Vorinostat and hydroxychloroquine improve immunity and inhibit autophagy in metastatic colorectal cancer

Arora, Sukeshi Patel; Hurez, Vincent; Nawrocki, Steffan T.; Goros, Martin; Michalek, Joel E.; Sarantopoulos, John; Curiel, Tyler J.; Mahalingam, Devalingam

doi:10.18632/oncotarget.10824

Cited by 68 publications

(39 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…None of the combinations tested in the earlier series of phase I studies were pursued in phase II studies except a phase II study of vorinostat and HCQ in metastatic colon cancer, which did show a reasonable progression-free survival (PFS) and safety profile for highly treatment-refractory colorectal cancer (132). More recently, a phase I/II trial of everolimus 10 mg daily and HCQ in patients with advanced clear cell renal cell carcinoma found no dose-limiting toxicity in the phase I trial.…”

Section: Repurposing Hcq In Clinical Oncology Trialsmentioning

confidence: 99%

Targeting Autophagy in Cancer: Recent Advances and Future Directions

2019

View full text Add to dashboard Cite

Autophagy, a multistep lysosomal degradation pathway that supports nutrient recycling and metabolic adaptation, has been implicated as a process that regulates cancer. Although autophagy induction may limit the development of tumors, evidence in mouse models demonstrates that autophagy inhibition can limit the growth of established tumors and improve response to cancer therapeutics. Certain cancer genotypes may be especially prone to autophagy inhibition. Different strategies for autophagy modulation may be needed depending on the cancer context. Here, we review new advances in the molecular control of autophagy, the role of selective autophagy in cancer, and the role of autophagy within the tumor microenvironment and tumor immunity. We also highlight clinical efforts to repurpose lysosomal inhibitors, such as hydroxychloroquine, as anticancer agents that block autophagy, as well as the development of more potent and specifi c autophagy inhibitors for cancer treatment, and review future directions for autophagy research. Signifi cance: Autophagy plays a complex role in cancer, but autophagy inhibition may be an effective therapeutic strategy in advanced cancer. A deeper understanding of autophagy within the tumor microenvironment has enabled the development of novel inhibitors and clinical trial strategies. Challenges and opportunities remain to identify patients most likely to benefi t from this approach.

show abstract

Section: Repurposing Hcq In Clinical Oncology Trialsmentioning

confidence: 99%

Targeting Autophagy in Cancer: Recent Advances and Future Directions

2019

View full text Add to dashboard Cite

show abstract

“…68 The first phase 1 trials involving HCQ that included autophagy markers combined HCQ with vorinostat (VOR), TEM, temozolomide (TMZ), doxorubicin, or bortezomib (BOR) in patients who had refractory solid tumors, melanoma, glioblastoma multiforme, and relapsed/refractory myeloma (Table 1). 46,61,63,[69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84][85][86][87] In these studies, across >200 patients enrolled on the trials, there was a grade 3 an 4 nonhematologic adverse event rate of <10%, which is surprising because each of drug that was combined with HCQ has significant toxicity (eg, fatigue [VOR], mouth sores and hyperglycemia [TEM], myelosuppression [TMZ], neuropathy [BOR]) that could become dose limiting, and the population was a very sick phase 1 population or patients with glioblastoma multiforme. Multiple patients with melanoma, colorectal carcinoma, myeloma, and renal cell carcinoma achieved a partial response or had prolonged stable disease on these HCQ combinations; however, overall response rates were not high (detailed below).…”

Section: Autophagy Inhibition In Clinical Trialsmentioning

confidence: 99%

Targeting autophagy in cancer

Onorati

Dyczynski

Ojha

et al. 2018

Cancer

537

431

View full text Add to dashboard Cite

Autophagy is a conserved, self-degradation system that is critical for maintaining cellular homeostasis during stress conditions. Dysregulated autophagy has implications in health and disease. Specifically, in cancer, autophagy plays a dichotomous role by inhibiting tumor initiation but supporting tumor progression. Early results from clinical trials that repurposed hydroxychloroquine for cancer have suggested that autophagy inhibition may be a promising approach for advanced cancers. In this review of the literature, the authors present fundamental advances in the biology of autophagy, approaches to targeting autophagy, the preclinical rationale and clinical experience with hydroxychloroquine in cancer clinical trials, the potential role of autophagy in tumor immunity, and recent developments in next-generation autophagy inhibitors that have clinical potential. Autophagy is a promising target for drug development in cancer. Cancer 2018. © 2018 American Cancer Society.

show abstract

“…Our practice in treating chemotherapy‐associated SCLE has been to control the cutaneous eruption with topical therapy with or without hydroxychloroquine, and to continue chemotherapy. Hydroxychloroquine may inhibit tumour autophagy and has been combined with small molecule inhibitors to treat malignancies . However, its true impact on the PD‐1 inhibitor anti‐tumour response is still unknown.…”

Section: Discussionmentioning

confidence: 99%

Subacute cutaneous lupus erythematosus and dermatomyositis associated with anti‐programmed cell death 1 therapy

et al. 2018

View full text Add to dashboard Cite

Summary Programmed cell death 1 (PD‐1) blockade has rapidly emerged as an effective therapy for a wide variety of metastatic malignancies. It has been associated with multiple immune‐related adverse effects, including cutaneous eruptions. We describe two patients with clinical and histological findings that were consistent with subacute cutaneous lupus erythematosus (SCLE) after receiving PD‐1 inhibitor therapy for metastatic lung cancer. We successfully treated our first patient with systemic and topical steroids, photoprotection and hydroxychloroquine. However, he subsequently developed dermatomyositis after continuing PD‐1 inhibitor therapy. Our second patient presented with a protracted course of a cutaneous eruption in spite of discontinuation of anti‐PD‐1 therapy and treatment with systemic corticosteroids and infliximab. This patient's SCLE resolved after the addition of topical steroids and photoprotection and discontinuation of anti‐tumour necrosis factor therapy. She and her oncology team decided to pursue non‐PD‐1 inhibitor treatment for lung cancer owing to a lack of tumour response. We add SCLE and dermatomyositis to the growing list of autoimmune complications of PD‐1 blockade. Our cases raise a number of questions, particularly in relation to the viability of continuing anti‐PD‐1 therapy after developing SCLE and the role of immunosuppressive therapy in patients with PD‐1 inhibitor‐associated connective tissue disease. What's already known about this topic? Programmed cell death 1 (PD‐1) blockade, which is rapidly emerging as a therapy for a wide variety of metastatic malignancies, has been associated with multiple immune‐related adverse effects. These include systemic autoimmune diseases such as colitis and thyroiditis in addition to numerous cutaneous adverse events. Cutaneous side‐effects of PD‐1 inhibitors most commonly reported in clinical trials include lichenoid reactions, eczematous dermatitis and vitiligo. What does this study add? We report two cases of PD‐1 inhibitor‐associated subacute cutaneous lupus erythematosus (SCLE), with one patient progressing to dermatomyositis with continued PD‐1 inhibitor treatment. In addition to being a novel cutaneous adverse event, we also demonstrate the possibility of development of multiple autoimmune diseases in one patient, which is different from classic drug‐related SCLE. We discuss the treatment challenges for patients with autoimmune skin disease receiving PD‐1 inhibitor therapy.

show abstract

Vorinostat and hydroxychloroquine improve immunity and inhibit autophagy in metastatic colorectal cancer

Cited by 68 publications

References 37 publications

Targeting Autophagy in Cancer: Recent Advances and Future Directions

Targeting Autophagy in Cancer: Recent Advances and Future Directions

Targeting autophagy in cancer

Subacute cutaneous lupus erythematosus and dermatomyositis associated with anti‐programmed cell death 1 therapy

Contact Info

Product

Resources

About