The overall objectives of this project are to investigate the roles of tumor hypoxia and the new bioreductive drug tirapazamine (SR 4233) in the treatment of advanced head and neck cancer, and to determine whether various assays can be used, first to predict, and second to measure the response of these tumors. In addition to these questions, which we believe are relevant to the treatment of any solid tumor, we are seeking to establish a new paradigm by which the response of tumors to a new modifying agent can be assessed during therapy without having to wait for overall response or control rates. This new paradigm, based on the fact that increased chromosome aberrations correlate with increased cell killing, uses new advances in fluorescent in situ hybridization (FISH) using whole chromosome probes. In preclinical studies, we have demonstrated that increased tumor cell kill by the addition of tirapazamine to fractionated radiation also produces increased chromosome aberrations which can be readily detected using this FISH technology. We propose to extend these studies to further human tumors in experimental animals and also in clinical samples in the present project. We will be able to assess dose-modification factors using this technique and to compare this with increased response rates when tirapazamine is added to fractionated radiation. We also wish to test the possibility of detecting those tumors which should respond best to the addition of tirapazamine, either to fractionated radiation or to induction chemotherapy and chemoradiotherapy with drug regimens based on cisplatin. The hypothesis that it is only those tumors which show a large number of single-strand breaks in individual cells assessed by the Comet Assay that will respond to the addition of tirapazamine will be tested with experimental animal tumors and with human tumors. The clinical trial to be performed will have two groups: those with smaller neck nodes, which will be randomized to radiation alone or radiation + tirapazamine, and those with larger, more advanced (N2 to N3) neck nodes, which will be randomized to chemotherapy + radiotherapy with or without the addition of tirapazamine. The focus of the trial will be on the neck nodes, and we will perform all of the pretherapy measurements of tumor oxygenation, the measurements of single-strand breaks with tirapazamine alone, and the increased chromosome aberration caused by radiation on these neck nodes. This clinical trial should answer the question of whether hypoxia contributes significantly to the outcome of radiation therapy or chemoradiotherapy in head and neck cancer neck nodes, whether tirapazamine can improve the outcome in those tumors that are hypoxic, and whether one can establish pretreatment predictive assays of which tumor will benefit from the addition of tirapazamine, and also, whether the benefit can be detected during therapy. This latter assay has the potential of establishing a new paradigm for the detection of the results of a modifying agent during therapy, rather than having to wait for clinical outcome.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA067166-01A1
Application #
5209423
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
1996
Total Cost
Indirect Cost
Vilalta, Marta; Brune, Jourdan; Rafat, Marjan et al. (2018) The role of granulocyte macrophage colony stimulating factor (GM-CSF) in radiation-induced tumor cell migration. Clin Exp Metastasis 35:247-254
Tandon, Neha; Thakkar, Kaushik N; LaGory, Edward L et al. (2018) Generation of Stable Expression Mammalian Cell Lines Using Lentivirus. Bio Protoc 8:
Yang, Zhifen; Zhang, Jing; Jiang, Dadi et al. (2018) A Human Genome-Wide RNAi Screen Reveals Diverse Modulators that Mediate IRE1?-XBP1 Activation. Mol Cancer Res 16:745-753
Benej, Martin; Hong, Xiangqian; Vibhute, Sandip et al. (2018) Papaverine and its derivatives radiosensitize solid tumors by inhibiting mitochondrial metabolism. Proc Natl Acad Sci U S A 115:10756-10761
Rafat, Marjan; Aguilera, Todd A; Vilalta, Marta et al. (2018) Macrophages Promote Circulating Tumor Cell-Mediated Local Recurrence following Radiotherapy in Immunosuppressed Patients. Cancer Res 78:4241-4252
Saiki, Julie P; Cao, Hongbin; Van Wassenhove, Lauren D et al. (2018) Aldehyde dehydrogenase 3A1 activation prevents radiation-induced xerostomia by protecting salivary stem cells from toxic aldehydes. Proc Natl Acad Sci U S A 115:6279-6284
Olcina, Monica M; Kim, Ryan K; Melemenidis, Stavros et al. (2018) The tumour microenvironment links complement system dysregulation and hypoxic signalling?. Br J Radiol :20180069
Castellini, Laura; Moon, Eui Jung; Razorenova, Olga V et al. (2017) KDM4B/JMJD2B is a p53 target gene that modulates the amplitude of p53 response after DNA damage. Nucleic Acids Res 45:3674-3692
VandeKopple, Matthew J; Wu, Jinghai; Baer, Lisa A et al. (2017) Stress-responsive HILPDA is necessary for thermoregulation during fasting. J Endocrinol 235:27-38
Peinado, Héctor; Zhang, Haiying; Matei, Irina R et al. (2017) Pre-metastatic niches: organ-specific homes for metastases. Nat Rev Cancer 17:302-317

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