BAY 87–2243, a novel inhibitor of hypoxia-induced gene activation, improves local tumor control after fractionated irradiation in a schedule-dependent manner in head and neck human xenografts

Radiation Oncology

Ala Yaromina⁴  Daniel Zips⁶  Michael Baumann¹  Kerstin Unterschemmann³  Holger Hess-Stumpp³  Kristin Gurtner²  Kerstin Brüchner¹  Lydia Koi⁵  Linda Helbig² 

[1] Institute of Radiooncology Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany;Department of Radiation Oncology, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany;Global Drug Discovery, Bayer Pharma AG, Berlin and Wuppertal, Germany;Department of Radiation Oncology (MAASTRO Lab), GROW – School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands;German Cancer Consortium (DKTK), Dresden and German Cancer Research center (DKFZ), Heidelberg, Germany;German Cancer Consortium (DKTK), Tübingen, Germany

关键词: Human tumor xenograft;    Tumor microenvironment;    Local tumor control;    Fractionated radiation;    Cisplatin;    HIF pathway inhibition;   

Others  :  1151369
DOI  :  10.1186/1748-717X-9-207

 received in 2014-07-01, accepted in 2014-09-09,  发布年份 2014

【 摘 要 】

Background

The transcription factor hypoxia-inducible factor-1 (HIF-1) pathway plays an important role in tumor response to cytotoxic treatments. We investigated the effects of a novel small molecule inhibitor of mitochondrial complex I and hypoxia-induced HIF-1 activity BAY-87-2243, on tumor microenvironment and response of human squamous cell carcinoma (hSCC) to clinically relevant fractionated radiotherapy (RT) with and without concomitant chemotherapy.

Methods

When UT-SCC-5 hSCC xenografts in nude mice reached 6 mm in diameter BAY-87-2243 or carrier was administered before and/or during RT or radiochemotherapy with concomitant cisplatin (RCT). Local tumor control was evaluated 150 days after irradiation and the doses to control 50% of tumors (TCD₅₀) were compared between treatment arms. Tumors were excised at different time points during BAY-87-2243 or carrier treatment for western blot and immunohistological investigations.

Results

BAY-87-2243 markedly decreased nuclear HIF-1α expression and pimonidazole hypoxic fraction already after 3 days of drug treatment. BAY-87-2243 prior to RT significantly reduced TCD₅₀ from 123 to 100 Gy (p=0.037). Additional BAY-87-2243 application during RT did not decrease TCD₅₀. BAY-87-2243 before and during radiochemotherapy did not improve local tumor control.

Conclusions

Pronounced reduction of tumor hypoxia by application of BAY-87-2243 prior to RT improved local tumor control. The results demonstrate that radiosensitizing effect importantly depends on treatment schedule. The data support further investigations of HIF-1 pathway inhibitors for radiotherapy and of predictive tests to select patients who will benefit from this combined treatment.

【 授权许可】

   
2014 Helbig et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Bachtiary B, Schindl M, Potter R, Dreier B, Knocke TH, Hainfellner JA, Horvat R, Birner P: Overexpression of hypoxia-inducible factor 1alpha indicates diminished response to radiotherapy and unfavorable prognosis in patients receiving radical radiotherapy for cervical cancer. Clin Cancer Res 2003, 9:2234-2240.
• [2]Birner P, Schindl M, Obermair A, Breitenecker G, Oberhuber G: Expression of hypoxia-inducible factor 1alpha in epithelial ovarian tumors: its impact on prognosis and on response to chemotherapy. Clin Cancer Res 2001, 7:1661-1668.
• [3]Schindl M, Schoppmann SF, Samonigg H, Hausmaninger H, Kwasny W, Gnant M, Jakesz R, Kubista E, Birner P, Oberhuber G: Overexpression of hypoxia-inducible factor 1alpha is associated with an unfavorable prognosis in lymph node-positive breast cancer. Clin Cancer Res 2002, 8:1831-1837.
• [4]Aebersold DM, Burri P, Beer KT, Laissue J, Djonov V, Greiner RH, Semenza GL: Expression of hypoxia-inducible factor-1alpha: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. Cancer Res 2001, 61:2911-2916.
• [5]dos Santos M, Mercante AM, Louro ID, Goncalves AJ, de Carvalho MB, da Silva EH, da Silva AM: HIF1-alpha expression predicts survival of patients with squamous cell carcinoma of the oral cavity. PLoS One 2012, 7:e45228.
• [6]Li F, Sonveaux P, Rabbani ZN, Liu S, Yan B, Huang Q, Vujaskovic Z, Dewhirst MW, Li CY: Regulation of HIF-1alpha stability through S-nitrosylation. Mol Cell 2007, 26:63-74.
• [7]Doe MR, Ascano JM, Kaur M, Cole MD: Myc posttranscriptionally induces HIF1 protein and target gene expression in normal and cancer cells. Cancer Res 2011, 72:949-957.
• [8]Moeller BJ, Cao Y, Li CY, Dewhirst MW: Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell 2004, 5:429-441.
• [9]Majmundar AJ, Wong WJ, Simon MC: Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell 2010, 40:294-309.
• [10]Schwartz DL, Powis G, Thitai-Kumar A, He Y, Bankson J, Williams R, Lemos R, Oh J, Volgin A, Soghomonyan S, Nishii R, Alauddin M, Mukhopadhay U, Peng Z, Bornmann W, Gelovani J: The selective hypoxia inducible factor-1 inhibitor PX-478 provides in vivo radiosensitization through tumor stromal effects. Mol Cancer Ther 2009, 8:947-958.
• [11]Kessler J, Hahnel A, Wichmann H, Rot S, Kappler M, Bache M, Vordermark D: HIF-1alpha inhibition by siRNA or chetomin in human malignant glioma cells: effects on hypoxic radioresistance and monitoring via CA9 expression. BMC Cancer 2010, 10:605. BioMed Central Full Text
• [12]Staab A, Loeffler J, Said HM, Diehlmann D, Katzer A, Beyer M, Fleischer M, Schwab F, Baier K, Einsele H, Flentje M, Vordermark D: Effects of HIF-1 inhibition by chetomin on hypoxia-related transcription and radiosensitivity in HT 1080 human fibrosarcoma cells. BMC Cancer 2007, 7:213. BioMed Central Full Text
• [13]Dikmen ZG, Gellert GC, Dogan P, Yoon H, Lee YB, Ahn CH, Shay JW: In vivo and in vitro effects of a HIF-1alpha inhibitor, RX-0047. J Cell Biochem 2008, 104:985-994.
• [14]Sasabe E, Zhou X, Li D, Oku N, Yamamoto T, Osaki T: The involvement of hypoxia-inducible factor-1alpha in the susceptibility to gamma-rays and chemotherapeutic drugs of oral squamous cell carcinoma cells. Int J Cancer 2007, 120:268-277.
• [15]Song X, Liu X, Chi W, Liu Y, Wei L, Wang X, Yu J: Hypoxia-induced resistance to cisplatin and doxorubicin in non-small cell lung cancer is inhibited by silencing of HIF-1alpha gene. Cancer Chemother Pharmacol 2006, 58:776-784.
• [16]Harada H, Itasaka S, Zhu Y, Zeng L, Xie X, Morinibu A, Shinomiya K, Hiraoka M: Treatment regimen determines whether an HIF-1 inhibitor enhances or inhibits the effect of radiation therapy. Br J Cancer 2009, 100:747-757.
• [17]Moeller BJ, Dreher MR, Rabbani ZN, Schroeder T, Cao Y, Li CY, Dewhirst MW: Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer Cell 2005, 8:99-110.
• [18]Meijer TW, Kaanders JH, Span PN, Bussink J: Targeting hypoxia, HIF-1, and tumor glucose metabolism to improve radiotherapy efficacy. Clin Cancer Res 2012, 18:5585-5594.
• [19]Harada H, Inoue M, Itasaka S, Hirota K, Morinibu A, Shinomiya K, Zeng L, Ou G, Zhu Y, Yoshimura M, McKenna WG, Muschel RJ, Hiraoka M: Cancer cells that survive radiation therapy acquire HIF-1 activity and translocate towards tumour blood vessels. Nat Commun 2012, 3:783.
• [20]Tredan O, Galmarini CM, Patel K, Tannock IF: Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst 2007, 99:1441-1454.
• [21]Su W, Huang L, Ao Q, Zhang Q, Tian X, Fang Y, Lu Y: Noscapine sensitizes chemoresistant ovarian cancer cells to cisplatin through inhibition of HIF-1alpha. Cancer Lett 2011, 305:94-99.
• [22]Liu Y, Bernauer AM, Yingling CM, Belinsky SA: HIF1alpha regulated expression of XPA contributes to cisplatin resistance in lung cancer. Carcinogenesis 2012, 33:1187-1192.
• [23]Ellinghaus P, Heisler I, Unterschemmann K, Haerter M, Beck H, Greschat S, Ehrmann A, Summer H, Flamme I, Oehme F, Thierauch K, Michels M, Hess-Stumpp H, Ziegelbauer K: BAY 87–2243, a highly potent and selective inhibitor of hypoxia-induced gene activation has antitumor activities by inhibition of mitochondrial complex I. Cancer Med 2013, 2:611-624.
• [24]Helbig L, Koi L, Bruchner K, Gurtner K, Hess-Stumpp H, Unterschemmann K, Pruschy M, Baumann M, Yaromina A, Zips D: Hypoxia-inducible factor pathway inhibition resolves tumor hypoxia and improves local tumor control after single-dose irradiation. Int J Radiat Oncol Biol Phys 2014, 88:159-166.
• [25]Yaromina A, Kroeber T, Meinzer A, Boeke S, Thames H, Baumann M, Zips D: Exploratory study of the prognostic value of microenvironmental parameters during fractionated irradiation in human squamous cell carcinoma xenografts. Int J Radiat Oncol Biol Phys 2011, 80:1205-1213.
• [26]Yaromina A, Zips D, Thames HD, Eicheler W, Krause M, Rosner A, Haase M, Petersen C, Raleigh JA, Quennet V, Walenta S, Mueller-Klieser W, Baumann M: Pimonidazole labelling and response to fractionated irradiation of five human squamous cell carcinoma (hSCC) lines in nude mice: the need for a multivariate approach in biomarker studies. Radiother Oncol 2006, 81:122-129.
• [27]Helbig L, Yaromina A, Sriramareddy SN, Boke S, Koi L, Thames HD, Baumann M, Zips D: Prognostic value of HIF-1alpha expression during fractionated irradiation. Strahlenther Onkol 2012, 188:1031-1037.
• [28]Wouters BG, Koritzinsky M: Hypoxia signalling through mTOR and the unfolded protein response in cancer. Nat Rev Cancer 2008, 8:851-864.
• [29]Lee K, Qian DZ, Rey S, Wei H, Liu JO, Semenza GL: Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells. Proc Natl Acad Sci U S A 2009, 106:2353-2358.
• [30]Secomb TW, Hsu R, Ong ET, Gross JF, Dewhirst MW: Analysis of the effects of oxygen supply and demand on hypoxic fraction in tumors. Acta Oncol 1995, 34:313-316.
• [31]Sattler UG, Meyer SS, Quennet V, Hoerner C, Knoerzer H, Fabian C, Yaromina A, Zips D, Walenta S, Baumann M, Mueller-Klieser W: Glycolytic metabolism and tumour response to fractionated irradiation. Radiother Oncol 2010, 94:102-109.
• [32]Goetze K, Meyer SS, Yaromina A, Zips D, Baumann M, Mueller-Klieser W: Glycolysis-related gene induction and ATP reduction during fractionated irradiation: Markers for radiation responsiveness of human tumor xenografts. Strahlenther Onkol 2013, 189:782-788.
• [33]Yaromina A, Quennet V, Zips D, Meyer S, Shakirin G, Walenta S, Mueller-Klieser W, Baumann M: Co-localisation of hypoxia and perfusion markers with parameters of glucose metabolism in human squamous cell carcinoma (hSCC) xenografts. Int J Radiat Biol 2009, 85:972-980.
• [34]Steel GG: Cell survival as a determinant of tumour response. In Basic clinical radiobiology. 3rd edition. Edited by Steel GG. London: Arnold; 2002:52-63.
• [35]Ayrapetov MK, Xu C, Sun Y, Zhu K, Parmar K, D'Andrea AD, Price BD: Activation of Hif1alpha by the prolylhydroxylase inhibitor dimethyoxalyglycine decreases radiosensitivity. PLoS One 2011, 6:e26064.
• [36]Rouschop KM, Dubois LJ, Keulers TG, van den Beucken T, Lambin P, Bussink J, van der Kogel AJ, Koritzinsky M, Wouters BG: PERK/eIF2alpha signaling protects therapy resistant hypoxic cells through induction of glutathione synthesis and protection against ROS. Proc Natl Acad Sci U S A 2013, 110:4622-4627.
• [37]Monti E, Gariboldi MB: HIF-1 as a target for cancer chemotherapy, chemosensitization and chemoprevention. Curr Mol Pharmacol 2011, 4:62-77.
• [38]Martin LP, Hamilton TC, Schilder RJ: Platinum resistance: the role of DNA repair pathways. Clin Cancer Res 2008, 14:1291-1295.
• [39]Zhang N, Zhang H, Xia L, Zheng Y, Yu Y, Zhu Y, Chen G, Di W: NSC606985 induces apoptosis, exerts synergistic effects with cisplatin, and inhibits hypoxia-stabilized HIF-1alpha protein in human ovarian cancer cells. Cancer Lett 2009, 278:139-144.
• [40]van den Broek GB, Wildeman M, Rasch CR, Armstrong N, Schuuring E, Begg AC, Looijenga LH, Scheper R, van der Wal JE, Menkema L, van Diest PJ, Balm AJ, van Velthuysen ML, van den Brekel MW: Molecular markers predict outcome in squamous cell carcinoma of the head and neck after concomitant cisplatin-based chemoradiation. Int J Cancer 2009, 124:2643-2650.
• [41]Bartelink H, Kallman RF, Rapacchietta D, Hart GA: Therapeutic enhancement in mice by clinically relevant dose and fractionation schedules of cis-diamminedichloroplatinum (II) and irradiation. Radiother Oncol 1986, 6:61-74.
• [42]Begg AC, Bohlken S, Bartelink H: The effect of cisplatin on the repair of radiation damage in RIF1 mouse tumours in vivo. Radiother Oncol 1989, 15:79-91.
• [43]Cooper JS, Zhang Q, Pajak TF, Forastiere AA, Jacobs J, Saxman SB, Kish JA, Kim HE, Cmelak AJ, Rotman M, Lustig R, Ensley JF, Thorstad W, Schultz CJ, Yom SS, Ang KK: Long-term Follow-up of the RTOG 9501/Intergroup Phase III Trial: Postoperative Concurrent Radiation Therapy and Chemotherapy in High-Risk Squamous Cell Carcinoma of the Head and Neck. Int J Radiat Oncol Biol Phys 2012, 84:1198-1205.
• [44]Pignon JP, le Maitre A, Maillard E, Bourhis J: Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 2009, 92:4-14.