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Clinical importance of autophagy dependency and inhibition in cancer treatment

Date

2021

Authors

Van Eaton, Kristen M., author
Gustafson, Daniel L., advisor
Munsky, Brian, committee member
Thamm, Douglas, committee member
Thorburn, Andrew, committee member
Yao, TingTing, committee member

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Abstract

Autophagy, a lysosomal degradation recycling process, has a complex and context-dependent role in cancer. Certain cancers have been found to be inherently dependent on autophagy for survival regardless of the environment. Autophagy is also implicated as a mechanism of resistance to many chemotherapies. More autophagy dependent tumors are generally more sensitive to autophagy inhibition genetically and pharmacologically. Therefore, determining what tumors are autophagy dependent is important for selecting patients that are viable candidates for autophagy inhibition. Currently, autophagy inhibition is being tested in over 90 clinical trials using FDA- approved hydroxychloroquine (HCQ) alone or in combination with other therapies. However, responses have been variable, especially in trials where HCQ is used as a monotherapy. Further, the relationship between HCQ pharmacokinetics and pharmacodynamics is not well understood in patients. Pharmacokinetics of HCQ and one of its active metabolites DHCQ was assessed in non-tumor bearing mice. Both parent and metabolite were observed at clinically relevant concentrations after 72 hr and this corresponded with evident autophagy inhibition in various tissues, although autophagy inhibition was inconsistent across the mice. The pharmacokinetic data established 60 mg/kg as the human equivalent dose observed in patients based on HCQ exposure. Cellular responses to HCQ were assessed in 2D cell culture, 3D tumor organoids, and in vivo tumor xenografts using autophagy dependent and autophagy independent tumors. Overall, cellular responses were similar across the in vitro and in vivo methods. Autophagy was inhibited regardless of autophagy status, but autophagy dependent tumors had increased cell death and decreased cell proliferation at earlier time points and lower doses of HCQ, suggesting autophagy dependency matters for optimal results. Since autophagy inhibition was inconsistent in vivo, it is still important to determine better biomarkers and possibly consider using more potent autophagy inhibitors in the clinic. Since there have not been any major advancements in osteosarcoma survival over the past four decades, autophagy dependency was assessed in osteosarcoma. Osteosarcoma was found to be intermediately to very dependent on autophagy following a genetic screen. Further, initially autophagy dependent tumor cells were able to survive and adapt to autophagy loss. Not all tumor cells adapted in the same way nor were these autophagy deficient tumor cells more sensitive to standard osteosarcoma chemotherapy, highlighting the difficulty of determining what context autophagy inhibition should be used in the clinic. Since some autophagy inhibitors like HCQ are lysosomal inhibitors and do not specifically target autophagy alone, the results of these studies also emphasized the importance of understanding whether autophagy inhibition via lysosomal degradation or autophagy inhibition of the autophagic pathway itself is superior. Overall, these results indicate targeting autophagy in osteosarcoma is a promising therapy.

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