Mechanisms of action and resistance to anti-angiogenic small-molecule tyrosine kinase inhibitors in preclinical breast cancer and pancreatic neuroendocrine tumor mouse models

Bill, Ruben. Mechanisms of action and resistance to anti-angiogenic small-molecule tyrosine kinase inhibitors in preclinical breast cancer and pancreatic neuroendocrine tumor mouse models. 2015, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: http://edoc.unibas.ch/diss/DissB_11529

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„Cancer“ – this one term is used to name a large spectrum of different syndromes, ranging from the relatively indolent chronic lymphocytic leukemia to highly lethal cancer types such as glioblastoma multiforme with a median survival of about 15 months even when treated with upfront treatment schedules. Based on the notion that tumors critically rely on their own blood supply, targeting the tumor blood vasculature by anti-angiogenic therapeutics has been implemented as an important treatment modality for certain cancer types.
Pancreatic neuroendocrine tumors (PNETs) are rare but represent a deadly disease when detected at a metastatic stage. Importantly, PNETs have proven to respond especially well to the anti-angiogenic compound sunitinib – however, not without a significant amount of side effects. To increase the treatment options for PNET patients, we performed a preclinical evaluation of nintedanib, a small-molecule anti-angiogenic tyrosine kinase inhibitor (TKI), in the Rip1Tag2 PNET mouse model. Our work revealed that nintedanib exerted a strong anti-angiogenic and thus anti-tumor effect translating into improved animal survival. Based on our data we therefore suggest the clinical evaluation of nintedanib as a new treatment modality in PNET patient care.
In contrast, numerous large clinical trials in breast cancer patients treated with compounds targeting tumor angiogenesis only resulted in improved progression-free survival (PFS) at best, without increasing overall survival (OS). This observation suggests the rapid establishment of therapy resistance. We therefore set out to investigate mechanisms of resistance to nintedanib and sunitinib in a murine syngeneic transplantation model of breast cancer. Similar to the clinical observations, targeting tumor angiogenesis in this mouse model resulted in the rapid development of resistance. Interestingly however, tumor re-growth was occurring despite a sustained reduction of the number of tumor blood vessels (i.e. microvessel density; MVD) and increased hypoxia. Mechanistically, this tumor re-growth was enabled by the upregulation of glycolysis and the establishment of a metabolic symbiosis between hypoxic and normoxic tumor areas. Interestingly, similar mechanisms might be also responsible for re-growing tumors occasionally observed in nintedanib-treated Rip1Tag2 mice.
Taken together, our data provide a preclinical basis for the evaluation of nintedanib as a new treatment modality for PNET patients. Furthermore, we describe the upregulation of glycolysis as a mechanism how tumor cells can escape the action of anti-angiogenic therapies allowing them to survive and proliferate in a detrimental environment of low oxygen tension, acidic pH and nutrient deprivation.
Advisors:Christofori, Gerhard and Affolter, Markus
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Former Units at DBM > Tumor Biology (Christofori)
UniBasel Contributors:Affolter, Markus
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:11529
Thesis status:Complete
Number of Pages:1 Online-Ressource (vi, 169 Seiten)
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Last Modified:22 Jan 2018 15:52
Deposited On:17 Feb 2016 15:36

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