作者: Gawali, Mruniya V. ; Amaravadi, Ravi ; D’Alessandro, Angelo ; Choi, Kwangmin ; Arora, Priyanka ; Gupta, Nishtha ; Reisz, Julie A. ; Komurov, Kakajan ; Cáceres, Román ; Subramanian, Srividhya ; Dasgupta, Biplab ; Congrove, Sunny ; Murugesan, Narmadha ; Sukumaran, Abitha ; Abdel-Malek, Zalfa ; Desai, Pankaj ; Stephenson, Daniel ; Oatman, Nicole

Abstract:

The genetic landscape of cancer cells can lead to specific metabolic dependencies for tumor growth. Dietary interventions represent an attractive strategy to restrict the availability of key nutrients to tumors. In this study, we identified that growth of a subset of melanoma was severely restricted by a rationally designed combination therapy of a stearoyl-CoA desaturase (SCD) inhibitor with an isocaloric low-oleic acid diet. Despite its importance in oncogenesis, SCD underwent monoallelic codeletion along with PTEN on chromosome 10q in approximately 47.5% of melanoma, and the other SCD allele was methylated, resulting in very low-SCD expression. Although this SCD-deficient subset was refractory to SCD inhibitors, the subset of PTEN wild-type melanoma that retained SCD was sensitive. As dietary oleic acid could potentially blunt the effect of SCD inhibitors, a low oleic acid custom diet was combined with an SCD inhibitor. The combination reduced monounsaturated fatty acids and increased saturated fatty acids, inducing robust apoptosis and growth suppression and inhibiting lung metastasis with minimal toxicity in preclinical mouse models of PTEN wild-type melanoma. When combined with anti-PD1 immunotherapy, the SCD inhibitor improved T-cell functionality and further constrained melanoma growth in mice. Collectively, these results suggest that optimizing SCD inhibitors with diets low in oleic acid may offer a viable and efficacious therapeutic approach for improving melanoma treatment.Significance: Blockade of endogenous production of fatty acids essential for melanoma combined with restriction of dietary intake blocks tumor growth and enhances response to immunotherapy, providing a rational drug–diet treatment regimen for melanoma.

2024-05-01·Gastroenterology

Oncogenic Fatty Acid Metabolism Rewires Energy Supply Chain in Gastric Carcinogenesis

Article

作者: Zhang, Changqing ; Caprioli, Richard M ; Jang, Bogun ; Tan, Marcus C B ; Trinh, Vincent Q ; Lee, Su-Hyung ; Lee, Cheol ; Kim, Kwangho ; Reyzer, Michelle L ; Caldwell, Brianna ; Won, Yoonkyung ; Kim, Hyesung ; Lee, Hye Seung ; Presentation, Kimberly S ; Choi, Eunyoung

BACKGROUND & AIMS:

Gastric carcinogenesis develops within a sequential carcinogenic cascade from precancerous metaplasia to dysplasia and adenocarcinoma, and oncogenic gene activation can drive the process. Metabolic reprogramming is considered a key mechanism for cancer cell growth and proliferation. However, how metabolic changes contribute to the progression of metaplasia to dysplasia remains unclear. We have examined metabolic dynamics during gastric carcinogenesis using a novel mouse model that induces Kras activation in zymogen-secreting chief cells.

METHODS:

We generated a Gif-rtTA;TetO-Cre;Kras^G12D (GCK) mouse model that continuously induces active Kras expression in chief cells after doxycycline treatment. Histologic examination and imaging mass spectrometry were performed in the GCK mouse stomachs at 2 to 14 weeks after doxycycline treatment. Mouse and human gastric organoids were used for metabolic enzyme inhibitor treatment. The GCK mice were treated with a stearoyl- coenzyme A desaturase (SCD) inhibitor to inhibit the fatty acid desaturation. Tissue microarrays were used to assess the SCD expression in human gastrointestinal cancers.

RESULTS:

The GCK mice developed metaplasia and high-grade dysplasia within 4 months. Metabolic reprogramming from glycolysis to fatty acid metabolism occurred during metaplasia progression to dysplasia. Altered fatty acid desaturation through SCD produces a novel eicosenoic acid, which fuels dysplastic cell hyperproliferation and survival. The SCD inhibitor killed both mouse and human dysplastic organoids and selectively targeted dysplastic cells in vivo. SCD was up-regulated during carcinogenesis in human gastrointestinal cancers.

CONCLUSIONS:

Active Kras expression only in gastric chief cells drives the full spectrum of gastric carcinogenesis. Also, oncogenic metabolic rewiring is an essential adaptation for high-energy demand in dysplastic cells.

2024-01-01·European journal of pharmacology

Identification and experimental validation of Stearoyl-CoA desaturase is a new drug therapeutic target for osteosarcoma

Article

作者: Huang, Ping ; Shu, Zhiguo ; Yang, Feng ; Liu, Ning ; Liu, Zhili ; Long, Xinhua ; He, Cheng ; Zhong, Yanxin ; Nie, Jiangbo ; Liu, Jiaming

Osteosarcoma (OS) is the most common malignant bone tumor. Fatty acid reprogramming plays an essential role in OS progression. However, new fatty acid related therapeutic targets of OS have not been completely elucidated. Therefore, we firstly identified 113 differentially expressed fatty acid metabolism genes using bioinformatic analysis, 19 of which were found to be associated with OS prognosis. Then, 7 hub genes were screened out and yielded a strong prediction accuracy (AUC value = 0.88, at 3 years) for predicting the survival status of OS patients. Furthermore, we confirmed that SCD was highly expressed in OS cells and patients. And Knock-down of SCD impaired proliferation and migration of OS cells. Moreover, SCD was transcriptionally activated by c-Myc to promote proliferation and migration of OS cells. Finally, SCD inhibitor could significantly induce OS ferroptosis in vitro and in vivo. In conclusion, we identified that SCD was a reliable risk factor for OS patients. And SCD was activated by c-Myc. The inhibitor of SCD could significantly impaired OS growth and induce OS ferroptosis, which indicated that SCD was a potential drug target for OS treatment.

项与 SCD-1 inhibitor (Pfizer Inc) 相关的新闻（医药）

2024-09-19

·Business Wire

Sparrow Pharmaceuticals Presented New Data on Clofutriben and Prednisolone for Polymyalgia Rheumatica Treatment at DGRh Kongress 2024

PORTLAND, Ore.--( BUSINESS WIRE )-- Sparrow Pharmaceuticals today announced that it presented new data from its ongoing Phase 2 clinical trial of its HSD-1 inhibitor, clofutriben (referred to SPI-62 in the study), in combination with prednisolone for the treatment of polymyalgia rheumatica (PMR) at the German Congress of Rheumatology (DGRh Kongress 2024) in Dusseldorf, Germany on 18 – 21 September, 2024. The data was presented in an oral presentation that took place on Thursday, September 19 th at 3:25PM CEST and a poster session. David Katz, PhD, Chief Scientific Officer at Sparrow discussed the abstract titled “ An 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor to Optimize the Effects of Prednisolone in Patients with Polymyalgia Rheumatica (PMR) .” Key findings were highlighted from the trial, which investigated the potential of clofutriben to reduce or prevent side effects of prednisolone while maintaining its effectiveness in PMR patients. The trial included 40 participants with confirmed PMR who were given prednisolone 10 mg, 15 mg, or 20 mg together with clofutriben 6 mg for 2 weeks. Patients also were given prednisolone 10 mg with placebo for clofutriben for 2 weeks. Result highlights are: No PMR relapses occurred when prednisolone 15 mg or 20 mg was co-administered with clofutriben. A combination of prednisolone 20 mg with clofutriben showed similar efficacy as prednisolone 10 mg with placebo, based on analysis of participants’ symptoms, physical function, and biomarkers of inflammation. All prednisolone doses in combination with clofutriben showed less glucocorticoid toxicity compared to prednisolone with placebo. "The data suggest that by using an HSD-1 inhibitor like clofutriben, we may be able to improve the balance between the therapeutic benefits and side effects of glucocorticoid therapy in patients with PMR," said Dr. Katz. "These encouraging findings support Sparrow’s innovative approach to develop treatments that may spare patients from the negative effects of glucocorticoid use, while maintaining the therapeutic benefits. This could potentially offer a new treatment paradigm for patients with rheumatic diseases and the many other conditions treated with glucocorticoids." Additionally, Sparrow has expanded its PROST! Phase 2 clinical trial ( NCT05436652 ) with a fifth cohort to explore clofutriben in combination with prednisolone for the treatment of PMR. This will allow for the continued study of how clofutriben can maintain the efficacy of steroid medicines without the harsh side effects. To learn more about Sparrow Pharmaceuticals and clofutriben (SPI-62), visit www.sparrowpharma.com . About Sparrow Pharmaceuticals Sparrow Pharmaceuticals was founded to spare patients the ravages of steroids. Leveraging underappreciated scientific insights into glucocorticoid biology, the company is working to provide better treatment options for serious disorders of hypercortisolism, and to revolutionize the treatment of autoimmune and inflammatory conditions. Its lead product, clofutriben (SPI-62), is an oral, small molecule, novel therapeutic treatment designed to target a source of active intracellular glucocorticoids in key tissues.

临床结果临床2期

100 项与 SCD-1 inhibitor (Pfizer Inc) 相关的药物交易

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