Targeting of the breast cancer microenvironment with a potent and linkable oxindole based antiangiogenic small molecule.

Orestis Argyros,Demosthenes Fokas,Xenophon Asvos,Dimitris Beis,Adamantia Agalou,Constantin Tamvakopoulos,Aimilia Varela,Athanasios Papakyriakou,Theodoros Karampelas,Constantinos H Davos

doi:10.18632/oncotarget.16763

Abstract

The clinical efficacy of antiangiogenic small molecules (e.g., sunitinib) in breast carcinoma has largely failed with substantial off-target toxicity. We rationally designed and evaluated preclinically a novel sunitinib analogue, SAP, with favourable pharmacological properties and the ability to be readily conjugated to a targeting peptide or antibody for active tumour targeting.SAP was evaluated in silico and in vitro in order to verify target engagement (e.g., VEGFR2). Pharmacokinetic and biodistribution parameters were determined in mice using LC-MS/MS. SAP efficacy was tested in two breast cancer xenograft and two syngeneic animal models and pharmacodynamic evaluation was accomplished using phosphokinase assays and immunohistochemistry. Cardiac and blood toxicity of SAP were also monitored.SAP retained the antiangiogenic and cytotoxic properties of the parental molecule with an increased blood exposure and tumor accumulation compared to sunitinib. SAP proved efficacious in all animal models. Tumors from SAP treated animals had significantly decreased Ki-67 and CD31 markers and reduced levels of phosphorylated AKT, ERK and S6 compared to vehicle treated animals. In mice dosed with SAP there was negligible hematotoxicity, while cardiac function measurements showed a reduction in the percentage left ventricular fractional shortening compared to vehicle treated animals.In conclusion, SAP is a novel rationally designed conjugatable small antiangiogenic molecule, efficacious in preclinical models of breast cancer.

Highlights

Breast cancer (BrCa) is the most common malignancy among women and is clinically stratified into three major types depending on the expression of the estrogen (ER) and progesterone receptor (PR), or amplification/overexpression of the receptor tyrosine kinase (RTK) HER2/neu [1, 2]
SAP retained the indolin-2-one core of sunitinib responsible for RTK inhibition, while it provided a handle for conjugation to a targeting peptide or antibody through the amino group of piperazine
An underlying assumption regarding the rationale for using antiangiogenic therapies is that all types of cancer are angiogenesis-dependent and inhibiting angiogenesis would be highly effective as a generic cancer treatment

Summary

Introduction

Breast cancer (BrCa) is the most common malignancy among women and is clinically stratified into three major types depending on the expression of the estrogen (ER) and progesterone receptor (PR), or amplification/overexpression of the receptor tyrosine kinase (RTK) HER2/neu [1, 2]. Preclinical studies have shown that inhibition of the VEGF pathway impedes tumor growth and clinically the VEGF-neutralizing antibody bevacizumab was the first antiangiogenic treatment in BrCa due to the E2100 trial [7]. The details behind the clinical shortcomings of sunitinib in BrCa are not entirely clear but suggested explanations include the growing evidence that BrCa angiogenesis is driven by more than just VEGF, so inhibition of many other proangiogenic kinases might be necessary; the activation of cancer stem cells that overcome tumor remission [10]; and certainly the limitation of administering a higher drug dose due to offtarget toxicities such as left ventricular (LV) dysfunction and overt heart failure frequently encountered due to depletion of coronary microvascular pericytes [17]

Methods

Results

Conclusion