Harnessing Induced Essentiality: Targeting Carbonic Anhydrase IX and Angiogenesis Reduces Lung Metastasis of Triple Negative Breast Cancer Xenografts.

Hedlund Hedlund,Mcdonald Mcdonald,Nemirovsky Nemirovsky,Dedhar Dedhar,Awrey Awrey,Jensen Jensen

doi:10.3390/cancers11071002

Hedlund Hedlund, Mcdonald Mcdonald + Show 4 more

Open Access

https://doi.org/10.3390/cancers11071002

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Abstract

Triple Negative Breast Cancer (TNBC) is aggressive, metastatic and drug-resistant, limiting the spectrum of effective therapeutic options for breast cancer patients. To date, anti-angiogenic agents have had limited success in the treatment of systemic breast cancer, possibly due to the exacerbation of tumor hypoxia and increased metastasis. Hypoxia drives increased expression of downstream effectors, including Carbonic Anhydrase IX (CAIX), a critical functional component of the pro-survival machinery required by hypoxic tumor cells. Here, we used the highly metastatic, CAIX-positive MDA-MB-231 LM2-4 orthotopic model of TNBC to investigate whether combinatorial targeting of CAIX and angiogenesis impacts tumor growth and metastasis in vivo to improve efficacy. The administration of a small molecule inhibitor of CAIX, SLC-0111, significantly reduced overall metastatic burden, whereas exposure to sunitinib increased hypoxia and CAIX expression in primary tumors, and failed to inhibit metastasis. The administration of SLC-0111 significantly decreased primary tumor vascular density and permeability, and reduced metastasis to the lung and liver. Furthermore, combining sunitinib and SLC-0111 significantly reduced both primary tumor growth and sunitinib-induced metastasis to the lung. Our findings suggest that targeting angiogenesis and hypoxia effectors in combination holds promise as a novel rational strategy for the effective treatment of patients with TNBC.

Highlights

Breast cancer is composed of several distinct subtypes that exhibit markedly different outcomes [1,2]
60 mg/kg sunitinib for 11 days, a dose and duration previously reported to provide tumor growth inhibition while mitigating toxicity and emulating a clinically relevant dosing schedule [5], significantly inhibited primary tumor growth when compared to vehicle controls (Figure 1a,b)
Using a highly metastatic, in vivo model of Carbonic Anhydrase IX (CAIX)-positive human Triple Negative Breast Cancer (TNBC), we demonstrate that the administration of a clinically validated inhibitor of CAIX activity, SLC-0111, dramatically reduces spontaneous metastases, whereas the decrease in tumor growth, while evident, is more modest, suggesting that the reduction in metastasis observed with inhibition of CAIX is not due solely to reduced tumor growth

Summary

Introduction

Breast cancer is composed of several distinct subtypes that exhibit markedly different outcomes [1,2]. Triple negative breast cancer (TNBC) is aggressive and is often resistant to treatment [3,4]. TNBC is prone to metastasis, a major contributor to tumor recurrence and cancer-associated mortality. These features highlight a critical need for the development of novel therapeutic strategies that effectively target this malignancy. Anti-angiogenic agents have been reported to inhibit breast tumor growth [5]. As a consequence of their activity, these agents can exacerbate

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