Dynamics of changes in type 1 and 2 insulinlike growth factors in the blood of patients with oral squamous cell cancer after targeted therapy with cetuximab

Objective. Studying the blood levels of type 1 and 2 insulin-like growth factors in patients with squamous cell carcinoma of the tongue and mouth floor mucosa depending on the therapy effect.

Materials and Methods. The study included data from 30 patients with squamous cell carcinoma of the tongue and mouth floor mucosa T3–4N0–1M0 who received chemotherapy cycles together with targeted therapy with cetuximab. Twenty non-cancer donors were examined as well. Depending on the therapy effect, patients were divided into two groups: sensitive and resistant ones.

Results. Initial levels of IGF-1 and IGF-2 in the blood serum of patients prior to chemotherapy and targeted therapy with cetuximab were lower than the levels in donors by 53.5 % and 20.3 %, respectively. After chemotherapy and cetuximab therapy, patients with sensitivity to the treatment showed normalization of IGF-1 and its significant increase compared to the initial levels — by 87 %. Levels of IGF-2 were not statistically significantly different from the initial levels and were 32.5 % lower than in donors. The IGF-1 / IGF-2 coefficient was 58 % higher than the initial value.

Conclusions. Chemotherapy and cetuximab therapy normalized levels of IGF-1 in patients with sensitivity to the treatment which was demonstrated by an increase in IGF-1 up to the normal blood levels in effective treatment.

1. M. A. Weinberg, D. J. Estefan Assessing oral malignancies Am Fam Physician, 65 (2002), pp. 1379–1384

2. R. Fietkau Tumor volume as a prognostic factor in the radiotherapy of carcinomas in the head-neck area, Strahlenther Onkol, 176 (2000), pp. 382–383

3. B. Jeremic, B. Milicic Pretreatment prognostic factors of survival in patients with locally advanced nonmetastatic squamous cell carcinoma of the head and neck treated with radiation therapy with or without concurrent chemotherapy Am J Clin Oncol, 32 (2009), pp. 63–68)

4. Sundermann BV, Uhlmann L, Hoffmann J, Freier K, Thiele OC. The localization and risk factors of squamous cell carcinoma in the oral cavity: A retrospective study of 1501 cases. J Craniomaxillofac Surg. 2018 Feb;46 (2):177–182. doi: 10.1016/j.jcms.2017.10.019. Epub 2017 Oct 31. PMID: 29 242 026.

5. Foy JP, Saintigny P, Goudot P, Schouman T, Bertolus C. The promising impact of molecular profiling on treatment strategies in oral cancers. J Stomatol Oral Maxillofac Surg. 2017 Sep;118 (4):242–247. doi: 10.1016/j.jormas.2017.05.004. Epub 2017 May 30. PMID: 28 576 460

6. Чучалин А. Г. Инновационные лекарственные средства XXI века// Вестник Российской Академии наук.— 2016.— Т. 86.— № 6.— С. 480–483.

7. Ferrarotto R, William WN Jr, Tseng JE, Marur S, Shin DM, Murphy B, Cohen EEW, Thomas CY, Willey R, Cosaert J, Harun N, Jack Lee J, Wistuba IW, Haddad RI, Glisson BS. Randomized phase II trial of cixutumumab alone or with cetuximab for refractory recurrent / metastatic head and neck squamous cell carcinoma. Oral Oncol. 2018 Jul;82:83–90. doi: 10.1016j.oraloncology.2018.05.014. Epub 2018 May 19. PMID: 29 909 907.

8. Переводчикова Н. И., Горбунова В. А. Таргетные препараты и их клиническое использование: введение в про блему// Эффективная фармакотерапия в онкологии, гематологии и радиологии.— 2009.— № 2.— С. 6–13

9. Льянова А. А., Владимирова Л. Ю., Франциянц Е. М., Кутилин Д. С., Енгибарян М. А. Молекулярные механизмы основы современной таргетной терапии плоскоклеточного рака языка и слизистой дна полости рта монокло нальными антителами// Злокачественные опухоли. 2017.— Т. 7.— № 4.— С. 77–87.

10. Bonner J., Harari P., Giralt J. et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck// N. Eng. J. Med. 2006; 354: 567–78.

11. Barnes CJ, Ohshiro K, Rayala SK, El-Naggar AK, Kumar R. Insulin-like growth factor receptor as a therapeutic target in head and neck cancer. Clin Cancer Res. 2007 Jul 15;13 (14):4291–9. doi: 10.1158/1078–0432.CCR-06–2040. PMID: 17 634 559.

12. Arslan, I., Keles, E., Ozercan, I. H. et al. The role of insulin-like growth factor I–II receptor on development of pleomorphic adenoma. Eur Arch Otorhinolaryngol 274, 3443–3447 (2017). https://doi.org/10.1007/s00405–017–4644–2

13. Scartozzi M., Mandolesi A., Giampieri R. et. al. Insulin-growth factor 1 expression correlates with clinical outcome in K-RAS wild type colorectal cancer patients treated with cetuximab and irinotecan// Int J Cancer.— 2010.— Vol. 127 (8).— P. 1941–1947 /

14. Sclafani F, Kim TY, Cunningham D, Kim TW, Tabernero J, Schmoll HJ, Roh JK, Kim SY, Park YS, Guren TK, Hawkes E, Clarke SJ, Ferry D, Frödin JE, Ayers M, Nebozhyn M, Peckitt C, Loboda A, Mauro DJ, Watkins DJ. A Randomized Phase II / III Study of Dalotuzumab in Combination With Cetuximab and Irinotecan in Chemorefractory, KRAS Wild-Type, Metastatic Colorectal Cancer. J Natl Cancer Inst. 2015 Sep 23;107 (12):djv258. doi: 10.1093/jnci/djv258. PMID: 26 405 092.

15. Pollak M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat Rev Cancer. 2012 Feb 16;12 (3):159–69. doi: 10.1038/nrc3215. PMID: 22 337 149.)

16. Schumacher B., Garinis G. A., Hoeijmakers J. H. Age to survive: DNA damage and aging// Trends Genet.— 2008.— Vol. 24 (2).— P. 77–85

17. De Mattia E, Bignucolo A, Toffoli G, Cecchin E. Genetic Markers of the Host to Predict the Efficacy of Colorectal Cancer Targeted Therapy. Curr Med Chem. 2020; 27 (25):4249–4273. doi: 10.2174/0929867326666190712151417. PMID: 31 298 142.

18. Gallego R., Codony-Servat J., Garcia-Albeniz X. et al. Serum IGF-1, IGFBP-3, and matrix metalloproteinase-7 levels and acquired chemo-resistance in advanced colorectal cancer// Endocr Relat Cancer.— 2009.— Vol. 16 (1).— P. 311–317.

19. de Groot S., Geldebrom H., Fiocco M. et. al. Serum levels of IGF-1 and IGF-BP3 are associated with event-frr survival in adult Ewing sarcoma patients treated with chemotherapy// Onco Targets Ther.— 2017.— Vol. 10.— P. 2963–2970.— doi: 10.2147/OTT.S123726.

20. Shao Y. Y., Huang C. С., Lin S. D. et al. Predictive value of serum insulin-like growth factor-1 levels predict outcomes of patients with advanced hepatocellular carcinoma receiving antian-giogenic therapy// Clin Cancer Res.— 2012.— Vol. 18 (14).— Р. 3892–3899

21. Elmashad N., Ibrahim W. S., Mayah W. W. et. al. Predictive value of serum insulin-like growth factor-1 in hepatocellular carcinoma// Asian Pac. J. Cancer Prev.— 2015.— Vol. 162).— p. 613–619.

22. Tas F, Karabulut S, Serilmez M, Ciftci R, Duranyildiz D. Clinical significance of serum insulin-like growth factor-1 (IGF1) and insulin-like growth factor binding protein-3 (IGFBP-3) in patients with epithelial ovarian cancer. Tumour Biol. 2014;35 (4):3125–3132. [PubMed] [Google Scholar]

23. Huang YF, Cheng WF, Wu YP, Cheng YM, Hsu KF, Chou CY. Circulating IGF system and treatment outcome in epithelial ovarian cancer. Endocr Relat Cancer. 2014;21 (2):217–229. [PubMed] [Google Scholar]).

24. Minshall C, Arkins S, Straza J, Conners J, Dantzer R, Freund GG et al (1997) IL-4 and insulin-like growth factor-I inhibit the decline in Bcl-2 and promote the survival of IL-3 deprived myeloid progenitors. J Immunol 159:1225–1232].

25. Льянова, А. А. Изучение резистентности к анти-EGFR моноклональному антителу у больных плоскоклеточ ным раком языка и слизистой оболочки дна полости рта, автореф. дис. … канд. мед. наук: 14.01.12 / Льянова Аза Ахметовна,— Ростов-на-Дону, 2020.— С. 12.

26. Brahmkhatri, V. P., Prasanna, C., & Atreya, H. S. (2015). Insulin-like growth factor system in cancer: novel targeted therapies. BioMed research international, 2015, 538 019. doi:10.1155/2015/538019; Pollak M. N., Schernhammer E. S., Hankinson S. E. Insulin-like growth factors and neoplasia. Nature Reviews Cancer. 2004;4 (7):505–518. doi: 10.1038/nrc1387