Targeted deprivation of methionine with engineered Salmonella leads to oncolysis and suppression of metastasis in broad types of animal tumor models

Zhou, Sujin; Yang, Lin; Zhao, Z. X.; Lai, Yunhao; Lu, Mengmeng; Shao, Zhi Ming; Mo, Xinyu; Mu, Yunping; Liang, Zhipeng; Wang, Xinxing; Qu, Jingming; Su, Hua; Li, Fanghong; Zhao, Allan Z.

doi:10.1016/j.xcrm.2023.101070

Cited by 14 publications

(11 citation statements)

References 62 publications

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“…On this note, the recently developed SGN1, a genetically engineered bacterium drug (currently in global phase I trial), can fulfill this requirement [ 22 , 46 ]. Bacteria have the natural ability to target tumor tissues with insufficient oxygen and low pH owing to their high motility and chemoreceptors [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

“…Bacteria have the natural ability to target tumor tissues with insufficient oxygen and low pH owing to their high motility and chemoreceptors [ 47 ]. SGN1 still retains the ability to colonize in experimental tumors and overexpresses the L-methioninase to hydrolyze and deprive methionine (as well as SAM/SAH) only in the osteosarcoma tissues [ 22 ]. The treatment with SGN1 led to drastic retardation of osteosarcoma growth and pulmonary (also hepatic) metastasis in the orthotopic and metastatic models, and significantly prolonged the survival of the osteosarcoma metastatic model.…”

Section: Discussionmentioning

confidence: 99%

“…In our latest study, we have described the development of an attenuated Salmonella -based agent, SGN1, that can target methionine metabolism [ 22 ]. SGN1 is a genetically modified strain of attenuated Salmonella typhimurium (VNP20009) that can overexpress an L-methioninase—a pyridoxal phosphate-dependent enzyme that catalyzes the γ-elimination of amino group of L-methionine to methanethiol, α-ketobutyrate, and ammonia [ 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

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Deprivation of methionine inhibits osteosarcoma growth and metastasis via C1orf112-mediated regulation of mitochondrial functions

Zhang,

Zhao,

Wang

et al. 2024

Cell Death Dis

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Osteosarcoma is a malignant bone tumor that primarily inflicts the youth. It often metastasizes to the lungs after chemotherapy failure, which eventually shortens patients’ lives. Thus, there is a dire clinical need to develop a novel therapy to tackle osteosarcoma metastasis. Methionine dependence is a special metabolic characteristic of most malignant tumor cells that may offer a target pathway for such therapy. Herein, we demonstrated that methionine deficiency restricted the growth and metastasis of cultured human osteosarcoma cells. A genetically engineered Salmonella, SGN1, capable of overexpressing an L-methioninase and hydrolyzing methionine led to significant reduction of methionine and S-adenosyl-methionine (SAM) specifically in tumor tissues, drastically restricted the growth and metastasis in subcutaneous xenograft, orthotopic, and tail vein-injected metastatic models, and prolonged the survival of the model animals. SGN1 also sharply suppressed the growth of patient-derived organoid and xenograft. Methionine restriction in the osteosarcoma cells initiated severe mitochondrial dysfunction, as evident in the dysregulated gene expression of respiratory chains, increased mitochondrial ROS generation, reduced ATP production, decreased basal and maximum respiration, and damaged mitochondrial membrane potential. Transcriptomic and molecular analysis revealed the reduction of C1orf112 expression as a primary mechanism underlies methionine deprivation-initiated suppression on the growth and metastasis as well as mitochondrial functions. Collectively, our findings unraveled a molecular linkage between methionine restriction, mitochondrial function, and osteosarcoma growth and metastasis. A pharmacological agent, such as SGN1, that can achieve tumor specific deprivation of methionine may represent a promising modality against the metastasis of osteosarcoma and potentially other types of sarcomas as well.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Deprivation of methionine inhibits osteosarcoma growth and metastasis via C1orf112-mediated regulation of mitochondrial functions

Zhang,

Zhao,

Wang

et al. 2024

Cell Death Dis

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“…One preclinical study pursued i.t. delivery of a genetically modified Salmonella strain expressing a methioninase in nude mice bearing MDA-MB-231 xenografts ( 146 ). Salmonella had demonstrated preferential accumulation in the tumor in a previous study.…”

Section: Preclinical Studiesmentioning

confidence: 99%

“…Furthermore, bacteria were predominately found in the tumor rather than the lung, liver, or kidney at ratios between 500–62,000:1. Finally, methionine was reduced in tumor cells but not systemically ( 146 ). The safety and feasibility of the treatment is being evaluated in a phase 1 clinical trial (NCT05103345).…”

Section: Preclinical Studiesmentioning

confidence: 99%

Intratumoral delivery of immunotherapy to treat breast cancer: current development in clinical and preclinical studies

Mantooth,

Abdou,

Saez-Ibañez

et al. 2024

Front. Immunol.

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Breast cancer poses one of the largest threats to women’s health. Treatment continues to improve for all the subtypes of breast cancer, but some subtypes, such as triple negative breast cancer, still present a significant treatment challenge. Additionally, metastasis and local recurrence are two prevalent problems in breast cancer treatment. A newer type of therapy, immunotherapy, may offer alternatives to traditional treatments for difficult-to-treat subtypes. Immunotherapy engages the host’s immune system to eradicate disease, with the potential to induce long-lasting, durable responses. However, systemic immunotherapy is only approved in a limited number of indications, and it benefits only a minority of patients. Furthermore, immune related toxicities following systemic administration of potent immunomodulators limit dosing and, consequently, efficacy. To address these safety considerations and improve treatment efficacy, interest in local delivery at the site of the tumor has increased. Numerous intratumorally delivered immunotherapeutics have been and are being explored clinically and preclinically, including monoclonal antibodies, cellular therapies, viruses, nucleic acids, cytokines, innate immune agonists, and bacteria. This review summarizes the current and past intratumoral immunotherapy clinical landscape in breast cancer as well as current progress that has been made in preclinical studies, with a focus on delivery parameters and considerations.

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Programmable Bacteria with Dynamic Virulence Modulation System for Precision Antitumor Immunity

Wu,

Li,

Qiao

et al. 2024

Advanced Science

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Engineered bacteria‐mediated antitumor approaches have been proposed as promising immunotherapies for cancer. However, the off‐target bacterial toxicity narrows the therapeutic window. Living microbes will benefit from their controllable immunogenicity within tumors for safer antitumor applications. In this study, a genetically encoded microbial activation strategy is reported that uses tunable and dynamic expression of surface extracellular polysaccharides to improve bacterial biocompatibility while retaining therapeutic efficacy. Based on screening of genes associated with Salmonella survival in macrophages, a novel attenuated Salmonella chassis strain AIS (htrA gene‐deficient) highly enriched in tumors after administration and rapidly cleared from normal organs are reported. Subsequently, an engineered bacterial strain, AISI‐H, is constructed based on the AIS strain and an optimized quorum‐sensing regulatory system. The AISI‐H strain can achieve recovery of dynamic tumor‐specific bacterial virulence through a novel HTRA‐RCSA axis‐based and quorum‐sensing synthetic gene circuit‐mediated increase in extracellular polysaccharide content. These strains act “off” in normal organs to avoid unwanted immune activation and “on” in tumors for precise tumor suppression in mice. The AISI‐H strain shows significant tumor inhibition and potent activation of anticancer immunity in a melanoma mouse model. The AISI‐H strain exhibits excellent biocompatibility. This bacterial regulation strategy expands the applications of microbe‐based antitumor therapeutics.

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Targeted deprivation of methionine with engineered Salmonella leads to oncolysis and suppression of metastasis in broad types of animal tumor models

Cited by 14 publications

References 62 publications

Deprivation of methionine inhibits osteosarcoma growth and metastasis via C1orf112-mediated regulation of mitochondrial functions

Deprivation of methionine inhibits osteosarcoma growth and metastasis via C1orf112-mediated regulation of mitochondrial functions

Intratumoral delivery of immunotherapy to treat breast cancer: current development in clinical and preclinical studies

Programmable Bacteria with Dynamic Virulence Modulation System for Precision Antitumor Immunity

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