Suppression of cancer relapse and metastasis by inhibiting cancer stemness

Abstract

Partial or even complete cancer regression can be achieved in some patients with current cancer treatments. However, such initial responses are almost always followed by relapse, with the recurrent cancer being resistant to further treatments. The discovery of therapeutic approaches that counteract relapse is, therefore, essential for advancing cancer medicine. Cancer cells are extremely heterogeneous, even in each individual patient, in terms of their malignant potential, drug sensitivity, and their potential to metastasize and cause relapse. Indeed, hypermalignant cancer cells, termed cancer stem cells or stemness-high cancer cells, that are highly tumorigenic and metastatic have been isolated from cancer patients with a variety of tumor types. Moreover, such stemness-high cancer cells are resistant to conventional chemotherapy and radiation. Here we show that BBI608, a small molecule identified by its ability to inhibit gene transcription driven by Stat3 and cancer stemness properties, can inhibit stemness gene expression and block spherogenesis of or kill stemnesshigh cancer cells isolated from a variety of cancer types. Moreover, cancer relapse and metastasis were effectively blocked by BBI608 in mice. These data demonstrate targeting cancer stemness as a novel approach to develop the next generation of cancer therapeutics to suppress cancer relapse and metastasis.cancer stemness | relapse | BBI608 C urrent cancer treatments ultimately fail owing to metastasis and relapse. Although chemotherapy can induce partial or even complete cancer regression in some patients, such initial responses are invariably followed by relapse, with the recurrent cancer being highly resistant to further chemotherapy, resulting in very limited survival benefits (1-3). Modern therapeutics designed to specifically target activating mutations are quite effective in inducing cancer regression in patients driven by such activating mutations; however, these treatments are also invariably followed by relapse with tumors that no longer respond to the targeted agent (2, 3). The discovery of novel therapeutic approaches that counteract cancer relapse is, therefore, urgently required for advancing cancer treatment.The idea that cancer is composed of a group of near-homogenous, ectopically growing cells has been replaced with a more complex model in which cancer cells are extremely heterogeneous, even in each individual patient, in terms of their malignant potential to metastasize and cause relapse. The increased understanding of the genomic and proteomic complexity of tumor heterogeneity further highlights the extreme heterogeneity of cancer cells (4).Subpopulations of cancer cells with extremely high tumorigenic potential, termed cancer stem cells or stem-like cancer cells, have been isolated from cancer patients with a variety of tumor types (5-13) and found to have high stemness properties (5-15). Stemness, initially defined by the expression of stem cells genes, is a property shared by embryonic stem cells and adult stem cells (16). In ...

Mutations in the linker domain affect phospho-STAT3 function and suggest targets for interrupting STAT3 activity

“…While completing this work, we learned from a private confidential communication that the compound described by Y. Li et al (47) as a STAT3 inhibitor binds in a crystal structure in a pocket formed at the junction between the DNA binding domain and the linker domain as the basis for STAT3 inhibition.…”

Identifying and targeting cancer stem cells in the treatment of gastric cancer

“…Napabucasin targets the STAT3, β‐catenin, and NANOG signaling pathways and inhibits the critical genes necessary for maintaining stemness. Targeting STAT3 activation with napabucasin has produced antitumor and antimetastatic activity in both in vitro and in vivo models of cancer without affecting normal cells, suggesting that STAT3 could be a valid molecular target for cancer therapy 53, 54…”

Repurposing itraconazole as an anticancer agent

“…Aberrant signaling pathways, including AKT/mTOR, Hedgehog, and Wnt, have been reported in CSCs and multi-targeting therapies have been proposed (54). The first-in-class cancer stemness inhibitor napabucasin (BBI 608), which targets signal transducer and activator of transcription 3 (Stat3), Nanog, and Wnt/β-catenin pathways, has been reported to improve OS in patients with positive phospho-STAT3 recurrent colorectal cancer (55,56). Itraconazole may be a promising agent for targeting CSCs in relapsed disease of multiple types of cancer; therefore, further preclinical studies on CSCs and the surrounding stroma cells are warranted.…”