Acute Statin Treatment Improves Antibody Accumulation in EGFR- and PSMA-Expressing Tumors

Abstract

◥Purpose: Statins are cholesterol-depleting drugs used to treat patients with hypercholesterolemia. Preclinically, statins disrupt trafficking of receptors present at the cell membrane. Membrane receptors, defined as tumor biomarkers and therapeutic targets, are often internalized by an endocytic pathway. Indeed, receptor endocytosis and recycling are dynamic mechanisms that often affect receptor density at the cell surface. In therapies using monoclonal antibodies (mAb), a downregulation in receptor density at the cell surface decreases antibody binding to the extracellular domain of the membrane receptor. Here, we determined the potential of lovastatin, simvastatin, and rosuvastatin in preclinically modulating epidermal growth factor receptor (EGFR) and prostate-specific membrane antigen (PSMA) receptor density at the tumor cell surface.Experimental Design: Small-animal PET was used to study the binding of 89 Zr-labeled antibodies in ectopic xenografts. Ex vivo analyses were performed to determine changes in endocytic proteins, EGFR, and PSMA surface levels.Results: Acute statin treatment using lovastatin, simvastatin, or rosuvastatin enhanced tumors' avidity for the mAbs panitumumab, cetuximab, and huJ591. Statins temporarily modulated caveolin-1, cavin-1, endophilin, clathrin, and dynamin proteins in EGFR-and PSMA-overexpressing xenografts.Conclusions: These data show the potential of statins as pharmacologic modulators of endocytic proteins for improved tumors' accumulation of mAbs. The translational significance of these findings lies in the potential of statins to temporarily modulate the heterogeneous presence of receptors at the cell membrane, a characteristic often associated with poor response in tumors to therapeutic antibodies.

Caveolin-1 temporal modulation enhances trastuzumab and trastuzumab-drug conjugate efficacy in heterogeneous gastric cancer

“…This is consistent with previous preclinical studies temporally increasing cell-surface receptors to potentiate TDM1 therapy [58]. Controlled use of lovastatin, at doses lower than the maximum human dose, produce a temporal decrease in CAV1 protein levels [35]. Compared with lipophilic lovastatin, hydrophilic statins are less able to cross cancer cell membranes as they require active transport to enter cells [59].…”

“…Importantly, the lipophilic prodrug lovastatin depletes tumoral CAV1 in ways that improve antibody binding to tumors [22,34,35]. Similarly, lovastatin enhances TDM1 uptake in CAV1high PDXs, confirming an association between the loss of CAV1 and ADC uptake.…”

“…Additionally, statins do not alter TDM1 accumulation in tumors with low levels of CAV1. Still, a large number of other proteins involved in non-caveolae internalization pathways are temporally affected by statins [35]. Nonetheless, specific genetic depletion of CAV1 in vivo enhances ADC accumulation in tumors.…”

“…While CAV1-dependent endocytosis enhances cancer cells' chemosensitivity to TDM1 [29], others have shown a role for caveolae-mediated endocytosis in TDM1 resistance [25,28]. Because cholesterol is essential for caveolae assembly and stability [30], cholesterol-depleting drugs are used in preclinical studies to modulate CAV1 protein levels [31][32][33][34][35]. In this context, statins are promising pharmacologic CAV1 modulators, since they are FDA-approved drugs and prescribed to millions of people worldwide for the treatment of hypercholesterolemia [31].…”

Statins: a repurposed drug to fight cancer

“…Recent evidence suggests that simvastatin may enhance the sensitivity of C26 mouse colon cancer cells to 5-FU treatment [ 301 ]. Pereira et al found that statins temporarily modulated the epidermal growth factor receptor (EGFR) and prostate specific membrane antigen (PSMA) on the surface of tumor cells, which enhanced the tumor-binding avidity of the monoclonal antibodies panitumumab, cetuximab and huJ591, thereby synergizing with the antitumor effects of these agents [ 302 ]. It has also been reported that lovastatin enhanced the sensitivity of gallbladder cancer to cisplatin [ 303 ].…”