Mind the Gap: Potential for Rebounds during Antiangiogenic Treatment Breaks

Abstract

VEGF pathway inhibitors have shown benefits in many cancers, yet many (often controversial) questions remain about whether vascular and tumor regrowth can occur when therapy is stopped. Marked increases in endothelial cell proliferation could play a role in putative rebounds, potentially influencing overall efficacy, dosing schedules, and presurgical intervention strategies. Clin Cancer Res; 18(14); 3719–21. ©2012 AACR.

Prodding the Beast: Assessing the Impact of Treatment-Induced Metastasis

“…Indeed, persistent suppression or stimulation of tumor-mediating host responses could facilitate putative vascular "rebounds" when treatment is halted or lead to increased invasive and metastatic potential once primary or metastatic tumors are surgically removed (67). This may be of significance for certain antiangiogenic therapies with frequent breaks in dosing periods, or intermittent cessations because of toxicity (39).…”

A Transient Pseudosenescent Secretome Promotes Tumor Growth after Antiangiogenic Therapy Withdrawal

“…The concept of rebound growth after antiangiogenic treatment withdrawal remains controversial (Ebos and Kerbel, 2011). Previous publications in both mice (Mancuso et al, 2006) and humans (Griffioen et al, 2012) have demonstrated that revascularization and endothelial cell proliferation can occur in tumors when VEGFR TKI treatment is halted (Ebos and Pili, 2012). However, retrospective analyses of patients having TKI or antibody (bevacizumab) treatments stopped have shown no growth acceleration (Miles et al, 2011;Blagoev et al, 2013).…”

“…However, perhaps the most important issue related to transient treatment-induced senescent cell characteristics is the impact on tumor-promoting SASPs. Circulating secreted proteins are well known to be induced by multiple cancer therapies (Ebos and Pili, 2012), although a connection to SASPs in most cases remain unclear. While the SASP seems to be relatively conserved in mammals, it is highly context dependent and variable among cell types and senescence-inducing stimuli (Malaquin et al, 2016;Mastri et al, 2018).…”

“…While preclinical studies have uncovered several mechanisms to explain the invasive and metastatic consequences of angiogenesis inhibition (reviewed in Ebos, 2015), assessing the clinical impact remains a challenge (Blagoev et al, 2013). It is possible that the most deleterious consequence of this effect would arise when therapy is stopped (Ebos and Pili, 2012;Ebos and Kerbel, 2011). Antiangiogenic treatment cessation can occur in perioperative clinical trial treatment settings (i.e., neoadjuvant and adjuvant) (Ebos and Kerbel, 2011) and during established ''drug holiday'' periods for certain VEGF receptor tyrosine kinase inhibitors (VEGFR TKIs) (e.g., sunitinib).…”

Metastatic mechanisms in follicular cell-derived thyroid cancer

“…Thus, it has been postulated that inhibition of VEGF signaling is in part responsible for the stabilization and partial responses noted in clinical trials. As noted above however, the responses are transient and there are concerns that interrupting VEGF blockade may induce rapid tumor regrowth after initial response possibly related to the persistent basement membrane scaffolding from the prior vessels or other mechanisms (Ebos and Pili 2012; Kubota 2012). In fact sunitinib, a compound with activity against metastatic thyroid cancer, when given short-term has been reported to accelerate metastatic tumor growth, but not orthotopic “primary” tumors of breast and melanoma cancer cells in mice (Ebos, et al 2009).…”