Universität zu Köln

Chatterjee, Sampurna (2014). Targeting the tumor blood vessels: VEGFR2 as a Biomarker and Therapeutic Target in Non Small Cell Lung Cancer. PhD thesis, Universität zu Köln.

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Abstract

Blood vessels transport oxygen and nutrients within the body. However, blood vessels also nourish cancer. Numerous evidences indicate uniformly towards the fact that tumors cannot grow without access to and recruitment of blood vessels, a process widely known as tumor angiogenesis. It has been well described that endothelial cell migration and proliferation is primarily regulated by VEGF-­‐A binding to its receptor VEGFR2. However molecular mechanisms that control the shift in angiogenic switch in Non Small Cell Lung Cancer remain poorly understood till date. In this PhD thesis we have identified a novel autocrine feed-­‐forward loop active in the tumor where tumor-­‐ cell autonomous VEGF:VEGFR2 feed forward loop triggers signal amplification substantially amplifying the pro-­‐angiogenic signal required for establishing fully angiogenic tumors in lung cancer. In 20% of lung cancer patients this feed forward loop was active as the level of VEGF: VEGFR2 binding in tumor cells and directly correlated with tumor angiogenesis. Disruption of this feed forward loop using inhibitors against VEGFR2 or knockdown was sufficient to prevent tumor growth in vivo. Furthermore, inhibition of tumor cell VEGFR2 induced feedback activation of the IRS/MAPK signalling pathway switching the tumor cells from an angiogenic to a proliferative phenotype. Combined pharmacological inhibition of VEGFR2 with ZD6474 and MEK with PD0325901 resulted in dramatic tumor shrinkage. We thereby propose that high expression of tumor VEGF:VEGFR2 can serve as a predictive biomarker for therapeutic efficacy of dual VEGFR2/MEK inhibition in the patients with NSCLC. Our next project was to investigate the role of VEGFR2 in the tumor microenvironment using cancer cells, which do not have a high expression of VEGFR2. In most cancers, tumor vasculature is leaky, disorganized with a chaotic morphology resulting in a hostile tumor microenvironment characterized by increased hypoxia and high interstitial fluid pressure. These abnormal vessels interfere with effective delivery of drugs and supports tumor progression and resistance to treatment. The traditional concept of using anti-­‐ angiogenic therapy to eradicate tumors by starving them from oxygen and nutrient supply by destroying existing vessels has not seen much success. One reason for this failure can be attributed to the vessel-­‐leakiness hindering homogeneous drug delivery within the tumor. Alternative strong evidences are emerging that transient application of anti-­‐angiogenic agents can normalize the aberrant tumor vasculature and that cytotoxic therapy given during this normalization window might have the best outcome. Yet there remains a lack of clarity about how to optimize scheduling such drug combinations. In this PhD thesis, we observed that short-­‐term treatment with the VEGFR / PDGFR inhibitor PTK787 or VEGFR2 inhibitor ZD6474 initiated a transient window of improved blood flow using [15O] H2O Positron Emission Tomography (PET) in a preclinical mouse model of Non Small Cell Lung Cancer. This improvement was associated with reduced vessel leakiness and enhanced pericyte coverage. Initiation of cytotoxic treatment with erlotinib during this normalization window resulted in improved treatment efficacy. Additionally intermittent PTK787 treatment also facilitated long-­‐term tumor regression. Concisely, our findings offer strong evidence that short-­‐term anti-­‐angiogenic therapy can promote transient vessel normalization that can improve the delivery and efficacy of a targeted cytotoxic drug. In summary, VEGFR2 expressed on tumor cells plays a pivotal role in driving tumor angiogenesis and the same receptor expressed in the tumor microenvironment is relevant for normalization of tumor vasculature. Hence VEGFR2 can serve as an effective therapeutic target, which may lead to eradication of tumors or survival advantage in advanced NSCLC patients in the clinic.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Chatterjee, Sampurna sampurna.steele@gmail.com UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-66001
Journal or Publication Title:	Tumor VEGF:VEGFR2 autocrine feed-forward loop triggers angiogenesis in lung cancer
Date:	20 July 2014
Publisher:	JCI
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Zentrum für Molekulare Medizin
Subjects:	Life sciences Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language mTOR UNSPECIFIED VEGFR UNSPECIFIED cancer UNSPECIFIED
Date of oral exam:	19 September 2014
Referee:	Name Academic Title Uhlirova, Mirka Prof. Dr. Brachvogel, Bent Prof. Dr.
References:	PD. Dr. Dr. Rolland Ullrich, ZMMK, Cologne Prof. Dr. Roman Thomas, Dept. of Translational Genomics, University of Cologne
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/6600