Authors:
V. Karantza, R. A. Moss, J. M. Mehnert, M. N. Stein, E. Poplin, B. Saraiya, J. Aisner, A. R. Tan, E. White, & R. S. DiPaola
Summary:
Background - Autophagy is a catabolic cellular process whereby cytoplasm, proteins and organelles are sequestered in double- membrane vesicles, the autophagosomes, and are delivered to and degraded in lysosomes. Autophagy is induced under stress, such as nutrient deprivation. In tumors, autophagy is activated in hypoxic areas and in response to anticancer drugs, providing a survival mechanism that counteracts endogenous and treatment-induced metabolic stress. As such, autophagy prolongs tumor cell survival and is a treatment resistance mechanism. Preclinical studies showed that autophagy inhibition concurrently with chemotherapy preferentially sensitized tumor cells to treatment by depriving them of a critical prosurvival function. Thus, autophagy inhibition in combination with chemotherapy is expected to increase therapeutic efficacy in cancer treatment.
Methods - Several phase I/II studies involving autophagy modulation by hydroxychloroquine (HCQ) in combination with chemotherapy for the treatment of different cancers, including breast, colon, prostate and NSCLC, are currently accruing patients at the Cancer Institute of New Jersey. As an example, for patients with metastatic breast cancer who have received no more than 3 prior regimens, we are conducting a phase I/II study of ixabepilone given every 3 weeks with daily HCQ. The phase I portion will determine the MTD. The endpoints for phase II are to assess antitumor activity and time to progression, determine change in CTCs upon treatment, evaluate pharmacodynamic markers for autophagy detection in tumor specimens and characterize the effects of drug treatment on autophagy in PBMCs as a surrogate tissue. The autophagy potential of breast tumors prior to treatment is evaluated by IHC for the autophagy regulators Beclin 1 and LC3, for p62, which accumulates upon autophagy inhibition, and for PTEN and phospho-Akt, as both PTEN loss and Akt activation suppress autophagy. Ixabepilone is given alone on Day 1 of Cycle 1 (HCQ is started on Day 3), and PBMCs are examined for autophagy induction by monitoring Beclin 1, p62 and LC3 levels, as well as LC3 cleavage, by WB at 24 and 48 hours. The same assays are performed in Cycle 2, when both drugs are started on Day 1.
Source:
2010 American Society of Clinical Oncology; TPS343, S Hall A2, 8:00AM-12:00PM (06/07/10)