Therapeutic targeting of SLC6A8 creatine transporter suppresses colon cancer progression and modulates human creatine levels

Kurth, Isabel; Yamaguchi, Norihiro; Andreu-Agulló, Celia; Tian, Helen S.; Sridhar, Subhasree; Takeda, Shugaku; Gonsalves, Foster C.; Loo, Jia Min; Barlas, Afsar; Manova‐Todorova, Katia; Busby, Robert; Bendell, Johanna C.; Strauss, James; Fakih, Marwan; McRee, Autumn J.; Hendifar, Andrew Eugene; Rosen, Lee S.; Cercek, Andrea; Wasserman, Robert; Szarek, Michael; Spector, Scott L.; Raza, Syed Hyder; Tavazoie, Masoud; Tavazoie, Sohail F.

doi:10.1126/sciadv.abi7511

Cited by 25 publications

(37 citation statements)

References 32 publications

(56 reference statements)

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“…Preclinical studies demonstrated that inhibiting phosphocreatine import with the small molecule drug, RGX-202, inhibited primary, metastatic and patient derived xenograft (PDX) colorectal tumors in association with reducing phosphocreatine levels [ 14 ]. A phase 1 trial of RGX-202 in advanced gastrointestinal cancers documented increased serum and urine creatine levels consistent with the decreased creatine uptake in tumors of preclinical models treated with RGX-202 [ 14 ]. This phase 1 trial showed no dose-limiting toxicity in the first 17 patients enrolled, and a durable partial response in the highest dose cohort [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

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Identification of Candidate Biomarker and Drug Targets for Improving Endometrial Cancer Racial Disparities

Javadian

Sjoelund

et al. 2022

IJMS

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Racial disparities in incidence and survival exist for many human cancers. Racial disparities are undoubtedly multifactorial and due in part to differences in socioeconomic factors, access to care, and comorbidities. Within the U.S., fundamental causes of health inequalities, including socio-economic factors, insurance status, access to healthcare and screening and treatment biases, are issues that contribute to cancer disparities. Yet even these epidemiologic differences do not fully account for survival disparities, as for nearly every stage, grade and histologic subtype, survival among Black women is significantly lower than their White counterparts. To address this, we sought to investigate the proteomic profiling molecular features of endometrial cancer in order to detect modifiable and targetable elements of endometrial cancer in different racial groups, which could be essential for treatment planning. The majority of proteins identified to be significantly altered among the racial groups and that can be regulated by existing drugs or investigational agents are enzymes that regulate metabolism and protein synthesis. These drugs have the potential to improve the worse outcomes of endometrial cancer patients based on race.

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Section: Discussionmentioning

confidence: 99%

“…Combinations of various metabolic inhibitors also have potential for improving endometrial cancer outcomes based on preclinical studies. For example, RGX-202 demonstrated anti-cancer synergy with F-FU and leflunomide, an inhibitor of dihydroorotate dehydrogenase-induced nucleotide biosynthesis levels [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of Candidate Biomarker and Drug Targets for Improving Endometrial Cancer Racial Disparities

Javadian

Sjoelund

et al. 2022

IJMS

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“…LUM-001 was tested in rodents to treat neurodevelopmental cognitive disorders, including autism [ 68 ]. More recently, a novel, oral small molecule creatine mimetic, RGX-202 (Inspirna), was shown to inhibit creatine import, to induce apoptosis and to inhibit metastasis to the liver in a variety of pre-clinical colorectal cancer models [ 72 ]. Data from early clinical trials (ClinicalTrials.gov: NCT03597581) suggest a favorable safety profile from dosages given twice a day, and confirmed in humans that RGX-202-01, the compound optimized for clinical trials, increases serum and urine levels of creatine in patients with gastrointestinal cancer [ 72 ].…”

Section: Discussionmentioning

confidence: 99%

HIF-Dependent CKB Expression Promotes Breast Cancer Metastasis, Whereas Cyclocreatine Therapy Impairs Cellular Invasion and Improves Chemotherapy Efficacy

Krutilina

Playa

Schwab

et al. 2021

Cancers

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The oxygen-responsive hypoxia inducible factor (HIF)-1 promotes several steps of the metastatic cascade. A hypoxic gene signature is enriched in triple-negative breast cancers (TNBCs) and is correlated with poor patient survival. Inhibiting the HIF transcription factors with small molecules is challenging; therefore, we sought to identify genes downstream of HIF-1 that could be targeted to block invasion and metastasis. Creatine kinase brain isoform (CKB) was identified as a highly differentially expressed gene in a screen of HIF-1 wild type and knockout mammary tumor cells derived from a transgenic model of metastatic breast cancer. CKB is a cytosolic enzyme that reversibly catalyzes the phosphorylation of creatine, generating phosphocreatine (PCr) in the forward reaction, and regenerating ATP in the reverse reaction. Creatine kinase activity is inhibited by the creatine analog cyclocreatine (cCr). Loss- and gain-of-function genetic approaches were used in combination with cCr therapy to define the contribution of CKB expression or creatine kinase activity to cell proliferation, migration, invasion, and metastasis in ER-negative breast cancers. CKB was necessary for cell invasion in vitro and strongly promoted tumor growth and lung metastasis in vivo. Similarly, cyclocreatine therapy repressed cell migration, cell invasion, the formation of invadopodia and lung metastasis. Moreover, in common TNBC cell line models, the addition of cCr to conventional cytotoxic chemotherapy agents was either additive or synergistic to repress tumor cell growth.

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“…Endogenous guanidino compounds (GCs) in microorganisms, , plants, − and animals − perform essential physiological activities in a series of biochemical processes. , For example, creatinine (CTN), guanidine (G), guanidinosuccinic acid (GSA), and methylguanidine (MG) are called “uremic neurotoxins”, which play a basic role in the etiology of uremic encephalopathy. , MG, GSA, and G have been found to cause generalized seizures after intracerebroventricular administration in mice . Moreover, the abnormal distribution of GCs is also potentially associated with the evolution of cancers. , Therefore, accurately characterizing the distribution of endogenous GCs and monitoring their concentration variations are of great significance in investigating the effects of medicine, diseases, and clinical treatments on organisms.…”

mentioning

confidence: 99%

“…15 Moreover, the abnormal distribution of GCs is also potentially associated with the evolution of cancers. 16,17 Therefore, accurately characterizing the distribution of endogenous GCs and monitoring their concentration variations are of great significance in investigating the effects of medicine, diseases, and clinical treatments on organisms.…”

mentioning

confidence: 99%

Multiplexed Analysis of Endogenous Guanidino Compounds via Isotope-Coded Doubly Charged Labeling: Application to Lung Cancer Tissues as a Case

et al. 2021

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Endogenous guanidino compounds (GCs), nitrogen-containing metabolites, have very important physiological activities and participate in biochemical processes. Therefore, accurately characterizing the distribution of endogenous GCs and monitoring their concentration variations are of great significance. In this work, a new derivatization reagent, 4,4′-bis[3-(dimethylamino)propyl]benzyl (BDMAPB), with isotope-coded reagents was designed and synthesized for doubly charged labeling of GCs. BDMAPB-derivatized GCs not only promote the MS signal but also form multicharged quasimolecular ions and abundant fragment ions. With this reagent, an isotope-coded doubly charged labeling (ICDCL) strategy was developed for endogenous GCs with high-resolution liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF MS). The core of this methodology is a 4-fold multiplexed set of [d 0 ]-/[d 4 ]-/[d 8 ]-/[d 12 ]-BDMAPB that yields isotope-coded derivatized GCs. Following a methodological assessment, good linear responses in the range of 25 nM to 1 μM with correlation coefficients over 0.99 were achieved. The limit of detection and the limit of quantitation were below 5 and 25 nM, respectively. The intra-and interday precisions were less than 18%, and the accuracy was in the range of 77.3−122.0%. The percentage recovery in tissues was in the range of 85.1−113.7%. The results indicate that the developed method facilitates long-term testing and ensures accuracy and reliability. Finally, the method was applied for the simultaneous analysis of endogenous GCs in four types of lung tissues (solid adenocarcinoma, solid squamous-cell carcinoma, ground-glass carcinoma, and paracancerous tissues) for absolute quantification, nontargeted screening, and metabolic difference analysis. It is strongly believed that ICDCL combined with isotope-coded BDMAPB will benefit the analysis and study of endogenous GCs.

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Therapeutic targeting of SLC6A8 creatine transporter suppresses colon cancer progression and modulates human creatine levels

Abstract: RGX-202, a small-molecule creatine transporter SLC6A8 inhibitor, suppresses colorectal cancer and modulates human creatine levels.

Cited by 25 publications

References 32 publications

Identification of Candidate Biomarker and Drug Targets for Improving Endometrial Cancer Racial Disparities

Identification of Candidate Biomarker and Drug Targets for Improving Endometrial Cancer Racial Disparities

HIF-Dependent CKB Expression Promotes Breast Cancer Metastasis, Whereas Cyclocreatine Therapy Impairs Cellular Invasion and Improves Chemotherapy Efficacy

Multiplexed Analysis of Endogenous Guanidino Compounds via Isotope-Coded Doubly Charged Labeling: Application to Lung Cancer Tissues as a Case

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