A Phase 1 Randomized, Placebo‐Controlled Trial With a Topical Inhibitor of Stearoyl‐Coenzyme A Desaturase 1 Under Occluded and Nonoccluded Conditions

Brigandi, Richard A.; Zhu, John; Murnane, Amy A.; Reedy, Beth Ann; Shakib, Sepehr

doi:10.1002/cpdd.644

Cited by 11 publications

(6 citation statements)

References 7 publications

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“…Many of these compounds have nanomolar values of IC 50 . The inhibitor GSK1940029 has been in a phase I clinical trial as a topical treatment for acne and found to be well tolerated 177 . Intriguingly, SCD1 inhibition can alleviate α-synuclein cytotoxicity associated with Parkinson disease 178 , and clinical trials are being implemented.…”

Section: Fatty Acid Synthesismentioning

confidence: 99%

Targeting cancer metabolism in the era of precision oncology

Stine¹,

Schug

Salvino

et al. 2021

Nat Rev Drug Discov

627

402

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Before Sidney Farber published his seminal paper in 1948 in The New England Journal of Medicine describing anti-folate-induced remissions 1 , childhood acute lymphocytic leukaemia (ALL) was universally fatal. Thirty years before this article was published, Otto Warburg's determination to conquer cancer led him to discover that many tumours used aerobic glycolysis (also known as the Warburg effect) to convert almost all glucose to lactate even in the presence of oxygen 2 . Aerobic glycolysis, however, has never been successfully exploited clinically, particularly as the use of 2-deoxyglucose, which inhibits glycolysis, was proved to have undesirable side effects and limited efficacy in humans 3 . Farber noted the clinical 'accelerated phenomenon' among 11 children treated with an active form of folate, pteroyltriglutamic acid, which was thought to have broad anticancer activity, and thus sought folate antagonists as therapeutic agents. Working with chemist Yellapragada Subbarow, the anti-folate aminopterin was synthesized, and Farber was able to induce remissions in children with ALL, thus providing the foundation for cancer chemotherapy 4 . Today, another folate antagonist, methotrexate, is still used in the multi-chemotherapy treatment of childhood ALL and, used together with l-asparaginase, induces a remarkable 90% cure rate. Indeed, many anti-metabolite drugs, particularly those targeting nucleotide metabolism, have been approved and used in the clinic (Table 1). The recent approval of drugs that target mutant isocitrate dehydrogenases in acute myeloid leukaemias (AMLs) (Table 1) provides a milestone in targeting cancer metabolism with precision and establishes that metabolic therapy can be highly effective.Warburg's and Farber's ideas were conceptually displaced in the 1980s as oncogenes and tumour suppressors became recognized as targets in human cancer treatments. Molecular biology took centre stage, and the drive to target oncogenes began with vigour, resulting in many effective anticancer kinase drugs that displaced interest in targeting metabolism. However, the links between oncogenes, tumour suppressors and metabolism began to emerge in the 1990s, ushering in a resurgence of interest in cancer metabolism [5][6][7] . More recently, the success of immunotherapy underscores the importance of non-cancer-cell autonomous components of the tumour immune microenvironment (TIME) [8][9][10] , which is a neoplastic hub of metabolically active cells comprising tumour cells, immune cells, stromal cells and blood and lymph vessel cells, all of which are involved in tumour growth. In this regard, targeting cancer metabolism must be based on a thorough understanding of how inhibiting specific metabolic pathways affects the TIME cells, which can either dampen or promote tumour progression. In this Review, we cover the fundamentals of cancer metabolism and focus on recent small-molecule drug discovery efforts to target cancer.

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Section: Fatty Acid Synthesismentioning

confidence: 99%

Targeting cancer metabolism in the era of precision oncology

Stine¹,

Schug

Salvino

et al. 2021

Nat Rev Drug Discov

627

402

View full text Add to dashboard Cite

show abstract

“…55 SCD1 is a potential target in the treatment of acne. 56 Nonetheless, little information is available about the role of desaturation of FFAs in lipoinflammation in sebocytes. The observed lipogenic effects of C16:0 in SZ95 cells are to be considered, also supported by the EGF presence in the culture medium.…”

Section: Discussionmentioning

confidence: 99%

“…Upregulation of SCD1 and FADS2 expression is associated with activation of inflammatory response in sebocytes 55 . SCD1 is a potential target in the treatment of acne 56 . Nonetheless, little information is available about the role of desaturation of FFAs in lipoinflammation in sebocytes.…”

Section: Discussionmentioning

confidence: 99%

Desaturation of sebaceous‐type saturated fatty acids through the SCD1 and the FADS2 pathways impacts lipid neosynthesis and inflammatory response in sebocytes in culture

Flori

Mastrofrancesco

Ottaviani

et al. 2023

Experimental Dermatology

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Sebum is a lipid-rich mixture secreted by the sebaceous gland (SG) onto the skin surface. By penetrating through the epidermis, sebum may be involved in the regulation of epidermal and dermal cells in both healthy and diseased skin conditions. Saturated and monounsaturated fatty acids (FAs), found as free FAs (FFAs) and in bound form in neutral lipids, are essential constituents of sebum and key players of the inflammatory processes occurring in the pilosebaceous unit in acne-prone skin. Little is known on the interplay among uptake of saturated FFAs, their biotransformation, and induction of proinflammatory cytokines in sebocytes. In the human SG, palmitate (C16:0) is the precursor of sapienate (C16:1n-10) formed by insertion of a double bond (DB) at the Δ6 position catalysed by the fatty acid desaturase 2 (FADS2) enzyme. Conversely, palmitoleate (C16:1n-7) is formed by insertion of a DB at the Δ9 position catalysed by the stearoyl coenzyme A desaturase 1 (SCD1) enzyme. Other FFAs processed in the SG, also undergo these main desaturation pathways. We investigated lipogenesis and release of IL-6 and IL-8 pro-inflammatory cytokines in SZ95 sebocytes in vitro after treatment with saturated FFAs, that is, C16:0, margarate (C17:0), and stearate (C18:0) with or without specific inhibitors of SCD1 and FADS2 desaturase enzymes, and a drug with mixed inhibitory effects on FADS1 and FADS2 activities. C16:0 underwent extended desaturation through both SCD1 and FADS2 catalysed pathways and displayed the strongest lipoinflammatory effects. Inhibition of desaturation pathways proved to enhance lipoinflammation induced by SFAs in SZ95 sebocytes. Palmitate (C16:0), margarate (C17:0), and stearate (C18:0) are saturated fatty acids that induce different arrays of neutral lipids (triglycerides) and dissimilar grades of inflammation in sebocytes.

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“…The elevated FAS in p53-inactivated cancer cells raises the hypothesis that these cells may be more sensitive to disruption of this process. Several SCD1 and FASN inhibitors are currently ongoing clinical trials (59,(68)(69)(70)(71), emphasizing the clinical importance of identifying biomarkers for drug sensitivity. We therefore analyzed the sensitivity to SCD1 inhibition across 26 human BC cell lines.…”

Section: P53 Inactivation-induced Fas Renders Cells Sensitive To Scd1...mentioning

confidence: 99%

Inactivation of p53 drives breast cancer brain metastasis by altering fatty acid metabolism

Laue,

Pozzi,

Cohen-Sharir

et al. 2023

Preprint

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Brain metastasis (BM) is a dire prognosis across cancer types. It is largely unknown why some tumors metastasize to the brain whereas others do not. We analyzed genomic and transcriptional data from clinical samples of breast cancer BM (BCBM) and found that nearly all of them carried p53-inactivating genetic alterations through mutations, copy-number loss, or both. Importantly, p53 pathway activity was already perturbed in primary tumors giving rise to BCBM, often by loss of the entire 17p chromosome-arm. This association was recapitulated across other carcinomas. Experimentally, p53 knockout was sufficient to drastically increase BCBM formation and growthin vivo, providing a causal link between p53 inactivation and brain tropism. Mechanistically, p53-deficient BC cells exhibited altered lipid metabolism, particularly increased fatty acid (FA) synthesis and uptake, which are characteristic of brain-metastasizing cancer cells. FA metabolism was further enhanced by astrocytes in a p53-dependent manner, as astrocyte-conditioned medium increased FASN, SCD1, and CD36 expression and activity, and enhanced the survival, proliferation and migration of p53-deficient cancer cells. Consequently, these cells were more sensitive than p53-competent cells to FA synthesis inhibitors, in isogenic cell cultures, in BCBM-derived spheroids, and across dozens of BC cell lines. Lastly, a significant association was observed between p53 inactivation, astrocyte infiltration, and SCD1 expression in clinical human BCBM samples. In summary, our study identifies p53 inactivation as a driver of BCBM and potentially of BM in general; suggests a p53-dependent effect of astrocytes on BC cell behavior; and reveals FA metabolism as an underlying, therapeutically-targetable molecular mechanism.

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A Phase 1 Randomized, Placebo‐Controlled Trial With a Topical Inhibitor of Stearoyl‐Coenzyme A Desaturase 1 Under Occluded and Nonoccluded Conditions

Cited by 11 publications

References 7 publications

Targeting cancer metabolism in the era of precision oncology

Targeting cancer metabolism in the era of precision oncology

Desaturation of sebaceous‐type saturated fatty acids through the SCD1 and the FADS2 pathways impacts lipid neosynthesis and inflammatory response in sebocytes in culture

Inactivation of p53 drives breast cancer brain metastasis by altering fatty acid metabolism

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