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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

Background: Cancer stem cells (CSC) have self-renewal capability and can differentiate into heterogeneous cancer cells. CSC have been isolated from a variety of human cancers and are considered to be fundamentally responsible for malignant growth, relapse, metastasis, and resistance to conventional therapies [J Clin Oncol. 2008 Jun 10;26(17)]. Therefore, targeting CSC may hold significant clinical promise for treating cancer. BBI608 is the first-in-class cancer cell stemness inhibitor discovered from Boston Biomedical’s cancer stem cell pathway inhibitor program (BBI6000). This novel orally-administered cancer cell stemness inhibitor blocks CSC self-renewal and induces cell death in CSC as well as non-stem cancer cells. In preclinical models, BBI608 showed potent and broad-spectrum anti-tumor and anti-metastatic activities in vitro and in vivo. Methods: A phase 1 dose escalation study in adult patients with advanced cancer who had failed standard therapies was initiated to determine the safety, tolerability, recommended phase 2 dose (RP2D), pharmacokinetics and preliminary anti-tumor activity of BBI608. A cycle consists of twice-daily oral administration of BBI608 for 4 weeks. Cycles were repeated every 4 weeks (28 days) until progression of disease, unacceptable toxicity, or another discontinuation criterion was met. A modified Simon accelerated titration scheme was used for dose escalation. Results: As of March 26th, 2010, eighteen patients have been enrolled with safety data available for 15 patients. Thus far, seven cohorts have been dosed from 20 mg to 600 mg/day and the dose escalation has been well tolerated. Adverse events have generally been mild with the most common being grade 1-2 diarrhea and nausea. Two grade 3 events included fatigue and diarrhea. To date, neither MTD nor RP2D has been reached. Thus far, BBI608 has exhibited favorable pharmacokinetics. At the 400 mg/day dose level the plasma concentration of BBI608 was sustained for over 8 hours at a concentration above 1.5 μM (several folds above the IC50). Of the patients enrolled to date, 9 were evaluable for tumor response; 6 (6/9 evaluable patients) have achieved stable disease for at least 8 weeks. Prolonged stable disease was observed in two patients with colon cancer (54+ and 20+ weeks) and one with head and neck cancer (17 weeks). Complete regression of a metastatic lesion to the kidney was also observed in one colon cancer patient. No new metastatic lesions have been observed in any patients except one patient with gastric adenocarcinoma on 40mg/day of BBI608. Conclusions: Initial dose escalation of BBI608, a first-in-class cancer stem cell pathway inhibitor, has been achieved without dose limiting toxicity. Thus far, BBI608 has shown an excellent safety profile, favorable pharmacokinetics, and preliminary signs of clinical activity. Enrollment and dose escalation are continuing and updated results will be presented. Citation Format: Adrian Langleben, Jeffrey G. Supko, Sebastien Hotte, Patricia Lorusso, Wilson H. Miller, Annie Hurtubise, David S. Leggett, Wei Li, Laura Borodyanski, Chiang J. Li. A phase 1 dose escalation study of BBI608, a first-in-class cancer stem cell pathway inhibitor in patients with advanced malignancies [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-171.