Cisplatin and Radiotherapy With or Without Erlotinib in Locally Advanced Squamous Cell Carcinoma of the Head and Neck: A Randomized Phase II Trial

Martins, Renato; Parvathaneni, Upendra; Bauman, Julie E.; Sharma, Anand K.; Raez, Luis E.; Papagikos, Michael A.; Yunus, Furhan; Kurland, Brenda F.; Eaton, Keith D.; Liao, Jay J.; Méndez, Eduardo; Futran, Neal D.; Wang, David X.; Chai, Xiaoyu; Wallace, Stephen S.; Austin, Melissa; Schmidt, Rodney A.; Hayes, D. Neil

doi:10.1200/jco.2012.46.3299

Cited by 176 publications

(102 citation statements)

References 21 publications

(9 reference statements)

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“…Previous models relied on a single injection of high-dose cisplatin, resulting in high toxicity and little reduction in hearing sensitivity (8)(9)(10). We developed a new mouse model of cisplatin ototoxicity that approximates the pattern of multiple cycles of cisplatin administration in humans (11)(12)(13). We evaluated two cisplatin administration protocols.…”

Section: Resultsmentioning

confidence: 99%

Sound preconditioning therapy inhibits ototoxic hearing loss in mice

Roy¹,

Ryals²,

Bruele³

et al. 2013

J. Clin. Invest.

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Therapeutic drugs with ototoxic side effects cause significant hearing loss for thousands of patients annually. Two major classes of ototoxic drugs are cisplatin and the aminoglycoside antibiotics, both of which are toxic to mechanosensory hair cells, the receptor cells of the inner ear. A critical need exists for therapies that protect the inner ear without inhibiting the therapeutic efficacy of these drugs. The induction of heat shock proteins (HSPs) inhibits both aminoglycoside-and cisplatin-induced hair cell death and hearing loss. We hypothesized that exposure to sound that is titrated to stress the inner ear without causing permanent damage would induce HSPs in the cochlea and inhibit ototoxic drug-induced hearing loss. We developed a sound exposure protocol that induces HSPs without causing permanent hearing loss. We used this protocol in conjunction with a newly developed mouse model of cisplatin ototoxicity and found that preconditioning mouse inner ears with sound has a robust protective effect against cisplatin-induced hearing loss and hair cell death. Sound therapy also provided protection against aminoglycoside-induced hearing loss. These data indicate that sound preconditioning protects against both classes of ototoxic drugs, and they suggest that sound therapy holds promise for preventing hearing loss in patients receiving these drugs. IntroductionOur goal is to develop a clinical therapy that inhibits hearing loss in patients receiving ototoxic drugs. Heat shock protein (HSP) induction is a critical stress response in the inner ear that can promote survival of hair cells exposed to both classes of ototoxic drugs (1-5). Given that HSP induction is a ubiquitous response to stress (6), we hypothesized that sound that is loud enough to stress the inner ear without causing permanent damage would induce HSPs and inhibit ototoxic drug-induced hearing loss.

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Section: Resultsmentioning

confidence: 99%

Sound preconditioning therapy inhibits ototoxic hearing loss in mice

Roy¹,

Ryals²,

Bruele³

et al. 2013

J. Clin. Invest.

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“…SCCs do not commonly harbor somatic oncogene-activating mutations, but instead are associated with frequent mutational inactivation of tumor suppressor pathways including p53 and NOTCH, the therapeutic implications of which remain to be established (2,3). In addition, although the EGFR is an attractive therapeutic target that is overexpressed or amplified in a subset of cases, only limited success with EGFR-directed therapy has been achieved in SCC despite intensive efforts over many years (4,5). Recent systematic sequencing studies of HNSCC have confirmed the remarkable rarity of tumor-associated somatic mutations in well-established oncogenic drivers, which include HRAS (4% of cases) and the PI3K catalytic subunit PIK3CA (7% of cases) (2,3).…”

Section: Introductionmentioning

confidence: 99%

FGFR2 signaling underlies p63 oncogenic function in squamous cell carcinoma

Ramsey

Wilson²,

Ory³

et al. 2013

J. Clin. Invest.

101

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Oncogenic transcription factors drive many human cancers, yet identifying and therapeutically targeting the resulting deregulated pathways has proven difficult. Squamous cell carcinoma (SCC) is a common and lethal human cancer, and relatively little progress has been made in improving outcomes for SCC due to a poor understanding of its underlying molecular pathogenesis. While SCCs typically lack somatic oncogene-activating mutations, they exhibit frequent overexpression of the p53-related transcription factor p63. We developed an in vivo murine tumor model to investigate the function and key transcriptional programs of p63 in SCC. Here, we show that established SCCs are exquisitely dependent on p63, as acute genetic ablation of p63 in advanced, invasive SCC induced rapid and dramatic apoptosis and tumor regression. In vivo genome-wide gene expression analysis identified a tumor-survival program involving p63-regulated FGFR2 signaling that was activated by ligand emanating from abundant tumor-associated stroma. Correspondingly, we demonstrate the therapeutic efficacy of extinguishing this signaling axis in endogenous SCCs using the clinical FGFR2 inhibitor AZD4547. Collectively, these results reveal an unanticipated role for p63-driven paracrine FGFR2 signaling as an addicting pathway in human cancer and suggest a new approach for the treatment of SCC.

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“…Targeting the EGFR by tyrosine kinase inhibitors is another well-studied field of oncology, particularly in the case of EGFR-mutated non-small cell lung cancer (NSCLC), in which erlotinib and gefitinib serve as useful drugs that aid the improvement of progression-free survival and overall survival (19). Unfortunately, in an unselected cohort of head and neck cancer patients, erlotinib failed to improve progression-free survival when used in combination with cisplatin and radiotherapy (20). The role of erlotinib in head and neck cancer may be more efficacious in the field of chemoprevention.…”

Section: Introductionmentioning

confidence: 99%

Melanoma-associated antigen expression and the efficacy of tyrosine kinase inhibitors in head and neck cancer

et al. 2015

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Abstract. Melanoma-associated antigen (MAGE) has been identified in a variety of types of cancer. The expression of several MAGE subgroups is correlated with poor prognosis and chemotherapeutic resistance. One target of chemotherapeutic treatment in head and neck cancer is the epidermal growth factor receptor (EGFR). The efficacy of tyrosine kinase inhibitors (TKI) in the context of melanoma-associated antigens is discussed in the present study. Five human squamous cell carcinoma cell lines were treated with the EGFR TKIs, erlotinib and gefitinib. The efficacy of these agents was measured using a crystal violet assay. Furthermore, the expression levels of MAGE-A1, -A5, -A8, -A9, -A11 and -A12 were determined by reverse transcription-quantitative polymerase chain reaction. The association between TKI efficacy and MAGE-A expression was analyzed by linear regression. The cell lines revealed inhomogeneous expression patterns for the MAGE-A subgroups. Four of the five cell lines demonstrated a good response to erlotinib and gefitinib. However, treatment with erlotinib induced better results than those of gefitinib, and revealed a concentration-dependent effect. The expression of MAGE-A5 and -A11 were significantly correlated with lower efficacy of erlotinib and gefitinib. By contrast, MAGE-A12 was associated with a superior response to these two drugs. One cell line, which expressed all investigated MAGE-A subgroups, was entirely resistant to the two TKIs. These results revealed a notable correlation between MAGE-A5 and -A11 and lower efficacy of EGFR TKIs. Pretreatment analysis of MAGE-A status may therefore aid improvement of chemoprevention using erlotinib and gefitinib in head and neck cancer.

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Cisplatin and Radiotherapy With or Without Erlotinib in Locally Advanced Squamous Cell Carcinoma of the Head and Neck: A Randomized Phase II Trial

Abstract: Erlotinib did not increase the toxicity of cisplatin and radiotherapy in patients with locally advanced HNSCC but failed to significantly increase CRR or PFS.

Cited by 176 publications

References 21 publications

Sound preconditioning therapy inhibits ototoxic hearing loss in mice

Sound preconditioning therapy inhibits ototoxic hearing loss in mice

FGFR2 signaling underlies p63 oncogenic function in squamous cell carcinoma

Melanoma-associated antigen expression and the efficacy of tyrosine kinase inhibitors in head and neck cancer

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