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

Sukeshi R. Patel, MD

Medical Oncologist, Gastrointestinal Malignancies

The University of Texas Health Science Center at San Antonio

Devalingam Mahalingam, MD, PhD

Assistant Professor, Medicine

Cancer Therapy & Research Center

The University of Texas Health Science Center at San Antonio

San Antonio, TX

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

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

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.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

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.

The maximum tolerated dose of the combination therapy is hydroxychloroquine 600 mg by mouth daily with vorinostat 400 mg daily. One patient with renal cell carcinoma who had failed seven lines of prior therapy had a confirmed durable partial response (RECIST 1.0 criteria, active on study with 50+ cycles) (Figure 1). Two patients with KRAS-mutated colorectal cancer (CRC) had prolonged stable disease (>4 cycles).

Studies in CRC and Other Tumor Types

The addition of hydroxychloroquine did not significantly impact the pharmacokinetic profile of vorinostat.These promising data have led to the opening of a phase II randomized study comparing autophagy inhibition with vorinostat and hydroxychloroquine with regorafenib, the current standard in patients with CRC who are failing standard therapies (Figure 2).¹⁰ This study, which has a primary endpoint of progression-free survival, is currently open to enrollment. Preplanned pharmacodynamic analyses will help us identify which patients with refractory metastatic CRC benefit from autophagy inhibition versus angiogenic inhibition.

Table. Open Phase II Clinical Trials of Autophagy Modulation in Malignancies

CQ indicates chloroquine; HCQ, hydroxychloroquine; IL-2, interleukin-2 (aldesleukin).

If the early clinical finding holds true for survival benefit in patients with advanced CRC with minimal toxicity to patients, then autophagy modulation with vorinostat and hydroxychloroquine could one day become a treatment option for patients with advanced CRC. This study could result in better treatment choices for patients with refractory metastatic CRC and lay the foundation for future studies of a new class of therapeutics in metastatic CRC. In addition to CRC, autophagy modulation has demonstrated the potential to improve the treatment efficacy of other chemotherapeutic and targeted agents in other cancers.¹¹ Many clinical trials of autophagy modulators are currently recruiting cancer patients, with several ongoing phase II studies in refractory malignancies (Table).

Preliminary results demonstrate tolerability of autophagy modulators with chemotherapy. Final survival and pharmacodynamic analyses of these studies will allow us to better understand the therapeutic potential of autophagy modulation across a variety of cancer types.

References

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