have recently reported the results from a phase 1 study of everolimus plus low-dose weekly cisplatin and definitive intensity-modulated radiation therapy (IMRT) for patients with head and neck cancer, 39 and that chemoradiation regimen could be used after induction chemotherapy with everolimus plus docetaxel and cisplatin in an efficacy-based phase 2 study.…”

Section: Discussionmentioning

confidence: 99%

A phase 1 study of everolimus plus docetaxel plus cisplatin as induction chemotherapy for patients with locally and/or regionally advanced head and neck cancer

Fury

Sherman

et al. 2013

Cancer

Self Cite

View full text Add to dashboard Cite

BACKGROUND: Activation of the phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is common in head and neck cancers, and it has been demonstrated that inhibition of mTOR complex 1 sensitizes cell lines to platinum and taxane chemotherapy. The authors conducted a phase 1 study to evaluate the addition of oral everolimus to cisplatin and docetaxel as induction chemotherapy for head and neck cancer. METHODS: In this single-institution phase 1 study, 3 doses of daily everolimus were explored: 5 mg daily, 7.5 mg daily (administered as 5 mg daily alternating with 10 mg daily), and 10 mg daily of each 21-day cycle. Cisplatin and docetaxel doses were fixed (both were 75 mg/m 2 on day 1 of 21-day cycle) at each dose level with pegfilgrastim support. A standard 3 þ 3 dose-escalation plan was used. After induction, patients were removed from protocol. RESULTS: Eighteen patients were enrolled (15 men, 3 women), and their median Karnofsky performance status was 90. The most common toxicities were hyperglycemia, low hemoglobin, fatigue, and thrombocytopenia. Dose-limiting toxicities (DLTs) were neutropenic fever (1 event at dose level 2, 2 events at dose level 3), and all patients recovered fully from these DLTs. The maximum tolerated dose was exceeded at dose level 3. The progression-free survival rate at 1 year was 87.5% (95% confidence interval, 56.8%-96.7%); and, at 2 years, it was 76.6% (95% confidence interval, 41.2%-92.3%). Activating PI3K catalytic subunit a (PIK3CA) gene mutations were identified in 2 human papillomavirus-associated oropharyngeal cancers. CONCLUSIONS: The phase 2 recommended dose was 7.5 mg daily for everolimus plus cisplatin and docetaxel (both at 75 mg/m 2 on day 1 of a 21-day cycle) given with pegfilgrastim support. Cancer

show abstract

A Phase 1 Study of Everolimus + Weekly Cisplatin + Intensity Modulated Radiation Therapy in Head-and-Neck Cancer

Cited by 52 publications

References 45 publications

Hedgehog Signaling Drives Radioresistance and Stroma-Driven Tumor Repopulation in Head and Neck Squamous Cancers

Hedgehog Signaling Drives Radioresistance and Stroma-Driven Tumor Repopulation in Head and Neck Squamous Cancers

Improved antitumor effect of ionizing radiation in combination with rapamycin for treating nasopharyngeal carcinoma

A phase 1 study of everolimus plus docetaxel plus cisplatin as induction chemotherapy for patients with locally and/or regionally advanced head and neck cancer

Contact Info

Product

Resources

About