Mechanisms of Resistance to Anti-Angiogenic Therapy and Development of Third-Generation Anti-Angiogenic Drug Candidates

Loges, Sonja; Schmidt, Thomas; Carmeliet, Peter

doi:10.1177/1947601909356574

Cited by 231 publications

(214 citation statements)

References 141 publications

(280 reference statements)

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“…These include the use of metronomic chemotherapy that targets endothelial cells, the concurrent inhibition of multiple pro-angiogenic molecules, the disruption of tumor vasculature using DLL4 inhibitors, the inhibition of the recruitment of bone marrow derived cells by the tumor, the blockade of neuropilins thus interrupting vessel maturation and the synchronous inhibition of factors that promote tumor progression, such as MET proto-oncogene, receptor tyrosine kinase (MET) (82,83). Importantly, simultaneous blockade of multiple mechanisms is crucial in order to effectively suppress redundant escape processes and to prevent the emergence of resistance and disease progression.…”

Section: Discussionmentioning

confidence: 99%

Targeting angiogenesis in small cell lung cancer

Stratigos

Matikas

Voutsina

et al. 2016

Transl. Lung Cancer Res.

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Small cell lung cancer (SCLC) is a highly aggressive and lethal malignancy. Despite high initial response rates to systemic chemotherapy, the disease eventually relapses; further treatment only modestly improves outcomes and overall survival (OS) for patients with extensive stage disease is less than one year.Little progress has been made during the past decades, with no new drugs approved. Consequently, the development of novel strategies is an unmet need. The inhibition of angiogenesis, a defining characteristic of cancer, has demonstrated modest efficacy in several human malignancies, including non-small cell lung cancer (NSCLC). However, results from clinical trials in SCLC have been disappointing, and no anti-angiogenic agent has received regulatory approval due to lack of clinical efficacy. The elucidation of underlying mechanisms responsible for tumor resistance to angiogenic therapy and the simultaneous blockade of multiple elements that play a role in angiogenesis need to be further explored.

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Section: Discussionmentioning

confidence: 99%

Targeting angiogenesis in small cell lung cancer

Stratigos

Matikas

Voutsina

et al. 2016

Transl. Lung Cancer Res.

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“…Another advantage of antiangiogenic treatments is that these evoke only aquired resistance (resistance induced by the drug) instead of intrinsic resistance. New results of medical research give alternative solutions to overcome drug induced resistance [21], which makes these cancer treatment methods more prosperous. Prevalent angiogenic inhibitors are endostatin [22] and bevacizumab [23].…”

Section: Biomedical Backgroundmentioning

confidence: 99%

Model-based Angiogenic Inhibition of Tumor Growth using Adaptive Fuzzy Techniques

Szeles

Drexler

Sápi

et al. 2014

Per. Pol. Elec. Eng.

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Fighting tumors is one of the most important problems of medical research. In this paper, antiangiogenic cancer therapy is investigated through its mathematical model. This tumor treatment method targets the endothelium of a growing tumor and belongs to the targeted molecular therapies. The aim of the IntroductionCancer treatment is one of the most rapidly developing research fields of medicine. Modern techniques including targeted molecular therapies target only cancerous cells opposed to conventional therapies, e.g. chemotherapy or radiotherapy where both tumorous and normal cells are affected by the applied drugs. In this paper, antiangiogenic therapy is investigated, this method inhibits the tumor from growing own blood vessel cappilaries which serve the tumor to nourish from the host body [1,2]. The most important advantage of the therapy is that patients do not have to suffer from severe side-effects during antiangiogenic treatment, and tumor cells do not develop intrinsic resistance to the angiogenic inhibitors.Philip Hahnfeldt et al. proposed a biologically validated, population based model described by ordinary differential equations in 1999 [3]. Since then, the mathematical model was modified and reformulated many times [4,5]. In this paper a simplified second order model is used to investigate adaptive fuzzy control methodology. For the same model, bang-singular-bang control was designed in [6] and optimal linear control was implemented in [7]. A set-valued protocol was elaborated in [8].More different approaches were used to handle the nonlinearity of the system. Working point linearization was performed to design and analyze state-space and robust control in former papers [7,9,10], flatness based technique was proposed in [11] for the original model using constant Hurwitz polinomial,and in [12] for the simplified model using tumor volume dependent Hurwitz polinomials. Linear controllers could not handle the nonlinearity of the system appropriately, since the magnitude of the control input was infeasible, and the avascular state of the tumor was not attained. Flatness based techniques were not efficient when nominal model parameters changed due to parametric uncertainties. In this paper, adaptive fuzzy control is designed, that can handle both the nonlinearity of the system and the effects of model parameter perturbations.Section 2 focuses on the biomedical background of tumor growth and applied treatments. Section 3 presents the nonlinear model of tumor growth under angiogenic inhibition. In Section 4, the theoretical background of fuzzy control is shortly in-

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“…It is also secreted by HCC and contributes to tumor growth [34]. Experiences from other cancers showed the expression of FGF and other angiogenic factors were upregulated upon anti-VEGF treatment, suggesting FGF pathway is one of the alternate escape mechanisms that contributes to resistance or failure of anti-VEGF treatment [35]. Brivanib (BMS-582664) is a novel TKI of both VEGF and Basic FGF (bFGF).…”

Section: Brivanibmentioning

confidence: 99%