Tirapazamine, Cisplatin, and Radiation Versus Cisplatin and Radiation for Advanced Squamous Cell Carcinoma of the Head and Neck (TROG 02.02, HeadSTART): A Phase III Trial of the Trans-Tasman Radiation Oncology Group

Rischin, Danny; Peters, Lester J.; O’Sullivan, Brian; Giralt, Jordi; Fisher, Richard; Yuen, Kally; Trotti, Andy; Bernier, Jacques; Bourhis, Jean; Ringash, Jolie; Henke, Michael; Kenny, Liz

doi:10.1200/jco.2009.27.4449

Cited by 322 publications

(155 citation statements)

References 26 publications

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“…Tirapazamine, is a prodrug that is solely reduced in hypoxic cells, provoking highly genotoxic DNA double-strand breaks. Its use before radiotherapy enhanced 3-year survival rates in phase-II trials (Rischin et al, 2005), but it was found ineffectual in all considered parameters in a multinational phase-III trial (Rischin et al, 2010). On the other hand, astounding results in human cancer patients have been achieved with small-molecule glycolysis inhibitors.…”

Section: The Rise Of Anticancer Therapeutics Targeting Metabolismmentioning

confidence: 99%

Metabolic reprogramming of the tumor

2012

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Cancer is classically considered as a genetic and, more recently, epigenetic multistep disease. Despite seminal studies in the 1920s by Warburg showing a characteristic metabolic pattern for tumors, cancer bioenergetics has often been relegated to the backwaters of cancer biology. This review aims to provide a historical account on cancer metabolism research, and to try to integrate and systematize the metabolic strategies in which cancer cells engage to overcome selective pressures during their inception and evolution. Implications of this renovated view on some common concepts and in therapeutics are also discussed.

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Section: The Rise Of Anticancer Therapeutics Targeting Metabolismmentioning

confidence: 99%

Metabolic reprogramming of the tumor

2012

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“…TPZ showed promising activity in early clinical studies (12,13). However, the addition of TPZ to chemoradiotherapy for head and neck squamous cell carcinoma (HNSCC) failed to extend survival in a pivotal trial (14). This disappointing outcome has been attributed to poor compliance with radiotherapy protocols at some centers (15), differential impact of TPZ in HPV-positive and -negative tumors (16) and failure to select patients for presence of tumor hypoxia (17,18).…”

Section: Introductionmentioning

confidence: 99%

Identification of P450 Oxidoreductase as a Major Determinant of Sensitivity to Hypoxia-Activated Prodrugs

et al. 2015

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Hypoxia is a prevalent feature of many tumors contributing to disease progression and treatment resistance, and therefore constitutes an attractive therapeutic target. Several hypoxiaactivated prodrugs (HAP) have been developed, including the phase III candidate TH-302 (evofosfamide) and the preclinical agent SN30000, which is an optimized analogue of the well-studied HAP tirapazamine. Experience with this therapeutic class highlights an urgent need to identify biomarkers of HAP sensitivity, including enzymes responsible for prodrug activation during hypoxia. Using genome-scale shRNA screens and a high-representation library enriched for oxidoreductases, we identified the flavoprotein P450 (cytochrome) oxidoreductase (POR) as the predominant determinant of sensitivity to SN30000 in three different genetic backgrounds. No other genes consistently modified SN30000 sensitivity, even within a POR-negative background. Knockdown or genetic knockout of POR reduced SN30000 reductive metabolism and clonogenic cell death and similarly reduced sensitivity to TH-302 under hypoxia. A retrospective evaluation of head and neck squamous cell carcinomas showed heterogeneous POR expression and suggested a possible relationship between human papillomavirus status and HAP sensitivity. Taken together, our study identifies POR as a potential predictive biomarker of HAP sensitivity that should be explored during the clinical development of SN30000, TH-302, and other hypoxia-directed agents. Cancer Res; 75(19); 4211-23. Ó2015 AACR.

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“…This study comprised a cohort of 240 patients enrolled in 3 successive clinical trials (phases I, II, and III) administered from our institution, all of which have been previously described (29)(30)(31). The treatment regimens involved definitive radiotherapy concurrently with cisplatin plus tirapazamine (phase I), cisplatin plus tirapazamine or cisplatin/5-fluorouracil (phase II), or cisplatin plus tirapazamine or high-dose cisplatin alone (phase III).…”

Section: Patientsmentioning

confidence: 99%

Relationship between Epidermal Growth Factor Receptor Status, p16INK4A, and Outcome in Head and Neck Squamous Cell Carcinoma

Young

Rischin

Fisher

et al. 2011

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: Human papilloma virus (HPV) infection is a powerful prognostic biomarker in head and neck squamous cell carcinoma (HNSCC). Increased epidermal growth factor receptor (EGFR) gene copy number and protein expression have been reported to be negative predictors of outcome. This study examined the relationship between HPV status, EGFR gene copy number, EGFR protein expression, and clinical outcome in HNSCC patients treated with chemoradiation. Methods: HPV status was determined using p16INK4A immunohistochemistry (IHC), EGFR gene copy number was evaluated with FISH, and EGFR protein expression by IHC in 212 subjects. Results: EGFR FISH was positive in 41 of 204 (20%) patients and was negatively correlated with failure-free survival (FFS; HR = 1.84, P = 0.027) and overall survival (OS; HR = 1.78, P = 0.082). For p16INK4A, 85 of 200 (42.5%) patients were found to be p16 positive, including 75 of 131 (57%) with oropharyngeal cancer. Patients with p16-positive oropharyngeal cancer had significantly improved FFS (HR = 0.28, P < 0.001) and OS (HR = 0.31, P = 0.002). Only 2 of 126 (1.6%) oropharyngeal cancer patients were found to be p16+/EGFR FISH+. EGFR IHC was positive in 81 of 93 (87%) of patients and was associated with poorer FFS (HR = 1.98, P = 0.35) and OS (HR = 2.52, P = 0.22). Conclusions: Increased EGFR gene copy number is largely restricted to p16INK4A-negative oropharyngeal cancer. Although p16INK4A and EGFR FISH are both predictive of outcome in univariate analyses, only p16INK4A remains independently predictive. Impact: Knowledge of HPV and EGFR status can have implications for treatment options and prognosis in HNSCC. Cancer Epidemiol Biomarkers Prev; 20(6); 1230–7. ©2011 AACR.

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Tirapazamine, Cisplatin, and Radiation Versus Cisplatin and Radiation for Advanced Squamous Cell Carcinoma of the Head and Neck (TROG 02.02, HeadSTART): A Phase III Trial of the Trans-Tasman Radiation Oncology Group

Abstract: We found no evidence that the addition of TPZ to chemoradiotherapy, in patients with advanced head and neck cancer not selected for the presence of hypoxia, improves OS.

Cited by 322 publications

References 26 publications

Metabolic reprogramming of the tumor

Metabolic reprogramming of the tumor

Identification of P450 Oxidoreductase as a Major Determinant of Sensitivity to Hypoxia-Activated Prodrugs

Relationship between Epidermal Growth Factor Receptor Status, p16INK4A, and Outcome in Head and Neck Squamous Cell Carcinoma

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