Biomarker Analyses in Patients With Advanced Solid Tumors Treated With the LAT1 Inhibitor JPH203

Okano, Naohiro; Hana, Kiyomi; Nagashima, Daisuke; Kawai, Kirio; Kobayashi, Takaaki; Nagashima, Fumio; Endou, Hitoshi; Furuse, Junji

doi:10.21873/invivo.12077

Cited by 18 publications

(13 citation statements)

References 36 publications

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“…The study indicated that the safety and efficacy of JPH203 could be predicted by genetic variants in the NAT2 gene, which encodes an N -acetyltransferase responsible for phase II metabolism of JPH203. The study also suggested that plasma free amino acid levels and BMI are useful predictors of JPH203 efficacy ( 136 ). Randomized controlled phase II studies in patients with advanced biliary tract cancer are under way in Japan (University Hospital Medical Information Network [UMIN] Clinical Trials Registry UMIN000034080).…”

Section: Metabolic Inhibitors In Clinical Trialsmentioning

confidence: 99%

Clinical development of metabolic inhibitors for oncology

Lemberg¹,

Gori²,

Tsukamoto³

et al. 2022

Journal of Clinical Investigation

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Metabolic inhibitors have been used in oncology for decades, dating back to antimetabolites developed in the 1940s. In the past 25 years, there has been increased recognition of metabolic derangements in tumor cells leading to a resurgence of interest in targeting metabolism. More recently there has been recognition that drugs targeting tumor metabolism also affect the often acidic, hypoxic, immunosuppressive tumor microenvironment (TME) and non-tumor cell populations within it, including immune cells. Here we review small-molecule metabolic inhibitors currently in clinical development for oncology applications. For each agent, we evaluate the preclinical studies demonstrating antitumor and TME effects and review ongoing clinical trials. The goal of this Review is to provide an overview of the landscape of metabolic inhibitors in clinical development for oncology.

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Section: Metabolic Inhibitors In Clinical Trialsmentioning

confidence: 99%

Clinical development of metabolic inhibitors for oncology

Lemberg¹,

Gori²,

Tsukamoto³

et al. 2022

Journal of Clinical Investigation

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“…This finding opens also other perspectives when considering that a therapy acting on CD98 trafficking will surely impair the LAT1 chaperoning, with consequent high relevance to human therapy. Then, CD98 inhibition would act synergistically with specific LAT1 inhibitors, such as the tyrosine derivative JPH203 that is in human trial for anticancer therapy 41 .…”

Section: Discussionmentioning

confidence: 99%

N-glycosylation is crucial for trafficking and stability of SLC3A2 (CD98)

Console

Scalise

Salerno

et al. 2022

Sci Rep

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The type II glycoprotein CD98 (SLC3A2) is a membrane protein with pleiotropic roles in cells, ranging from modulation of inflammatory processes, host–pathogen interactions to association with membrane transporters of the SLC7 family. The recent resolution of CD98 structure in complex with LAT1 showed that four Asn residues, N365, N381, N424, N506, harbour N-glycosylation moieties. Then, the role of N-glycosylation on CD98 trafficking and stability was investigated by combining bioinformatics, site-directed mutagenesis and cell biology approach. Single, double, triple and quadruple mutants of the four Asn exhibited altered electrophoretic mobility, with apparent molecular masses from 95 to 70 kDa. The quadruple mutant displayed a single band of 70 kDa corresponding to the unglycosylated protein. The presence in the membrane and the trafficking of CD98 were evaluated by a biotinylation assay and a brefeldin assay, respectively. Taken together, the results highlighted that the quadruple mutation severely impaired both the stability and the trafficking of CD98 to the plasma membrane. The decreased presence of CD98 at the plasma membrane, correlated with a lower presence of LAT1 (SLC7A5) and its transport activity. This finding opens new perspectives for human therapy. Indeed, the inhibition of CD98 trafficking would act synergistically with LAT1 inhibitors that are under clinical trial for anticancer therapy.

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“…Importantly, IGN523, a humanized anti-CD98 (anti-SLC3A2) monoclonal antibody has been tested for relapsed or refractory acute myeloid leukemia, and preclinical data showed effective anti-tumor activity in xenograft models ( 173 ). On the other hand, LAT-1 inhibitor JPH203 showed promising results in a phase I clinical trial for biliary tract cancer ( 174 ). Even though these modalities were designed to inhibit the amino acid uptake of tumor cells, such approaches might also target Treg functions to attenuate their immunosuppressive mechanisms, which might also favor the elimination of tumor cells.…”

Section: Tcf-1 and Tregsmentioning

confidence: 99%

Immunometabolism – The Role of Branched-Chain Amino Acids

Yahsi

Günaydın

2022

Front. Immunol.

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Immunometabolism has been the focus of extensive research over the last years, especially in terms of augmenting anti-tumor immune responses. Regulatory T cells (Tregs) are a subset of CD4+ T cells, which have been known for their immunosuppressive roles in various conditions including anti-tumor immune responses. Even though several studies aimed to target Tregs in the tumor microenvironment (TME), such approaches generally result in the inhibition of the Tregs non-specifically, which may cause immunopathologies such as autoimmunity. Therefore, specifically targeting the Tregs in the TME would be vital in terms of achieving a successful and specific treatment. Recently, an association between Tregs and isoleucine, which represents one type of branched-chain amino acids (BCAAs), has been demonstrated. The presence of isoleucine seems to affect majorly Tregs, rather than conventional T cells. Considering the fact that Tregs bear several distinct metabolic features in the TME, targeting their immunometabolic pathways may be a rational approach. In this Review, we provide a general overview on the potential distinct metabolic features of T cells, especially focusing on BCAAs in Tregs as well as in their subtypes.

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Biomarker Analyses in Patients With Advanced Solid Tumors Treated With the LAT1 Inhibitor JPH203

Cited by 18 publications

References 36 publications

Clinical development of metabolic inhibitors for oncology

Clinical development of metabolic inhibitors for oncology

N-glycosylation is crucial for trafficking and stability of SLC3A2 (CD98)

Immunometabolism – The Role of Branched-Chain Amino Acids

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