Abstract 5863: RGX-202, a first-in-class small-molecule inhibitor of the creatine transporter SLC6a8, is a robust suppressor of cancer growth and metastatic progression

Kurth, Isabel; Andreu, Celia; Takeda, Shugaku; Tian, Helen S.; Gonsalves, Foster C.; Leites, Katya; Sridhar, Subhasree; Loo, Jia Min; Busby, Rob; Tavazoie, Sohail F.; Tavazoie, Masoud

doi:10.1158/1538-7445.am2018-5863

Cited by 8 publications

(4 citation statements)

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“…Depletion of SLC6a8 in colon and pancreatic cancer reduces the ability of cancer cells to colonize the liver in murine xenografts (133,134). The orally available small molecule RGX-202 inhibits SLC6a8 in KRAS wild-type and KRAS mutant cell lines, as well as human PDX models (135). Inhibition of SLC6a8 correlates with decreased tumor metabolic activity, decreased proliferation, and a dramatic reduction in cell survival.…”

Section: Creatinine Transporter Slc6a8 (Rgx-202)mentioning

confidence: 99%

“…Inhibition of SLC6a8 correlates with decreased tumor metabolic activity, decreased proliferation, and a dramatic reduction in cell survival. Tumors treated with RGX-202 are also more susceptible to gemcitabine, likely reflecting a change in cellular metabolism and nucleotide synthesis (135,136). Although the effect of SLC6a8 on normal cellular metabolism remains to be full understood, these results are exciting, and suggest that in phosphocreatine-dependent cells, SLC6a8 inhibition could effectively starve PDAC tumors.…”

Section: Creatinine Transporter Slc6a8 (Rgx-202)mentioning

confidence: 99%

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Pancreatic Adenocarcinoma: Unconventional Approaches for an Unconventional Disease

et al. 2020

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This review highlights current treatments, limitations, and pitfalls in the management of pancreatic cancer and discusses current research in novel targets and drug development to overcome these clinical challenges. We begin with a review of the clinical landscape of pancreatic cancer, including genetic and environmental risk factors, as well as limitations in disease diagnosis and prevention. We next discuss current treatment paradigms for pancreatic cancer and the shortcomings of targeted therapy in this disease. Targeting major driver mutations in pancreatic cancer, such as dysregulation in the KRAS and TGF-β signaling pathways, have failed to improve survival outcomes compared to non-targeted chemotherapy; thus, we describe new advances in therapy such as Ras binding pocket inhibitors. We then review next-generation approaches in nanomedicine and drug delivery, focusing on preclinical advancements in novel optical probes, antibodies, small molecule agents, and nucleic acids to improve surgical outcomes in resectable disease, augment current therapies, expand druggable targets, and minimize morbidity. We conclude by summarizing progress in current research, identifying areas for future exploration in drug development and nanotechnology, and discussing future prospects for management of this disease. Clinical Snapshot of Pancreatic AdenocarcinomaPancreatic cancer is the most lethal common tumor in America. The five-year survival is estimated to be 9.3% among all cases and 2.9% among patients with metastatic disease, both lowest amongst all common tumors (1). With its rising incidence and unabated mortality, pancreatic cancer is the third leading cause of cancer related death, with a projection that it will the second by 2030 (Figure 1) (2,3). In 2019, pancreatic ductal adenocarcinoma (PDAC; 95% of patients) represented 3.2% of all new cancer cases, with an estimated 56,770 new cases and 45,750 deaths (7.5% of all cancer deaths) (1).

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Section: Creatinine Transporter Slc6a8 (Rgx-202)mentioning

confidence: 99%

Section: Creatinine Transporter Slc6a8 (Rgx-202)mentioning

confidence: 99%

Pancreatic Adenocarcinoma: Unconventional Approaches for an Unconventional Disease

et al. 2020

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“…Consistent with these findings, a significant reduced liver colonization in mouse xenograft models has been observed due to genetic depletion of SLC6A8 in colon and pancreatic cancer cell lines. Regarding important function of this gene for cancer cell survival, expression inhibition of this gene or preventing import of phosphocreatine into the cells would be a therapeutic method to inhibit energy production of cancer cells [89]. This gene has a mixed trend in MvsP analysis.…”

Section: Discussionmentioning

confidence: 99%

Systems biomedicine of primary and metastatic colorectal cancer reveals potential therapeutic targets

Piran

Sepahi

et al. 2020

Preprint

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Colorectal cancer is one of the leading causes of cancer death worldwide. Patient survival at the time of diagnosis depends largely on the stage of the tumor. Therefore, understanding the molecular mechanisms promoting cancer progression from early stages to high-grade stages is essential for therapeutic approaches. In the present study, we conducted transcriptomic data analysis employing a systems biology method to identify potential molecular targets for colorectal cancer treatment. These targets went under investigation one by one. We proposed some genes that their expression induction or suppression alone or in combination with each other would inhibit tumor progression or metastasis based on their biological activity. They are involved in cell proliferation, energy production under hypoxic conditions, epithelial to mesenchymal transition (EMT) and angiogenesis.Employing a network analysis viewpoint, some genes were discovered that has not been reported noticeably in any kind of cancer so far. As a result, they might have some roles in progression of colorectal cancer.

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“…In fact, creatine has been in clinical use for its neuroprotective effects (Sullivan et al, 2000;Sakellaris et al, 2006). Also of interest is a report of a novel CRT1 inhibitor, shown to suppress cancer growth and metastatic progression (Kurth et al, 2018), which implicates CRT1 in cancer and prompts a closer survey of cancer incidence among CTD patients.…”

Section: Effects On the Sensory Organsmentioning

confidence: 99%

The Creatine Transporter Unfolded: A Knotty Premise in the Cerebral Creatine Deficiency Syndrome

Farr

El‐Kasaby

Freissmuth

et al. 2020

Front. Synaptic Neurosci.

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Creatine provides cells with high-energy phosphates for the rapid reconstitution of hydrolyzed adenosine triphosphate. The eponymous creatine transporter (CRT1/SLC6A8) belongs to a family of solute carrier 6 (SLC6) proteins. The key role of CRT1 is to translocate creatine across tissue barriers and into target cells, such as neurons and myocytes. Individuals harboring mutations in the coding sequence of the human CRT1 gene develop creatine transporter deficiency (CTD), one of the pivotal underlying causes of cerebral creatine deficiency syndrome. CTD encompasses an array of clinical manifestations, including severe intellectual disability, epilepsy, autism, development delay, and motor dysfunction. CTD is characterized by the absence of cerebral creatine, which implies an indispensable role for CRT1 in supplying the brain cells with creatine. CTD-associated variants dramatically reduce or abolish creatine transport activity by CRT1. Many of these are point mutations that are known to trigger folding defects, leading to the retention of encoded CRT1 proteins in the endoplasmic reticulum and precluding their delivery to the cell surface. Misfolding of several related SLC6 transporters also gives rise to detrimental pathologic conditions in people; e.g., mutations in the dopamine transporter induce infantile parkinsonism/dystonia, while mutations in the GABA transporter 1 cause treatment-resistant epilepsy. In some cases, folding defects are amenable to rescue by small molecules, known as pharmacological and chemical chaperones, which restore the cell surface expression and transport activity of the previously non-functional proteins. Insights from the recent molecular, animal and human case studies of CTD add toward our understanding of this complex disorder

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Abstract 5863: RGX-202, a first-in-class small-molecule inhibitor of the creatine transporter SLC6a8, is a robust suppressor of cancer growth and metastatic progression

Cited by 8 publications

References 0 publications

Pancreatic Adenocarcinoma: Unconventional Approaches for an Unconventional Disease

Pancreatic Adenocarcinoma: Unconventional Approaches for an Unconventional Disease

Systems biomedicine of primary and metastatic colorectal cancer reveals potential therapeutic targets

The Creatine Transporter Unfolded: A Knotty Premise in the Cerebral Creatine Deficiency Syndrome

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