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Autophagy Modulation May Be a Novel Approach to Treatment of Advanced Cancers

Sukeshi R. Patel, MD, and Devalingam Mahalingam, MD, PhD
Published: Sunday, Nov 29, 2015
UT Medicine CTRC Health Science Center San AntonioSukeshi R. Patel, MD
Sukeshi R. Patel, MD
Medical Oncologist, Gastrointestinal Malignancies
The University of Texas Health Science Center at San Antonio
Devalingam Mahalingam, MD, PhD
Devalingam Mahalingam, MD, PhD
Assistant Professor, Medicine
Cancer Therapy & Research Center
The University of Texas Health Science Center at San Antonio
San Antonio, TX
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Autophagy is a conserved protein degradation process that involves the vacuolar sequestration of long-lived cytoplasmic proteins and organelles into a structure called an autophagosome.1 Autophagosomes fuse with lysosomes, which results in the proteolytic degradation of the cytoplasmic contents.

In eukaryotic cells, autophagy plays an important role in the disposal of damaged organelles and proteins, and serves to generate alternative sources of energy for cell survival during cellular stress through the catabolization of protein substrates.2 The activation of stress response genes such as tumor protein p53 by anticancer therapies can stimulate autophagy in addition to apoptosis.3

Although prolonged autophagy can result in cancer cell death, recent investigations suggest that therapy-induced autophagy is a reversible response that promotes cancer cell survival, and thus may diminish the efficacy of some therapeutic agents.4-6 Therefore, autophagy may significantly contribute to resistance to a number of anticancer therapeutic modalities.

Figure 1. Responses to Autophagy-Targeting Therapy

Figure 1. Responses to Autophagy-Targeting Therapy

Treatment with vorinostat and hydroxychloroquine yielded a prolonged partial response in a patient with refractory renal cell carcinoma that has been durable for more than 50 cycles of therapy. MRI scans obtained at baseline and post cycles 10 and 50 (C10 and C50, respectively) are shown.

Examining the Role of HDACs

Our institution chose to study the role of histone deactelyase (HDAC) inhibitors, which are known to induce autophagy, to investigate the impact of targeting the process.

CTRC researchers showed that HDAC inhibitor– induced autophagy blunts its anticancer activity.6 Yet, genetic or pharmacologic disruption of autophagy synergistically modulated the proapoptotic and cytostatic effects of the HDAC inhibitor vorinostat in models of imatinib-resistant chronic myeloid leukemia and colon cancer.6,7 A therapy-induced increase in the levels of lysosomal protease cathepsin D was identified as a key downstream pharmacodynamic mediator of the proapoptotic effects of the combination of vorinostat and the autophagy inhibitor, chloroquine.7,8

Figure 2. Schema for Phase II Autophagy Study

Schema for Phase II Autophagy Study

HCQ indicates hydroxychloroquine; mCRC, metastatic colorectal cancer; po, by mouth; RGF, regorafenib; VOR, vorinostat.

Investigators at our institution have shown that autophagy inhibition with hydroxychloroquine enhanced vorinostat-induced apoptosis via ubiquitinated protein accumulation in preclinical cancer models.7

When this was translated to the clinic in a phase I study of 31 patients previously heavily pretreated with chemotherapeutic agents, the most common treatment-related toxicities were primarily grade 1-2 nausea, diarrhea, fatigue, anorexia, weight loss, anemia, and creatinine elevation.9 Most common significant toxicities were fatigue in three patients, with anemia, thrombocytopenia, and neutropenia in one patient each.


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