Top

Journal of Experimental & Clinical Cancer Research

Published in:

Open Access 01-12-2018 | Research

Anti-tumor effects of ONC201 in combination with VEGF-inhibitors significantly impacts colorectal cancer growth and survival in vivo through complementary non-overlapping mechanisms

Authors: Jessica Wagner, C. Leah Kline, Lanlan Zhou, Vladimir Khazak, Wafik S. El-Deiry

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2018

Abstract

Background

Small molecule ONC201 is an investigational anti-tumor agent that upregulates intra-tumoral TRAIL expression and the integrated stress response pathway. A Phase I clinical trial using ONC201 therapy in advanced cancer patients has been completed and the drug has progressed into Phase II trials in several cancer types. Colorectal cancer (CRC) remains one of the leading causes of cancer worldwide and metastatic disease has a poor prognosis. Clinical trials in CRC and other tumor types have demonstrated that therapeutics targeting the vascular endothelial growth factor (VEGF) pathway, such as bevacizumab, are effective in combination with certain chemotherapeutic agents.

Methods

We investigated the potential combination of VEGF inhibitors such as bevacizumab and its murine-counterpart; along with other anti-angiogenic agents and ONC201 in both CRC xenograft and patient-derived xenograft (PDX) models. We utilized non-invasive imaging and immunohistochemistry to determine potential mechanisms of action.

Results

Our results demonstrate significant tumor regression or complete tumor ablation in human xenografts with the combination of ONC201 with bevacizumab, and in syngeneic MC38 colorectal cancer xenografts using a murine VEGF-A inhibitor. Imaging demonstrated the impact of this combination on decreasing tumor growth and tumor metastasis. Our results indicate that ONC201 and anti-angiogenic agents act through distinct mechanisms while increasing tumor cell death and inhibiting proliferation.

Conclusion

With the use of both a murine VEGF inhibitor in syngeneic models, and bevacizumab in human cell line-derived xenografts, we demonstrate that ONC201 in combination with anti-angiogenic therapies such as bevacizumab represents a promising approach for further testing in the clinic for the treatment of CRC.

Available only for authorised users

Valentini V, Coco C, Gambacorta MA, Barba MC, Meldolesi E. Evidence and research perspectives for surgeons in the European rectal cancer consensus conference (EURECA-CC2). Acta Chir Iugosl. 2010;57:9–16.CrossRefPubMed

Palmer G, Holm T. Survival in locally advanced rectal cancer can be improved. Optimal management with centralized investigation and treatment. Lakartidningen. 2010;107:2014–7.PubMed

Jass JR, Whitehall VL, Young J, Leggett BA. Emerging concepts in colorectal neoplasia. Gastroenterology. 2002;123:862–76.CrossRefPubMed

Allen JE, Krigsfeld G, Mayes PA, Patel L, Dicker DT, Patel AS, Dolloff NG, Messaris E, Scata KA, Wang W, et al. Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects. Sci Transl Med. 2013;5:171ra117.CrossRef

Kline CL, Van den Heuvel AP, Allen JE, Prabhu VV, Dicker DT, El-Deiry WS. ONC201 kills solid tumor cells by triggering an integrated stress response dependent on ATF4 activation by specific eIF2α kinases. Sci Signal. 2016;9:ra18.CrossRefPubMedPubMedCentral

Prabhu VV, Allen JE, Dicker DT, El-Deiry WS. Small-molecule ONC201/TIC10 targets chemotherapy-resistant colorectal cancer stem-like cells in an Akt/Foxo3a/TRAIL-dependent manner. Cancer Res. 2015;75:1423–32.CrossRefPubMedPubMedCentral

Ishizawa J, Kojima K, Chachad D, Ruvolo P, Ruvolo V, Jacamo RO, Borthakur G, Mu H, Zeng Z, Tabe Y, et al. ATF4 induction through an atypical integrated stress response to ONC201 triggers p53-independent apoptosis in hematological malignancies. Sci Signal. 2016;9:ra17.CrossRefPubMedPubMedCentral

Allen JE, Prabhu VV, Talekar M, van den Heuvel AP, Lim B, Dicker DT, Fritz JL, Beck A, El-Deiry WS. Genetic and pharmacological screens converge in identifying FLIP, BCL2, and IAP proteins as key regulators of sensitivity to the TRAIL-inducing anticancer agent ONC201/TIC10. Cancer Res. 2015;75:1668–74.CrossRefPubMedPubMedCentral

Allen JE, Krigsfeld G, Patel L, Mayes PA, Dicker DT, Wu GS, El-Deiry WS. Identification of TRAIL-inducing compounds highlights small molecule ONC201/TIC10 as a unique anti-cancer agent that activates the TRAIL pathway. Mol Cancer. 2015;14:99.CrossRefPubMedPubMedCentral

10.

Allen JE, Kline CL, Prabhu VV, Wagner J, Ishizawa J, Madhukar N, Lev A, Baumeister M, Zhou L, Lulla A, et al. Discovery and clinical introduction of first-in-class imipridone ONC201. Oncotarget. 2016;7(45):74380-4392. doi: https://doi.org/10.18632/oncotarget.11814.

11.

Wagner J, Kline CL, Pottorf RS, Nallaganchu BR, Olson GL, Dicker DT, Allen JE, El-Deiry WS. The angular structure of ONC201, a TRAIL pathway-inducing compound, determines its potent anti-cancer activity. Oncotarget. 2014;5:12728–37.PubMed

12.

Jin ZZ, Wang W, Fang DL, Jin YJ. mTOR inhibition sensitizes ONC201-induced anti-colorectal cancer cell activity. Biochem Biophys Res Commun. 2016; doi:https://doi.org/10.1016/j.bbrc.2016.08.126.

13.

Zhang Q, Wang H, Ran L, Zhang Z, Jiang R. The preclinical evaluation of TIC10/ONC201 as an anti-pancreatic cancer agent. Biochem Biophys Res Commun. 2016;476:260–6.CrossRefPubMed

14.

Stein M, Mayer T, Moss R, Silk A, Chan N, Haffty B, DiPaola R, Beckett Y, Bentlyewski E, Zheng L, et al: First-in-human dose escalation study of oral ONC201 in advanced solid tumors. In 2015 ASCO Annual Meeting; Chicago, IL. http://meetinglibrary.asco.org/content/166310-176; 2016.

15.

Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995;1:27–31.CrossRefPubMed

16.

Kanno S, Oda N, Abe M, Terai Y, Ito M, Shitara K, Tabayashi K, Shibuya M, Sato Y. Roles of two VEGF receptors, Flt-1 and KDR, in the signal transduction of VEGF effects in human vascular endothelial cells. Oncogene. 2000;19:2138–46.CrossRefPubMed

17.

Nguyen M. Angiogenic factors as tumor markers. Investig New Drugs. 1997;15:29–37.CrossRef

18.

Bogenrieder T, Herlyn M. Axis of evil: molecular mechanisms of cancer metastasis. Oncogene. 2003;22:6524–36.CrossRefPubMed

19.

Yuan A, Yu CJ, Kuo SH, Chen WJ, Lin FY, Luh KT, Yang PC, Lee YC. Vascular endothelial growth factor 189 mRNA isoform expression specifically correlates with tumor angiogenesis, patient survival, and postoperative relapse in non-small-cell lung cancer. J Clin Oncol. 2001;19:432–41.CrossRefPubMed

20.

Lee JC, Chow NH, Wang ST, Huang SM. Prognostic value of vascular endothelial growth factor expression in colorectal cancer patients. Eur J Cancer. 2000;36:748–53.CrossRefPubMed

21.

Ikeda N, Adachi M, Taki T, Huang C, Hashida H, Takabayashi A, Sho M, Nakajima Y, Kanehiro H, Hisanaga M, et al. Prognostic significance of angiogenesis in human pancreatic cancer. Br J Cancer. 1999;79:1553–63.CrossRefPubMedPubMedCentral

22.

Presta LG, Chen H, O'Connor SJ, Chisholm V, Meng YG, Krummen L, Winkler M, Ferrara N. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 1997;57:4593–9.PubMed

23.

Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature. 1993;362:841–4.CrossRefPubMed

24.

Warren RS, Yuan H, Matli MR, Gillett NA, Ferrara N. Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis. J Clin Invest. 1995;95:1789–97.CrossRefPubMedPubMedCentral

25.

Puthillath A, Patel A, Fakih MG. Targeted therapies in the management of colorectal carcinoma: role of bevacizumab. Onco Targets Ther. 2009;2:1–15.PubMedPubMedCentral

26.

Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42.CrossRefPubMed

27.

Wildiers H, Guetens G, De Boeck G, Verbeken E, Landuyt B, Landuyt W, de Bruijn EA, van Oosterom AT. Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11. Br J Cancer. 2003;88:1979–86.CrossRefPubMedPubMedCentral

28.

Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357:2666–76.CrossRefPubMed

29.

Wilhelm SM, Dumas J, Adnane L, Lynch M, Carter CA, Schütz G, Thierauch KH, Zopf D. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer. 2011;129:245–55.CrossRefPubMed

30.

Teo YL, Ho HK, Chan A. Risk of tyrosine kinase inhibitors-induced hepatotoxicity in cancer patients: a meta-analysis. Cancer Treat Rev. 2013;39:199–206.CrossRefPubMed

31.

Inai T, Mancuso M, Hashizume H, Baffert F, Haskell A, Baluk P, Hu-Lowe DD, Shalinsky DR, Thurston G, Yancopoulos GD, McDonald DM. Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol. 2004;165:35–52.CrossRefPubMedPubMedCentral

32.

Xu L, Cochran DM, Tong RT, Winkler F, Kashiwagi S, Jain RK, Fukumura D. Placenta growth factor overexpression inhibits tumor growth, angiogenesis, and metastasis by depleting vascular endothelial growth factor homodimers in orthotopic mouse models. Cancer Res. 2006;66:3971–7.CrossRefPubMed

33.

Lin PC. Optical imaging and tumor angiogenesis. J Cell Biochem. 2003;90:484–91.CrossRefPubMed

34.

Purhonen S, Palm J, Rossi D, Kaskenpää N, Rajantie I, Ylä-Herttuala S, Alitalo K, Weissman IL, Salven P. Bone marrow-derived circulating endothelial precursors do not contribute to vascular endothelium and are not needed for tumor growth. Proc Natl Acad Sci U S A. 2008;105:6620–5.CrossRefPubMedPubMedCentral

35.

Fujio Y, Walsh K. Akt mediates cytoprotection of endothelial cells by vascular endothelial growth factor in an anchorage-dependent manner. J Biol Chem. 1999;274:16349–54.CrossRefPubMedPubMedCentral

Title: Anti-tumor effects of ONC201 in combination with VEGF-inhibitors significantly impacts colorectal cancer growth and survival in vivo through complementary non-overlapping mechanisms
Authors: Jessica Wagner
C. Leah Kline
Lanlan Zhou
Vladimir Khazak
Wafik S. El-Deiry
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2018
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-018-0671-0

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2018

Radiotherapy-induced cell death activates paracrine HMGB1-TLR2 signaling and accelerates pancreatic carcinoma metastasis

SPOP promotes ATF2 ubiquitination and degradation to suppress prostate cancer progression

SIRT7 suppresses the epithelial-to-mesenchymal transition in oral squamous cell carcinoma metastasis by promoting SMAD4 deacetylation

Reactive oxygen species in haematopoiesis: leukaemic cells take a walk on the wild side

Stearoyl-CoA desaturase-1 promotes colorectal cancer metastasis in response to glucose by suppressing PTEN

Regulation of tNOX expression through the ROS-p53-POU3F2 axis contributes to cellular responses against oxaliplatin in human colon cancer cells

Keynote webinar | Spotlight on antibody–drug conjugates in cancer