Targeting lipid metabolism for the treatment of anaplastic thyroid carcinoma

Abstract

Introduction Anaplastic thyroid carcinoma (ATC) is the rarest subtype of thyroid cancer, however it disproportionately accounts for a large percentage of all thyroid cancer related deaths and is considered one of the most lethal solid tumors in humans, having a median survival of only a few months upon diagnosis. While a variety of treatment options are available including surgery, radiation and targeted therapies, response rates are low, due in part to the drug-resistant nature of this disease; therefore, new avenues for therapeutic intervention are surely needed. Recent investigation into the metabolic profile of ATC has revealed a tumor-specific dependency for increased de novo lipogenesis, offering new insight into the molecular mechanisms that govern disease initiation and progression. Areas Covered Herein we summarize known oncogenic signaling pathways and current therapeutic strategies for the treatment of ATC. We further discuss the unique expression pattern of lipid metabolism constituents in this disease. Additionally, the current literature correlating aberrant lipogenesis with carcinogenesis is reviewed, and the implications of targeting this pathway as an innovative approach for treating ATC and other malignancies is discussed. As stearoyl-CoA desaturase (SCD) is the most differentially expressed constituent of lipid metabolism in ATC, an additional focus on this enzyme as a novel therapeutic target is applied. Expert Opinion This section is used to summarize the current research efforts underway in defining the role of lipid metabolism specifically in thyroid carcinoma. Included is a brief summary of lipid metabolism factors for which inhibitors have been generated and are under current investigation as anti-cancer agents. Finally, research limitations regarding the use of these inhibitors against components of this pathway are discussed.

Aberrant lipid metabolism as a therapeutic target in liver cancer

“…Five isoforms of SCD have been described, of which two are expressed in humans (SCD1 and SCD5) [17,51]. Each of these isoforms demonstrates differential tissue distribution and expression patterns, but preserved enzymatic function [52,53].…”

“…In more recent years, SCD1 inhibitors were discovered to also be anticancer agents and shown to inhibit tumor growth in numerous murine in vivo studies that include prostate, breast, liver, renal, and lung cancers [17,52,53,[63][64][65]. An example of recently discovered SCD1 inhibitors, von Roemeling et al developed and tested a novel computational-based drug discovery method aimed at development of a novel SCD1 inhibitor.…”

Y‑box binding protein 1 acts as a negative regulator of stearoyl CoA desaturase 1 in clear cell renal cell carcinoma

“…MUFAs are produced by the enzyme stearoyl-CoA desaturase (SCD1), a protein often highly expressed in tumors (7)(8)(9). Previous studies describe unsaturated fatty acid as a stabilizer of oncogenes that function to promote cell growth and inhibit apoptosis (10)(11)(12)(13)(14). This suggests that the presence of unsaturated lipids in ccRCC is necessary for growth and survival (15)(16)(17)(18)(19)(20)(21).…”

“…The unsaturated lipids made by SCD1 are critical to membrane synthesis, signal transduction, and energy storage (13). Targeting SCD1 activity has been suggested as a viable strategy to combat tumor development (9,12,28). However, blocking fatty acid desaturation creates an imbalance in the ratio of saturated to unsaturated fat, leading to a cellular stress response that includes inhibition of global mRNA translation, and ultimately death in both normal and transformed cells (29,30).…”

Beyond EGFR inhibition: multilateral combat strategies to stop the progression of head and neck cancer

“…This widespread but distinctive trait of cancer can be exploited as a therapeutic target and it is expected that it will complement the former targeted therapy by overcoming its current limitations. Recently, some have suggested a close relationship between oncogenic signaling such as the AKT-mTOR axis, which is the downstream signaling pathway of EGFR and other RTKs, and lipid metabolism, which is centered on oncogenic activation of sterol regulatory element-binding proteins 109,110 . A recent report has linked cetuximab resistance with the rewiring mechanism of cancer metabolism in HNC 111 .…”