Abstract
VEGF pathway-targeting antiangiogenic drugs, such as bevacizumab, when combined with chemotherapy have changed clinical practice for the treatment of a broad spectrum of human cancers. However, adaptive resistance often develops, and one major mechanism is elevated tumor hypoxia and upregulated hypoxia-inducible factor-1α (HIF1α) caused by antiangiogenic treatment. Reduced tumor vessel numbers and function following antiangiogenic therapy may also affect intratumoral delivery of concurrently administered chemotherapy. Nonetheless, combining chemotherapy and bevacizumab can lead to improved response rates, progression-free survival, and sometimes, overall survival, the extent of which can partly depend on the chemotherapy backbone. A rational, complementing chemotherapy partner for combination with bevacizumab would not only reduce HIF1α to overcome hypoxia-induced resistance, but also improve tumor perfusion to maintain intratumoral drug delivery. Here, we evaluated bevacizumab and CRLX101, an investigational nanoparticle-drug conjugate containing camptothecin, in preclinical mouse models of orthotopic primary triple-negative breast tumor xenografts, including a patient-derived xenograft. We also evaluated long-term efficacy of CRLX101 and bevacizumab to treat postsurgical, advanced metastatic breast cancer in mice. CRLX101 alone and combined with bevacizumab was highly efficacious, leading to complete tumor regressions, reduced metastasis, and greatly extended survival of mice with metastatic disease. Moreover, CRLX101 led to improved tumor perfusion and reduced hypoxia, as measured by contrast-enhanced ultrasound and photoacoustic imaging. CRLX101 durably suppressed HIF1α, thus potentially counteracting undesirable effects of elevated tumor hypoxia caused by bevacizumab. Our preclinical results show pairing a potent cytotoxic nanoparticle chemotherapeutic that complements and improves concurrent antiangiogenic therapy may be a promising treatment strategy for metastatic breast cancer. Cancer Res; 76(15); 4493-503. ©2016 AACR.
Highlights
Patients with triple-negative breast cancer (TNBC) have the highest risk of recurrence and metastasis [1]
One notable example is bevacizumab, a VEGF-targeting antibody, which was granted accelerated FDA approval with weekly paclitaxel for first-line treatment of metastatic breast cancer, but this approval was later revoked after follow-up phase III clinical trials with different chemotherapy
There has been renewed interest in reconsidering bevacizumab for the treatment of breast cancer based on several phase III clinical trial results, including one in the neoadjuvant and adjuvant setting (NSABP-B40) and two in the maintenance metastatic setting (IMELDA and TANIA; refs. 3–5)
Summary
Patients with triple-negative breast cancer (TNBC) have the highest risk of recurrence and metastasis [1]. One notable example is bevacizumab, a VEGF-targeting antibody, which was granted accelerated FDA approval with weekly paclitaxel for first-line treatment of metastatic breast cancer, but this approval was later revoked after follow-up phase III clinical trials with different chemotherapy. There has been renewed interest in reconsidering bevacizumab for the treatment of breast cancer based on several phase III clinical trial results, including one in the neoadjuvant and adjuvant setting (NSABP-B40) and two in the maintenance metastatic setting A number of trial results and meta-analyses suggest the extent of beneficial effect (and associated toxicities) of adding bevacizumab to chemotherapy may depend on the concurrent chemotherapy regimen used [2, 4, 6, 7]. One promising investigational chemotherapy drug is a nanoparticle–drug conjugate (NDC) known as CRLX101, which contains the payload camptothecin, a highly potent cytotoxic agent that inhibits topoisomerase-I [8, 9]
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