Pharmacodynamic evaluation of temsirolimus in patients with newly diagnosed advanced‐stage head and neck squamous cell carcinoma

Ekshyyan, Oleksandr; Mills, Glenn; Lian, Timothy; Amirghahari, Nazanin; Rong, Xiaohua; Lowery-Nordberg, Mary; Abreo, Fleurette; Veillon, Diana M.; Caldito, Gloria; Speicher, Lisa A.; Glass, Jonathan; Nathan, Cherie‐Ann O.

doi:10.1002/hed.21374

Cited by 28 publications

(31 citation statements)

References 30 publications

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“…As supported by extensive preclinical investigation, the use of mTOR inhibitors, including rapamycin (sirolimus) and its analogs, CCI-779 (temserolimus) and RAD001 (everolimus), can dramatically reduce tumor burden and even recurrence in HNSCC tumor xenografts and in chemically-induced and genetically-defined animal models recapitulating HNSCC initiation and progression (18–22). Furthermore, recent clinical evaluation of temserolimus as neoadjuvant prior to definitive treatment has revealed that all predicted biochemical targets for mTOR inhibitors in this tumor type are hit in the clinical setting, at clinically relevant doses and with limited side effects, resulting in cancer cell apoptosis and tumor shrinkage (32). We now show that activation of the mTOR pathway is a frequent event in human metastatic HNSCC lesions.…”

Section: Discussionmentioning

confidence: 99%

“…The blockade of mTOR in experimental and clinical HNSCC lesions leads to a rapid decrease in the phosphorylated state of S6 and 4EBP1 (18, 20, 32), two downstream targets of the mTOR complex 1 (mTORC1) (27), which also serves as a biomarker for the validation of the biochemical activity of mTOR inhibitors in their target tissues. In HNSCC, rapamycin also causes a rapid decrease in the phosphorylation of Akt in serine 473 (18–20), a target for mTORC2 (27), suggesting that, as shown in cultured cell systems (31), prolonged exposure to rapamycin and its analogs can reduce mTORC2 activity, likely by an indirect, yet unknown mechanism.…”

Section: Discussionmentioning

confidence: 99%

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Decreased Lymphangiogenesis and Lymph Node Metastasis by mTOR Inhibition in Head and Neck Cancer

et al. 2011

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Despite our improved understanding of cancer, the 5-year survival rate for head and neck squamous cell carcinomas (HNSCC) patients remains relatively unchanged at 50% for the past three decades. HNSCC often metastasize to locoregional lymph nodes, and lymph node involvement represents one of the most important prognostic factors of poor clinical outcome. Among the multiple dysregulated molecular mechanism in HNSCC, emerging basic, preclinical, and clinical findings support the importance of the mTOR signaling route in HNSCC progression. Indeed, we observed here that the activation of mTOR is a widespread event in clinical specimens of HNSCC invading locoregional lymph nodes. We developed an orthotopic model of HNSCC consisting in the implantation of HNSCC cells into the tongues of immunocompromised mice. These orthotopic tumors spontaneously metastasize to the cervical lymph nodes, where the presence of HNSCC cells can be revealed by histological and immunohistochemical evaluation. Both primary and metastatic experimental HNSCC lesions exhibited elevated mTOR activity. The ability to monitor and quantitate lymph node invasion in this model system enabled us to explore whether the blockade of mTOR could impact on HNSCC metastasis. We found that inhibition of mTOR with rapamycin and the rapalog RAD001 diminished lymphangiogenesis in the primary tumors and prevented the dissemination of HNSCC cancer cells to the cervical lymph nodes, thereby prolonging animal survival. These findings may provide a rationale for the future clinical evaluation of mTOR inhibitors, including rapamycin and its analogs, as part of a molecular-targeted metastasis preventive strategy for the treatment of HNSCC patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Decreased Lymphangiogenesis and Lymph Node Metastasis by mTOR Inhibition in Head and Neck Cancer

et al. 2011

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“…For example, rapamycin prevented tumour progression of benign or malignant tumours in mice possessing mutant K-ras, with or without loss of p53, respectively [36]. This preclinical model parallels recent finding using this small molecule inhibitor in HNSCC patients [68]. Similarly, Samuel et al [69] showed that deletion of RAC1 prevented oral papilloma development in mutant KRAS mice, providing another possible therapeutic target for mutant KRAS mice.…”

Section: Resultsmentioning

confidence: 62%

Animal Models to Study the Mutational Landscape for Oral Cavity and Oropharyngeal Cancers

Spiotto

Pytynia

Liu

et al. 2013

JOMR

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ObjectivesCancer is likely caused by alterations in gene structure or expression. Recently, next generation sequencing has documented mutations in 106 head and neck squamous cell cancer genomes, suggesting several new candidate genes. However, it remains difficult to determine which mutations directly contributed to cancer. Here, summarize the animal models which have already validated and may test cancer causing mutations identified by next generation sequencing approaches.Material and MethodsWe reviewed the existing literature on genetically engineered mouse models and next generation sequencing (NGS), as it relates to animal models of squamous cell cancers of the head and neck (HNSCC) in PubMed.ResultsNSG has identified an average of 19 to 130 distinct mutations per HNSCC specimen. While many mutations likely had biological significance, it remains unclear which mutations were essential to, or "drive," carcinogenesis. In contrast, "passenger" mutations also exist that provide no selection advantage. The genes identified by NGS included p53, RAS, Human Papillomavirus oncogenes, as well as novel genes such as NOTCH1, DICER and SYNE1,2. Animal models of HNSCC have already validated some of these common gene mutations identified by NGS.Conclusions The advent of next generation sequencing will provide new leads to the genetic changes occurring in squamous cell cancers of the head and neck. Animal models will enable us to validate these new leads in order to better elucidate the biology of squamous cell cancers of the head and neck.

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“…Temsirolimus appeared to be a more potent radiosensitizer than cisplatin in mice bearing squamous cell carcinoma xenografts [96]. In a pharmacodynamic evaluation of temsirolimus in SCCHN patients, Ekshyyan et al found a significant inhibition of the mTOR pathways in tumor cells and in peripheral blood mononuclear cells [97]. Everolimus 10 mg/day, days 1–21 can be safely combined with cisplatin 20 mg/m², days 1, 8, and 15 of a 28-day cycle in patients with solid tumors [98].…”

Section: Other Targetsmentioning

confidence: 99%

Biologic Therapy in Head and Neck Cancer: A Road with Hurdles

Specenier

Vermorken

2012

ISRN Oncology

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The epidermal growth factor receptor (EGFR) is overexpressed in the vast majority of cases of squamous cell carcinoma of the head and neck (SCCHN). A high EGFR expression is associated with an unfavorable prognosis. Cetuximab is a chimeric human/murine IgG1 antibody which binds with high affinity to the EGFR. It is the only targeted agent which got approval for the treatment of SCCHN from the regulatory agencies of Europe and the United States, both in locoregionally advanced disease, in association with radiation, and in recurrent/metastatic disease. The outcome of trials involving other EGFR-directed monoclonal antibodies, that is, zalutumumab and panitumumab, was consistent with the results with cetuximab. However these trials failed to meet their primary endpoint. The results with EGFR-directed tyrosine kinase inhibitors have been disappointing. Other potential targets for treatment in SCCHN include the entire ErbB family, the vascular endothelial growth factor (VEGF) and its receptor (VEGFR), the insulin-like growth factor 1 receptor (IGF-1R), the insulin receptor (IR), histone deacetylases (HDAC), the mammalian target of rapamycin (mTOR), the platelet-derived growth factor receptor (PDGFR), heat-shock protein 90 (HSP90), nuclear factor-kappa B (NF-κB), aurora A or B, and phosphatidylinositol 3-kinase (PIK3CA).

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Pharmacodynamic evaluation of temsirolimus in patients with newly diagnosed advanced‐stage head and neck squamous cell carcinoma

Abstract: Significant inhibition of the mTOR pathway was noted in both tumors and PBMCs of HNSCC with minimal side effects. The mTOR inhibitors can potentially be used as adjuvant therapy for patients with minimal residual disease and PBMCs are potential surrogate markers in this setting.

Cited by 28 publications

References 30 publications

Decreased Lymphangiogenesis and Lymph Node Metastasis by mTOR Inhibition in Head and Neck Cancer

Decreased Lymphangiogenesis and Lymph Node Metastasis by mTOR Inhibition in Head and Neck Cancer

Animal Models to Study the Mutational Landscape for Oral Cavity and Oropharyngeal Cancers

Biologic Therapy in Head and Neck Cancer: A Road with Hurdles

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