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.