Targeting lipid metabolism in cancer: neuroblastoma

Several tumors use fatty acids as a source of mitochondrial energy production [58]. In NB, MYCN amplification correlates with high expression of key genes involved in the regulation of fatty acid oxidation (FAO), including hydroxyacyl-CoA dehydrogenase (HADH), indicating that MYCN-amplified NB tumors are more dependent on OXPHOS compared to non-MYCN-amplified tumors [45]. Interestingly, high expression of some of these enzymes correlates with poor prognosis in NB patients, suggesting that fatty acids are a major substrate for OXPHOS-based energy metabolism in NB. Carnitine palmitoyl-transferase 1a (CPT1a) is the β-oxidation rate-limiting enzyme, and high expression of the gene correlates with poor prognosis in NB patients. Etomoxir is a small-molecule irreversible inhibitor of CPT1a used widely in preclinical studies. Recently, it has been shown that etomoxir treatment was able to reduce in vivo tumor growth of MYCN-amplified NB cells. Although, in phase II clinical trials, etomoxir has shown hepatic toxicity and has been suspended, these experiments are proof of concept that inhibition of FAO could be used for the development of novel therapeutic strategies. In addition, the novel reversible CPT1a inhibitor, teglicar, which was recently developed, does not show as severe toxicity as etomoxir [59]. Further studies are needed to assess the possibility of using teglicar for cancer treatment.

One common feature shared by almost all tumors is the reactivation of fatty acid synthesis (FAS) to support cancer cell proliferation, as cancer cells need lipids both as membrane components and as signaling molecules involved in cell homeostasis, cell death, and metastasis [54]. FAS, which takes place in cytoplasm, is regulated primarily by acetyl-CoA carboxylase (ACACA) and fatty acid synthase (FASN). Small-molecule inhibitors of these two enzymes, including TOFA and Soraphen A, target ACACA, and Cerulenin, Orlistat, and UB006 that target FASN are available and used largely in preclinical experiments that have shown promising antitumor activity [60]. Using these five inhibitors in different experimental approaches, including PDX-derived cell cultures and xenograft model of NB, it has been shown that inhibition of FAS resulted in decreased cell proliferation, reduced MYCN protein levels, and induction of neural differentiation [61]. Of note, these antitumor effects were independent from MYCN status. Among the inhibitors tested, only Orlistat has been approved by the FDA, although not for cancer treatment. Therefore, these observations strongly support the idea of developing more specific FAS inhibitors that can be used in the clinic.

The highest-risk group of patients is often treated with isotretinoin (13-cis-retinoic acid) to induce terminal differentiation of NB cells, thus reducing the risk of relapse [62]. However, the benefits of using retinoids are uncertain [8, 63]. Therefore, it would be important to develop novel agents able to induce differentiation for treatments of NB. In this respect, elovanoids (ELVs) are a novel class of endogenous lipid mediators that protect against excitotoxicity and cell damage and modulate neuronal homeostasis [47, 50]. Recently, it has also been shown that ELV-N34:6 may have pharmacological activity against glioblastoma multiforme (GBM). Indeed, in the orthotopic model of GBM treatment with LAU-0901 (a platelet-activating factor receptor antagonist), ELV-N34:6, and Avastin (angiogenesis inhibitors) individually and with all three compounds in combination resulted in a reduction of tumor size [64, 65]. Therefore, since ELV-N34:6 has shown in vivo pharmacological activity, it is possible to hypothesize that ELV-N34:6 may be exploited for NB treatment in alternative or in combination with isotretinoin for inducing neural differentiation and improving patient outcome.

Very-long-chain polyunsaturated fatty acids (VLC-PUFA) play an important role in the maintenance of the homeostasis of several tissues, including neural tissue [46]. Among the family of PUFA products [47], ELVs represent a class of recently characterized lipid mediators that sustain cellular integrity against hemostasis disturbances [48, 49]. The enzyme ELOVL4 (elongation of VLC fatty acids–4), which is responsible for the elongation of > C28 FAs, mediates the biosynthesis of the precursors of elovanoids (ELV-N32 and ELV-N34). The expression of ELOVL4, which is repressed by MYCN, increases during neuronal differentiation of NB cells, and its presence is necessary for the progression of the differentiation. In addition, ELOVL4 expression is required to increase the lipid droplet number and VLC-PUFAs in differentiated cells [50]. Interestingly, more differentiated tumors (low- and intermediate-risk) show higher expression of ELOVL4 when compared with those less differentiated tumors (high-risk), and high levels of ELOVL4 identify subsets of NB patients with a better prognosis. Therefore, these observations suggest that dysregulation of ELOVL4 expression may participate in the lipid alterations that occur in NB. Overall, there is compelling experimental evidence that cellular metabolism, including lipid metabolism, is deregulated in NB cells and may therefore provide a novel, potential therapeutic target (see Fig. 1). Here we discuss some possible clinical applications of targeting lipid metabolism in NB that may be explored for therapeutic purposes.