Abstract LB-253: Inhibition of stemness by BBI608 is sufficient to suppress cancer relapse and metastasis (2015)

Abstract Cancer cells are extremely heterogeneous, even in each individual patient, in terms of their malignant potential, drug-senstivity, and their potential to metastasize and cause relapse. Subpopulations of cancer cells with extremely high tumorigenic potential have been isolated from cancer patients with a variety of tumor types and found to have high stemness properties termed cancer stem cells. These stemness-high cancer cells are extremely tumorigenic and are resistant to conventional therapeutics due to activation of pro-survival and anti-apoptotic pathways, overexpression of drug efflux pumps, and increased DNA repair capacity. Moreover, chemotherapy and radiation have been found to induce stemness genes in cancer cells, converting stemness-low cancer cells to stemness-high cancer cells. Such highly tumorigenic and drug-resistant stemness-high cancer stem cells are, therefore, likely to be “left-over” following chemotherapy or radiotherapy and ultimately responsible for relapse. We hypothesized that cancer stemness inhibition is sufficient to suppress metastasis and relapse. Stemness, initially defined by the expression of stem cells genes, is a property shared by embryonic stem cells and adult stem cells. It has been demonstrated that the gene expression profiles of cancer stem cells more closely resemble embryonic stem cells than adult stem cells, suggesting the feasibility to identify molecular targets that are required for cancer stemness, but not (or less so) by normal adult stem cells. Through gene-silencing approaches, we have identified Stat3 as critically important for maintaining cancer stemness, yet largely dispensable for adult stem cells. Here we show that BBI608, a small molecule identified by its ability to inhibit gene-transcription driven by Stat3 and cancer cell stemness properties, displays anticancer properties that are highly different from chemotherapeutics agents. Stemness-high cancer cells enriched by multiple techniques are resistance to chemotherapeutics, yet highly sensitive to the stemness inhibitor BBI608. Blockade of spherogenesis and reduction of stemness gene expression by BBI608 were observed in stemness-high cancer cells isolated from a variety of cancer types. While treatment of xenografted tumor models with chemotherapeutics enriched stemness-high cancer cells, BBI608 induced significant depletion of stemness-high populations in vivo. Moreover, the inhibition of stemness by BBI608 is sufficient to suppress cancer relapse and metastasis in xenografted human cancers in mice. These data demonstrate targeting cancer stemness as an effective way to suppress cancer relapse and metastasis. Citation Format: Youzhi Li, Harry A. Rogoff, Sarah Keates, Yuan Gao, Sylaja Murikipudi, Keith Mikule, David Leggett, Wei Li, Arthur Pardee, Chiang J. Li. Inhibition of stemness by BBI608 is sufficient to suppress cancer relapse and metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-253. doi:10.1158/1538-7445.AM2015-LB-253