Phase I clinical trial and pharmacodynamic evaluation of combination hydroxychloroquine and doxorubicin treatment in pet dogs treated for spontaneously occurring lymphoma

Combined autophagy and proteasome inhibition

“…This was also observed in a phase I trial of vorinostat and HCQ in advanced solid tumors (Mahalingam et al, this issue 33 ), and a trial of HCQ in combination with doxorubicin for canine lymphoma showed a much higher concentration of HCQ in tumor tissue than in plasma (Barnard et al this issue 37 ). These findings suggest that direct measures of tumor cell autophagy should continue to be incorporated into future clinical trials of autophagy inhibitors, rather than using analyses of surrogate tissue.…”

Antitumor adaptive immunity remains intact following inhibition of autophagy and antimalarial treatment

“…Most studies investigating autophagy in cancer have focused on its cellintrinsic effects, including aiding cancer cell survival during extrinsic stress (2,3) as well as promoting drug resistance (4). Importantly, several clinical trials have combined traditional chemotherapy or targeted therapy with antimalarial lysosomotropic agents, such as hydroxychloroquine, which block the late stages of autophagic proteolysis (5)(6)(7)(8)(9)(10)(11)(12). Despite interest in inhibiting autophagy in the clinical oncology setting in combination with chemotherapies or other targeted therapies, emerging evidence has raised questions with regard to the efficacy of such approaches to cancer treatment.…”

Casein kinase 1α–dependent feedback loop controls autophagy in RAS-driven cancers

“…A growing number of clinical trials have been conducted to investigate whether inhibition of autophagic recycling by hydroxychloroquine (HCQ) or CQ can sensitize cancer cells to various types of anticancer drugs (12)(13)(14)(15)(16)(17). Given that autophagy plays context-dependent roles in cancer, the clinical benefits of targeting autophagy may be unpredictable.…”