Encouraging long‐term survival following autophagy inhibition using neoadjuvant hydroxychloroquine and gemcitabine for high‐risk patients with resectable pancreatic carcinoma

AlMasri, Samer; Zenati, Mazen S.; DeSilva, Annissa; Nassour, Ibrahim; Boone, Brian A.; Singhi, Aatur D.; Bartlett, David L.; Liotta, Lance A.; Espina, Virginia; Loughran, Patricia; Lotze, Michael T.; Paniccia, Alessandro; Zeh, Herbert J.; Zureikat, Amer H.; Bahary, Nathan

doi:10.1002/cam4.4211

Cited by 13 publications

(13 citation statements)

References 48 publications

(61 reference statements)

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“…Prior work which tested the effects of LC3B ligands and inhibitors did not examine their binding to GABARAP, leaving open the possibility that their biological effects were mediated in part (or perhaps even in full) by GABARAP inhibition. 8,30,52 Moving forward, we expect that GABARAPselective ligands and ligands that bind both LC3 and GABARAP proteins will be useful classes of ligands for exploring potential combination therapies with DNA-damaging agents and potentially with checkpoint inhibitors as well. 47 Autophagy, and specifically the LC3/GABARAP family of proteins, is also an emerging avenue for targeted protein degradation.…”

Section: ■ Discussionmentioning

confidence: 99%

Structure-Based Design of Stapled Peptides That Bind GABARAP and Inhibit Autophagy

et al. 2022

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The LC3/GABARAP family of proteins is involved in nearly every stage of autophagy. Inhibition of LC3/GABARAP proteins is a promising approach to blocking autophagy, which sensitizes advanced cancers to DNA-damaging chemotherapy. Here, we report the structure-based design of stapled peptides that inhibit GABARAP with nanomolar affinities. Small changes in staple structure produced stapled peptides with very different binding modes and functional differences in LC3/GABARAP paralog selectivity, ranging from highly GABARAP-specific to broad inhibition of both subfamilies. The stapled peptides exhibited considerable cytosolic penetration and resistance to biological degradation. They also reduced autophagic flux in cultured ovarian cancer cells and sensitized ovarian cancer cells to cisplatin. These small, potent stapled peptides represent promising autophagy-modulating compounds that can be developed as novel cancer therapeutics and novel mediators of targeted protein degradation.

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Section: ■ Discussionmentioning

confidence: 99%

Structure-Based Design of Stapled Peptides That Bind GABARAP and Inhibit Autophagy

et al. 2022

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“…Furthermore, a recent phase I/II clinical trial involving patients with advanced PDAC were treated with a neoadjuvant combination of HCQ and gemcitabine prior to resection [ 335 ]. The median overall survival was 31 months and 31% of the patients who received a pancreaticoduodenectomy survived after 5 years, which is a significant improvement when compared to current PDAC survival rates (discussed in Section 3.1 ) [ 336 ]. There are currently four active clinical trial studies on autophagy and PDAC, all of which include an established chemotherapeutic and HCQ as combination therapy ( Table 1 ).…”

Section: Inhibiting Autophagic Machinerymentioning

confidence: 99%

Autophagy: A Key Player in Pancreatic Cancer Progression and a Potential Drug Target

Gillson

El-Aziz

Leck

et al. 2022

Cancers

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Pancreatic cancer is known to have the lowest survival outcomes among all major cancers, and unfortunately, this has only been marginally improved over last four decades. The innate characteristics of pancreatic cancer include an aggressive and fast-growing nature from powerful driver mutations, a highly defensive tumor microenvironment and the upregulation of advantageous survival pathways such as autophagy. Autophagy involves targeted degradation of proteins and organelles to provide a secondary source of cellular supplies to maintain cell growth. Elevated autophagic activity in pancreatic cancer is recognized as a major survival pathway as it provides a plethora of support for tumors by supplying vital resources, maintaining tumour survival under the stressful microenvironment and promoting other pathways involved in tumour progression and metastasis. The combination of these features is unique to pancreatic cancer and present significant resistance to chemotherapeutic strategies, thus, indicating a need for further investigation into therapies targeting this crucial pathway. This review will outline the autophagy pathway and its regulation, in addition to the genetic landscape and tumor microenvironment that contribute to pancreatic cancer severity. Moreover, this review will also discuss the mechanisms of novel therapeutic strategies that inhibit autophagy and how they could be used to suppress tumor progression.

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“…HPLC purity 98.9% (t R = 23.43 min). 1 6-Bromo-N-(quinolin-8-yl)picolinamide (10). The title compound was prepared by the reaction of 6-bromopyridine-2-carboxylic acid 3g (152 mg, 0.75 mmol) and quinolin-8-ylamine 2a (72 mg, 0.5 mmol) according to the general procedure.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…Mutations in KRAS and p53 coupled with stress responses such as hypoxia, metabolic reprogramming, and autophagy play vital roles in pancreatic cancer progression. − Therefore, inhibition of autophagy may provide a unique opportunity to effectively treat PDAC and potentially increase response to chemotherapy. In fact, several ongoing clinical trials have combined autophagy inhibitors with standard-of-care chemotherapy in pancreatic cancer. − …”

Section: Introductionmentioning

confidence: 99%

Induction of Genes Implicated in Stress Response and Autophagy by a Novel Quinolin-8-yl-nicotinamide QN523 in Pancreatic Cancer

Kuang

Kyani

et al. 2022

J. Med. Chem.

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Using a cytotoxicity-based phenotypic screen of a highly diverse library of 20,000 small-molecule compounds, we identified a quinolin-8-yl-nicotinamide, QN519, as a promising lead. QN519 represents a novel scaffold with drug-like properties, showing potent in vitro cytotoxicity in a panel of 12 cancer cell lines. Subsequently, lead optimization campaign generated compounds with IC50 values < 1 μM. An optimized compound, QN523, shows significant in vivo efficacy in a pancreatic cancer xenograft model. QN523 treatment significantly increased the expression of HSPA5, DDIT3, TRIB3, and ATF3 genes, suggesting activation of the stress response pathway. We also observed a significant increase in the expression of WIPI1, HERPUD1, GABARAPL1, and MAP1LC3B, implicating autophagy as a major mechanism of action. Due to the lack of effective treatments for pancreatic cancer, discovery of novel agents such as the QN series of compounds with unique mechanism of action has the potential to fulfill a clear unmet medical need.

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Encouraging long‐term survival following autophagy inhibition using neoadjuvant hydroxychloroquine and gemcitabine for high‐risk patients with resectable pancreatic carcinoma

Cited by 13 publications

References 48 publications

Structure-Based Design of Stapled Peptides That Bind GABARAP and Inhibit Autophagy

Structure-Based Design of Stapled Peptides That Bind GABARAP and Inhibit Autophagy

Autophagy: A Key Player in Pancreatic Cancer Progression and a Potential Drug Target

Induction of Genes Implicated in Stress Response and Autophagy by a Novel Quinolin-8-yl-nicotinamide QN523 in Pancreatic Cancer

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