Abstract LB-254: Efficiently targeting cancer stem cells requires tactical activation from their dormant state and subsequent exhaustion

Abstract

Akin to normal tissue stem cells (NTSCs), cancer stem cells (CSCs) may have adopted dual active-dormant mechanisms to respectively sustain growth while eluding exhaustion from conventional chemotherapy such as 5-fluorouracil (5-FU). How to effectively target dual active-dormant CSCs while preserving NTSCs is essential to curing cancers. We compared the kinetic states of NTSCs in gut and bone marrow as well as leukemia stem cells following 5-FU treatment and found a narrow window of opportunity when forcibly activated dormant NTSC/CSCs can be targeted following depletion of proliferating progeny. Given that stemness factors predict poor overall survival (OS) in many cancers, we proposed a novel two-step ADAPT strategy_activate from dormancy and potentiate subsequent targeting_ in an attempt to synchronize cytotoxic effects of 5-FU on proliferating cells with stemness inhibitors targeting activated CSCs respectively. We applied the two-step protocol using capecitabine, an oral 5-FU prodrug, and celecoxib, a selective COX-2 inhibitor that is also a stemness inhibitor (it down-regulates LGR5/6, CD133, Oct4/Sox effectors, ALDH, CD24, Wnt, Sonic Hedghog) in patients with unresectable metastatic colorectal cancer. We found that the ADAPT strategy resulted in complete or near complete response rate in 27 patients with surgically unresectable metastatic colorectal cancer, especially if coupled with radiation. The median survival for this group of patients reached 92.7 months (95% CI, 53.5 months - not reached). Paradoxically, patients who had confirmed complete response without surgery but with long-term ADAPT therapy enjoyed 100% 5-year relapse free survival compared to 42% of patients who had undergone surgical resection of metastasis (p=0.04 log rank). Intriguingly, Celecoxib exerted many opposite biologic effects compared to 5-FU on cell cycle, apoptosis, DNA repair/synthesis, particularly stemness genes/pathways, and thus produced conflicting effect in short-term colon cancer cultures when combined with 5-FU. This observation potentially explains the 6 months gain in OS in the responding patients and the lack of OS for all patients in reported phase III BICC-C study that randomized Celecoxib vs placebo with 5FU based chemotherapy.. Thus, optimal ADAPT strategy to target CSCs requires initial cytoreduction of proliferating progeny and activation of dormant/drug-resistant CSCs, and subsequent cyclical exhaustion via long-term exposure to stemness inhibitors along with intermittent cytotoxic agents such as 5-FU.

Citation Format: {Authors}. {Abstract title} [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-254.