CRLX101, an investigational camptothecin-containing nanoparticle-drug conjugate, targets cancer stem cells and impedes resistance to antiangiogenic therapy in mouse models of breast cancer

Abstract

Antiangiogenic therapies inhibit the development of new tumor blood vessels, thereby blocking tumor growth. Despite the advances in developing antiangiogenic agents, clinical data indicate that these drugs have limited efficacy in breast cancer patients. Tumors inevitably develop resistance to antiangiogenics, which is attributed in part to the induction of intra-tumoral hypoxia and stabilization of hypoxia-inducible factor 1α (HIF-1α), a transcription factor that promotes tumor angiogenesis, invasion, metastasis, and cancer stem cell (CSC) self-renewal. Here, we tested whether inhibiting HIF-1α can reverse the stimulatory effects of antiangiogenic-induced hypoxia on breast CSCs. Breast cancer cells grown under hypoxic conditions were treated with the dual topoisomerase-1 (TOPO-1) and HIF-1α inhibitor camptothecin and assessed for their CSC content. In a preclinical model of breast cancer, treatment with bevacizumab was compared to the combination treatment of bevacizumab with CRLX101, an investigational nanoparticle-drug conjugate with a camptothecin payload or CRLX101 monotherapy. While exposure to hypoxia increased the number of breast CSCs, treatment with CPT blocked this effect. In preclinical mouse models, concurrent administration of CRLX101 impeded the induction of both HIF-1α and CSCs in breast tumors induced by bevacizumab treatment. Greater tumor regression and delayed tumor recurrence were observed with the combination of these agents compared to bevacizumab alone. Tumor reimplantation experiments demonstrated that the combination therapy effectively targets the CSC populations. The results from these studies support the combined administration of dual TOPO-1- and HIF-1α-targeted agents like CRLX101 with antiangiogenic agents to increase the efficacy of these treatments.

Taxotere-induced elevated expression of IL8 in carcinoma-associated fibroblasts of breast invasive ductal cancer

“…Drug resistance has severely restricted the application of chemotherapy and neoadjuvant chemotherapy, resulting in treatment failure. Therefore, various researchers have focused on the mechanism of chemotherapy resistance in breast cancer (11)(12)(13). Emerging evidences has indicated that the tumor microenvironment serves an important role in carcinogenesis and development, which has also been identified to participate in therapeutic resistance (14)(15)(16).…”

Preclinical Efficacy of Bevacizumab with CRLX101, an Investigational Nanoparticle–Drug Conjugate, in Treatment of Metastatic Triple-Negative Breast Cancer

“…Limited efficacy successes of approved VEGF pathway-targeting antiangiogenic drugs may be due to several possible factors, including reduced intratumoral delivery of concurrently administered drugs, such as chemotherapy, as well as elevated hypoxia (and hence HIF1a), which contributes to resistance and may promote metastases (24,(40)(41)(42). Given these considerations, a complementary chemotherapy partner for combination with an antiangiogenic agent would be a highly potent agent that is able to improve tumor perfusion and reduce HIF1a without increasing tumor dissemination and/or metastases.…”

“…CRLX101 was also shown to effectively and durably suppress elevated hypoxiainduced upregulation of hypoxia-inducible factor-1a (HIF1a) following therapy with bevacizumab, thus downregulating expression of downstream HIF1a-regulated markers, such as carbonic anhydrase IX (CAIX; ref. 23), and blocking the induction of cancer stem cells (24).…”

Nanomedicine applications in the treatment of breast cancer: current state of the art

“…It was found effective in durably blocking the hypoxia-inducible factor-1α, restoring the cancer sensitivity to bevacizumab, improving tumor perfusion and reducing hypoxia. 93 …”