Engineering Reduced-Immunogenicity Enzymes for Amino Acid Depletion Therapy in Cancer

Cantor, Jason R.; Panayiotou, Vasiliki; Agnello, Giulia; Georgiou, George; Stone, Everett

doi:10.1016/b978-0-12-416039-2.00015-x

Cited by 48 publications

(35 citation statements)

References 113 publications

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“…Inhibition of cancer growth by manipulation of dietary amino acids has previously been proposed (43,44), but leads to adverse effects of deficiency in essential amino acids. This contrasts with our approach, in which a well-tolerated dietary restriction of two nonessential amino acids sensitizes cancer cells to biguanide treatment.…”

Section: Discussionmentioning

confidence: 99%

Serine Deprivation Enhances Antineoplastic Activity of Biguanides

et al. 2014

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Metformin, a biguanide widely used in the treatment of type II diabetes, clearly exhibits antineoplastic activity in experimental models and has been reported to reduce cancer incidence in diabetics. There are ongoing clinical trials to evaluate its antitumor properties, which may relate to its fundamental activity as an inhibitor of oxidative phosphorylation. Here, we show that serine withdrawal increases the antineoplastic effects of phenformin (a potent biguanide structurally related to metformin). Serine synthesis was not inhibited by biguanides. Instead, metabolic studies indicated a requirement for serine to allow cells to compensate for biguanide-induced decrease in oxidative phosphorylation by upregulating glycolysis. Furthermore, serine deprivation modified the impact of metformin on the relative abundance of metabolites within the citric acid cycle. In mice, a serine-deficient diet reduced serine levels in tumors and significantly enhanced the tumor growth-inhibitory actions of biguanide treatment. Our results define a dietary manipulation that can enhance the efficacy of biguanides as antineoplastic agents that target cancer cell energy metabolism. Cancer Res; 74(24); 7521-33. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 99%

Serine Deprivation Enhances Antineoplastic Activity of Biguanides

et al. 2014

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“…These conserved functions included the transport of thiamine and cystine (Table S4), both of which were previously shown to strongly stimulate the growth of A. actinomycetemcomitans in culture media (63). Metabolic targets such as these could therefore be exploited in future drug development, as exemplified by cancer researchers who have engineered enzymes, such as cyst(e)inases, to degrade amino acids that support auxotrophic cancers (64). Cystine is only conditionally essential in humans (65), but thiamine requires dietary uptake, making its depletion potentially toxic.…”

Section: Discussionmentioning

confidence: 99%

Defining Genetic Fitness Determinants and Creating Genomic Resources for an Oral Pathogen

Narayanan

Ramsey

Stacy

et al. 2017

Appl Environ Microbiol

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Periodontitis is a microbial infection that destroys the structures that support the teeth. Although it is typically a chronic condition, rapidly progressing, aggressive forms are associated with the oral pathogen Aggregatibacter actinomycetemcomitans. One of this bacterium's key virulence traits is its ability to attach to surfaces and form robust biofilms that resist killing by the host and antibiotics. Though much has been learned about A. actinomycetemcomitans since its initial discovery, we lack insight into a fundamental aspect of its basic biology, as we do not know the full set of genes that it requires for viability (the essential genome). Furthermore, research on A. actinomycetemcomitans is hampered by the field's lack of a mutant collection. To address these gaps, we used rapid transposon mutant sequencing (Tn-seq) to define the essential genomes of two strains of A. actinomycetemcomitans, revealing a core set of 319 genes. We then generated an arrayed mutant library comprising Ͼ1,500 unique insertions and used a sequencing-based approach to define each mutant's position (well and plate) in the library. To demonstrate its utility, we screened the library for mutants with weakened resistance to subinhibitory erythromycin, revealing the multidrug efflux pump AcrAB as a critical resistance factor. During the screen, we discovered that erythromycin induces A. actinomycetemcomitans to form biofilms. We therefore devised a novel Tnseq-based screen to identify specific factors that mediate this phenotype and in follow-up experiments confirmed 4 mutants. Together, these studies present new insights and resources for investigating the basic biology and disease mechanisms of a human pathogen. IMPORTANCE Millions suffer from gum disease, which often is caused by Aggregatibacter actinomycetemcomitans, a bacterium that forms antibiotic-resistant biofilms. To fully understand any organism, we should be able to answer: what genes does it require for life? Here, we address this question for A. actinomycetemcomitans by determining the genes in its genome that cannot be mutated. As for the genes that can be mutated, we archived these mutants into a library, which we used to find genes that contribute to antibiotic resistance, leading us to discover that antibiotics cause A. actinomycetemcomitans to form biofilms. We then devised an approach to find genes that mediate this process and confirmed 4 genes. These results illuminate new fundamental traits of a human pathogen.KEYWORDS Aggregatibacter, Tn-seq, antibiotics, biofilms, essential genome O ne of the longest-studied human microbiomes is the "animalcules" (bacteria), first observed by van Leeuwenhoek (1), that inhabit the oral cavity. Oral bacteria readily attach to tooth surfaces and develop into spatially organized, multispecies biofilms (2). These communities also persist beneath the gum line in the subgingival pocket, where they are kept in check by host immune cells (3). Though normally benign, subgingival communities can accumulate opportunistic oral p...

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“…Instead, metabolic rewiring during tumorigenesis may also result in the development of specific metabolic liabilities that, while likely not selected for nor acting to promote proliferation, still arise as additional dependencies that must be met to maintain cell survival. In particular, several tumor types are auxotrophic for one or more amino acids owing to deficiencies in a corresponding endogenous biosynthesis or salvage pathway (101). Consequently, these cells have a particular reliance on the import of a given amino acid(s) from the extracellular serum pool.…”

Section: Deciphering Metabolic Heterogeneitymentioning

confidence: 99%

“…Consequently, these cells have a particular reliance on the import of a given amino acid(s) from the extracellular serum pool. Extensive in vitro , in vivo , and clinical evaluations conducted over the past sixty years have established that this type of metabolic liability can be exploited through enzyme-mediated systemic depletion of a circulating “tumor-essential” amino acid, resulting in the selective starvation and death of targeted auxotrophic malignant cells with minimal effect on normal cells (101). …”

Section: Deciphering Metabolic Heterogeneitymentioning

confidence: 99%

Cancer Cell Metabolism: One Hallmark, Many Faces

2012

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Cancer cells must rewire cellular metabolism to satisfy the demands of growth and proliferation. While many of the metabolic alterations are largely similar to those in normal proliferating cells, they are aberrantly driven in cancer by a combination of genetic lesions and non-genetic factors such as the tumor microenvironment. However, a single model of altered tumor metabolism does not describe the sum of metabolic changes that can support cell growth. Instead, the diversity of such changes within the metabolic program of a cancer cell can dictate by what means proliferative rewiring is driven, and can also impart heterogeneity in the metabolic dependencies of the cell. A better understanding of this heterogeneity may enable the development and optimization of therapeutic strategies that target tumor metabolism.

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Engineering Reduced-Immunogenicity Enzymes for Amino Acid Depletion Therapy in Cancer

Cited by 48 publications

References 113 publications

Serine Deprivation Enhances Antineoplastic Activity of Biguanides

Serine Deprivation Enhances Antineoplastic Activity of Biguanides

Defining Genetic Fitness Determinants and Creating Genomic Resources for an Oral Pathogen

Cancer Cell Metabolism: One Hallmark, Many Faces

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