RESUMO
Colorectal cancer (CRC) is a leading cause of cancer mortality. Creatine metabolism was previously shown to critically regulate colon cancer progression. We report that RGX-202, an oral small-molecule SLC6A8 transporter inhibitor, robustly inhibits creatine import in vitro and in vivo, reduces intracellular phosphocreatine and ATP levels, and induces tumor apoptosis. RGX-202 suppressed CRC growth across KRAS wild-type and KRAS mutant xenograft, syngeneic, and patient-derived xenograft (PDX) tumors. Antitumor efficacy correlated with tumoral expression of creatine kinase B. Combining RGX-202 with 5-fluorouracil or the DHODH inhibitor leflunomide caused regressions of multiple colorectal xenograft and PDX tumors of distinct mutational backgrounds. RGX-202 also perturbed creatine metabolism in patients with metastatic CRC in a phase 1 trial, mirroring pharmacodynamic effects on creatine metabolism observed in mice. This is, to our knowledge, the first demonstration of preclinical and human pharmacodynamic activity for creatine metabolism targeting in oncology, thus revealing a critical therapeutic target.
Assuntos
Antineoplásicos , Neoplasias do Colo , Neoplasias Colorretais , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Neoplasias Colorretais/patologia , Creatina/metabolismo , Creatina/farmacologia , Creatina/uso terapêutico , Humanos , Proteínas de Membrana Transportadoras , Camundongos , Camundongos Nus , Mutação , Proteínas do Tecido Nervoso/metabolismo , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/metabolismoRESUMO
Therapeutic harnessing of adaptive immunity via checkpoint inhibition has transformed the treatment of many cancers. Despite unprecedented long-term responses, most patients do not respond to these therapies. Immunotherapy non-responders often harbor high levels of circulating myeloid-derived suppressor cells (MDSCs)-an immunosuppressive innate cell population. Through genetic and pharmacological approaches, we uncovered a pathway governing MDSC abundance in multiple cancer types. Therapeutic liver-X nuclear receptor (LXR) agonism reduced MDSC abundance in murine models and in patients treated in a first-in-human dose escalation phase 1 trial. MDSC depletion was associated with activation of cytotoxic T lymphocyte (CTL) responses in mice and patients. The LXR transcriptional target ApoE mediated these effects in mice, where LXR/ApoE activation therapy elicited robust anti-tumor responses and also enhanced T cell activation during various immune-based therapies. We implicate the LXR/ApoE axis in the regulation of innate immune suppression and as a target for enhancing the efficacy of cancer immunotherapy in patients.
Assuntos
Apolipoproteínas E/imunologia , Imunidade Inata , Receptores X do Fígado/imunologia , Células Supressoras Mieloides/imunologia , Neoplasias Experimentais/imunologia , Animais , Apolipoproteínas E/genética , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Linhagem Celular Tumoral , Feminino , Receptores X do Fígado/genética , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Células Supressoras Mieloides/patologia , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Paramagnetic Mn2+ has emerged in the search for non-invasive magnetic resonance imaging (MRI) techniques to monitor Ca2+ in diagnostic and prognostic cardiovascular disease tests because it both alters MRI contrast and behaves as a Ca2+ 'surrogate' in vivo. However, the reliance on macroscopically averaged measurements to infer microscopic processes constitutes a major limitation of MRI. This investigation circumvents this limitation and contributes an MRI-based myocardial Ca2+-transporter assay, which probes the Na+/Ca2+-exchanger involvement in Mn2+ (and presumably Ca2+) transport by virtue of its response to pharmacological inhibition. In the model employed herein, ex vivo arrested rat hearts underwent normoxia and then hypoxia while a constant (hyperkalemic) perfusion minimized flow (and uncontrolled Ca2+-channel) contributions to Mn2+-enhanced MRI measurements. The results (i) demonstrate that Mn2+ (and presumably Ca2+) accumulates via Na+/Ca2+-exchanger-mediated transport during hyperkalemic hypoxia and further, (ii) implicate hypo-perfusion (rather than the diminished participation of an isolated sarcolemmal Ca2+-transporter) as the mechanism that underlies the reported reductions of Mn2+ accumulation (relative to healthy myocardium) subsequent to myocardial insults in MRI studies. Although myriad studies have employed Mn2+-enhanced MRI in myocardial investigations, this appears to be the first attempt to assay the Na+/Ca2+-exchanger with MRI under highly circumscribed conditions. MRI-based Ca2+)transporter assays, such as the Na+/Ca2+-exchanger assay utilized here, will inevitably impact disciplines in the medical sciences and beyond.