Abstract SY01-04: Chloroquine derivatives as anticancer agents

Abstract

Abstract Mouse models of cancer have demonstrated that therapy-induced autophagy in advanced cancer can promote tumor cell survival and resistance to therapy. Chloroquine derivatives impair autophagy by impairing lysosomal function. Preclinical studies in many, but not all, cancer models have shown that combining chloroquine derivatives with other anticancer agents produces autophagic vesicle accumulation followed by enhanced cancer cell death. Based on these results, clinical trials involving the hydroxychloroquine (HCQ) have been launched for patients with refractory malignancies. The results of the first 6 HCQ clinical trials (5 in humans, 1 in dogs) represent the first deliberate attempt to modulate autophagy therapeutically in patients. These studies indicate that autophagy can be modulated therapeutically with HCQ in patients. While the majority of patients did not experience unexpected toxicity, specific HCQ- chemotherapy combinations did produce enhanced myelosuppression, indicating treatment with HCQ and other chloroquine derivatives should continue to only be considered in the context of clinical trials. Encouraging antitumor activity of HCQ based combinations was observed in patients with melanoma, colon cancer, renal cell carcinoma, and in pet dogs, but randomized studies will be needed to determine if the activity can be attributed to the addition of HCQ. Preliminary results of currently enrolling or more recently completed clinical trials involving hydroxychloroquine will be highlighted. A serum-based approach based on secretome analysis of melanoma cells grown in three dimensional culture has identified potential quantitative biomarkers of low and high tumor cell autophagy. This approach could potentially lead to predictive and pharmacodynamic assays of response to autophagy modulation. To improve the potency of chloroquine derivatives against cancer we have previously reported a dimeric chloroquine Lys05, which is being evaluated for clinical development. Based on analysis of 70 new derivatives of Lys05, compounds which localize to the lysosome, inhibit autophagy and exhibit nanomolar cytotoxicity profiles have been identified. Finally we will discuss ongoing efforts to develop a more detailed understanding of the mechanism of action chloroquine as an anticancer agent. Citation Format: Ravi K. Amaravadi. Chloroquine derivatives as anticancer agents. [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 SY01-04. doi:10.1158/1538-7445.AM2015-SY01-04