Transient Antiangiogenic Treatment Improves Delivery of Cytotoxic Compounds and Therapeutic Outcome in Lung Cancer

Abstract

Extensive oncologic experience argues that the most efficacious applications of antiangiogenic agents rely upon a combination with cytotoxic drugs. Yet there remains a lack of clarity about how to optimize scheduling for such drug combinations. Prudent antiangiogenic therapy might transiently normalize blood vessels to improve tumor oxygenation and drug exposure. Using [ 15 O]H 2 O positron emission tomography imaging in a preclinical mouse model of non-small cell lung cancer, we observed that short-term treatment with the vascular endothelial growth factor receptor/platelet-derived growth factor receptor inhibitor PTK787 licensed a transient window of improved tumor blood flow. The improvement observed was associated with a reduced leakiness from tumor vessels, consistent with induction of a vascular normalization process. Initiation of a cytotoxic treatment in this window of tumor vessel normalization resulted in increased efficacy, as illustrated by improved outcomes of erlotinib administration after initial PTK787 treatment. Notably, intermittent PTK787 treatment also facilitated long-term tumor regression. In summary, our findings offer strong evidence that short-term antiangiogenic therapy can promote a transient vessel normalization process that improves the delivery and efficacy of a targeted cytotoxic drug. Cancer Res; 74(10); 2816-24. Ó2014 AACR.

Does Imaging αvβ3 Integrin Expression with PET Detect Changes in Angiogenesis During Bevacizumab Therapy?

“…However, normalization was a transient event as described previously (23,24). Continued bevacizumab therapy led to increased tumor necrosis after 3 wk of treatment, which likely explains the decrease in RGD peptide uptake from day 7 to 21.…”

“…This phenomenon is believed to be a consequence of a less chaotic blood flow and a decrease of interstitial pressure in treated tumors (23). Specifically, Chatterjee et al (24) have recently shown that treatment with 2 different VEGF receptor-targeting therapies steadily increases the perfusion of tumor xenografts (assessed by 15 O water PET) until day 8 of therapy. On day 8, tumor perfusion was 34% higher than at baseline.…”

Impact of bevacizumab in combination with erlotinib on EGFR‐mutated non–small cell lung cancer xenograft models with T790M mutation or MET amplification

“…Furthermore, subgroup analysis of EGFR‐mutated patients in the Phase III BeTa trial of second‐line treatment showed that PFS and overall survival (OS) seemed to be longer with BEV+ERL than with ERL alone . Several preclinical studies have shown that antitumor activity in NSCLC cells is enhanced by simultaneous inhibition of the VEGF and EGFR signaling pathways . However, the efficacy of BEV+ERL on EGFR ‐mutated NSCLC cells carrying mutations conferring resistance to EGFR‐TKIs, such as T790M mutation or MET amplification, has not been demonstrated in clinical or preclinical studies.…”

Outcomes and prognoses of patients with ovarian cancer using bevacizumab: 6-year experience in a tertiary care hospital of northern Taiwan

“…et al in 2012[29] and Arjaans M. et al in 2013,[27] and with vatalanib (PTK787) in lung cancer by Chatterjee S. et al in 2014. [30] In the present study, the bevacizumab dosage had a significant impact. Low-dose of bevacizumab infusion regimen is not inferior to standard dose of 15mg/m 2 infusion regimen.…”