Oncometabolites in Peritoneal Cancers and Precision Cancer Medicine: History
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Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Revathy Nadhan
,
Srishti Kashyap
,
Ji Hee Ha
,
Muralidharan Jayaraman
,
Yong Sang Song
,
Ciro Isidoro
,
Danny N. Dhanasekaran

Peritoneal cancers, encompassing both primary peritoneal cancers and secondary peritoneal metastases, present significant clinical challenges due to their aggressive nature and generally poor prognosis. Primary peritoneal cancers, such as peritoneal mesothelioma and primary peritoneal carcinoma, arise directly in the peritoneal cavity, while secondary peritoneal cancers result from the spread of cancer from other organs to the peritoneum. Understanding the role of cancer cell metabolism and cancer-promoting metabolites in peritoneal cancers can provide new insights into the mechanisms that drive tumor progression and can identify novel therapeutic targets and biomarkers for early detection, prognosis, and treatment response. Cancer cells dynamically reprogram their metabolism to facilitate tumor growth and overcome metabolic stress, with cancer-promoting metabolites such as kynurenine, lactate, and sphingosine-1-phosphate promoting cell proliferation, angiogenesis, and immune evasion.Targeting cancer-promoting metabolites and inhibiting the production or function of these metabolites could disrupt the metabolic pathways that contribute to tumor growth and progression. This approach could also lead to the development of effective combinatorial and adjuvant therapies for peritoneal cancers. With the observed metabolomic heterogeneity in cancer patients, defining peritoneal cancer metabolome and cancer-promoting metabolites holds great promise for improving patient outcomes by enabling personalized treatment approaches based on an individual's metabolic profile.

  • cancer metabolism
  • metabolite
  • metabolome
  • oncometabolite
  • peritoneal cancer

1. Targeting Glucose Metabolism

Peritoneal malignancies pose significant clinical challenges due to their poor prognosis [1][2][3][4]. Metabolic reprogramming is a hallmark of malignant cancer growth, and peritoneal cancers are no exception [5][6][7]. Understanding the role of cancer cell metabolism and cancer-promoting metabolites in the peritoneal tumor microenvironment (PTME) can provide new insights into the mechanisms that drive tumor progression and metastasis. The crosstalk between tumor microenvironment components determines the metabolic status of cancer cells and their response to therapeutic interventions [8][9]. Oncometabolites are those metabolites that are produced and accumulated in cancer cells due to altered metabolism and which can promote the growth and progression of tumors [10][11][12][13]. Here, researchers employ the term ‘oncometabolites’ to refer to specific metabolites that play a direct and well-established role in cancer-related pathways. It is important to note that not all metabolites with altered concentrations in cancer cells are automatically classified as oncometabolites. Cancer-promoting oncometabolites are key players in the metabolic reprogramming of cancer cells, and their identification and targeting can provide novel paradigms for tumor progression in peritoneal cancers [11][12][14]. Several such oncometabolites have been implicated in the pathogenesis and therapy resistance of both primary peritoneal cancers (PPCs) and secondary peritoneal cancers (SPCs) [11]. Oncometabolites can also contribute to the development of tumor heterogeneity and can influence the response of cancer cells to therapy [15][16]. Oncometabolites such as fumarate, glucose, 2-hydroxyglutarate, lactate, succinate, sarcosine, glutamine, asparagine, and choline have also been identified as potential biomarkers for different cancers [14]. Targeting cancer-promoting metabolites holds great promise for the development of novel diagnostic, prognostic, and therapeutic strategies for peritoneal cancers [17]. Combination therapy with metabolic inhibitors and chemotherapy or immunotherapy may also be effective in overcoming chemoresistance and improving patient outcomes [18][19]. Examining the role of oncometabolites in driving tumor progression and targeting them presents opportunities for precision cancer medicine. This includes identifying biomarkers for early detection and prognosis using metabolomic profiling, as well as developing personalized metabolic inhibitors based on individual tumor metabolic signatures. Overall, researchers aim to provide insights into the current state of research on targeting oncogenic metabolites as well as the pathways that generate them in peritoneal cancers and their potential for improving outcomes for patients with peritoneal cancers.

Several studies have demonstrated the potential of targeting glucose metabolism in cancer cells. Metabolic intermediate inhibitors have been used to treat peritoneal cancers since 1964, when 2-deoxyglucose (2-DG), a glycolytic inhibitor, was tested on cancer cells derived from patient ascites [20]. Furthermore, tumor metabolism was analyzed to predict the outcome of surgical procedures such as upfront debulking surgery in ovarian cancers and PPCs or post-chemotherapy [21][22][23]. Given the pivotal role of glucose metabolism in the PTME, targeting the oncogenic metabolites from these pathways could be a promising strategy for cancer therapy [24]. Targeting cancer-promoting metabolites from the tricarboxylic acid (TCA) cycle, glycolytic pathway, and pentose phosphate pathway (PPP) represents a promising therapeutic strategy for the treatment of peritoneal cancers. Several compounds targeting the key enzymes of the TCA cycle, glycolysis, and the PPP pathway have been identified as potential therapeutic agents, and their efficacy has been demonstrated in preclinical models [25].
Although cancer cells reprogram their metabolism towards the glycolytic pathway, recent studies have demonstrated the potential of targeting TCA cycle enzymes for many cancers [26][27]. Although their efficacy remains to be fully investigated in PPCs, their effectiveness as therapeutic targets has been well established in SPCs or cancers that progress to SPCs. For instance, the mitochondrial enzyme isocitrate dehydrogenase (IDH) has been shown to play a critical role in regulating cancer metabolism by producing the oncometabolite 2-hydroxyglutarate (2-HG). 2-HG has been shown to promote the growth, survival, and metastasis of colorectal, pancreatic, cholangiocarcinoma, ovarian, and gastric cancer cells [28][29][30][31]. Targeting IDH1, thereby inhibiting the production of 2-HG, has been shown to prevent peritoneal metastasis of ovarian cancers by inducing senescence [32][33]. More importantly, a small molecular inhibitor of IDH1 has been shown to provide a survival advantage to cholangiocarcinoma patients [34].
Several studies have investigated the use of drugs that target the glycolytic pathway in peritoneal cancers. Using a mouse model of PPCs, it has been observed that treatment with 2-DG results in a significant reduction in tumor growth and increased survival of animals, likely due to the inhibition of glycolysis and the resulting decrease in energy production within the cancer cells [35]. Another study has shown that 2-DG in combination with metformin could inhibit glucose uptake and reduce cell proliferation in the ovarian cancer cell lines, indicating that targeting glucose metabolism could be a promising approach for the treatment of peritoneal cancers [36].
One of the most widely studied targets in the glycolytic pathway is the enzyme hexokinase (HK2), which catalyzes the first step in glucose metabolism. The inhibition of HK2 has been shown to impair glycolysis and lead to decreased cell proliferation and tumor growth in various cancer types. The inhibition of HK2 using 3-bromopuryuvate has been shown to induce cytostatic and cytotoxic effects in both in vitro and in vivo models of peritoneal mesothelioma [37]. The efficacy of targeting HK2 has also been well characterized in cancers that can give rise to SPCs [38][39]. Likewise, small molecule inhibitors of the glycolytic enzyme, lactate dehydrogenase (LDH), have been shown to reduce lactate production and inhibit tumor growth in preclinical models of different SPCs [40][41][42].
The PPP is another attractive target for cancer therapy, as it plays a critical role in the production of nucleotides and antioxidants that are necessary for cancer cell survival and proliferation. The rate-limiting enzyme in PPP is glucose-6-phosphate dehydrogenase (G6PD), which converts glucose-6-phosphate into 6-phosphogluconolactone, accompanied by NADPH production. Through its key role in PPP, G6PD has been shown to play a pleiotropic role in cancer genesis and progression [43]. Inhibition of the PPP enzyme, G6PD, has been shown to reduce tumor growth in preclinical models of breast, ovarian, and pancreatic cancers [24][44][45]. Another enzyme that plays a central role in PPP is 6-phosphogluconate dehydrogenase (6PGD), which converts 6-phosphogluconate (6-PG) into ribulose-5-phosphate (Ru5P) with the generation of NADPH. Inhibitors of 6PGD and transketolase have been shown to have antitumor activity in preclinical models of ovarian and hepatocellular carcinoma [24][46][47].
Targeting cancer-promoting metabolites from the TCA cycle, glycolytic pathway, and PPP pathway represents a promising combinatorial therapeutic strategy for the treatment of peritoneal cancers. For instance, in peritoneal metastasis of gastric cancers, combinatorial therapy involving 5-fluorouracil (5-FU) and shRNA-mediated inhibition of phosphoglycerate kinase-1, which phosphorylates BECLIN-1 to induce autophagy, augments the cytotoxic effects of 5-FU [48]. While there is still much to be learned about the metabolic landscape of peritoneal tumors, preclinical studies have demonstrated the efficacy of several compounds targeting key enzymes in these pathways. Further investigation of these compounds in clinical trials may lead to the development of novel, effective therapies for peritoneal cancers. In addition to drug-based approaches, dietary interventions have also been explored as a way to target glucose metabolism in peritoneal cancers [49]. For example, a ketogenic diet has been associated with decreased tumor growth and increased patient survival, likely due to the reduction in glucose availability to the cancer cells and the resulting shift in the cells’ energy metabolism. 

2. Targeting Lipid Metabolism

Targeting lipid metabolism has shown promise as a therapeutic strategy for peritoneal cancers. One approach is to inhibit fatty acid uptake by cancer cells. Several preclinical studies have demonstrated the efficacy of targeting fatty acid transporters such as fatty acid translocase, CD36, and fatty acid binding protein 4 (FABP4) in reducing tumor growth in various cancer types [50][51][52][53]. In addition, targeting lipid metabolism enzymes such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN) has also shown promise in reducing cancer growth [54][55][56][57]. This is more pronounced in the case of FASN, a key enzyme in fatty acid synthesis. Increased expression of FASN has been correlated with chemoresistance to drugs such as cisplatin in ovarian and lung carcinomas, doxorubicin or 5-FU in breast cancers, and gemcitabine in pancreatic cancers [58]. FASN inhibitors have been shown to synergistically sensitize cancer cells to numerous chemotherapeutic drugs [59]. Under conditions of chemotherapeutic stress, FASN inhibits apoptosis by promoting the synthesis of fatty acids for energy production through β-oxidation, thereby offering pro-survival signals to the cancer cells. Inhibitors of FASN, such as orlistat and cerulenin, have shown anticancer activity in preclinical studies and are being evaluated in clinical trials [59].
Furthermore, targeting the sphingolipid metabolism pathway, which is involved in the synthesis of ceramides and other bioactive lipids, has also shown potential for cancer therapy [60]. Several sphingolipid metabolism inhibitors, such as ceramide synthase inhibitors and sphingosine kinase inhibitors, have been developed and are currently under investigation for cancer treatment [61][62]. Using preclinical animal models, it has also been shown that targeting LPA signaling is a potential therapeutic strategy in ovarian cancer [63][64]. Furthermore, lipid metabolic intermediates, such as sphingolipids and LPA, which serve as signaling lipids, confer chemoresistance toward numerous therapeutic agents by promoting diverse adaptive rescue survival signaling cascades [65]. Further research into targeting lipid metabolism may provide additional therapeutic options for peritoneal cancers.
Clinical studies have also identified components of lipid metabolism as potential biomarkers for predicting treatment response and prognosis in peritoneal cancers. For example, elevated levels of FABP1 and FASN have been shown to predict poor prognosis in patients with many different SPCs, such as those of gastric cancer [55][66].

3. Targeting Amino Acid Metabolism

Targeting amino acid metabolism has also emerged as a promising strategy for cancer therapy, including peritoneal cancers. Several amino acid metabolic pathways have been identified as potential targets, including the glutamine and methionine pathways. Glutamine metabolism is an attractive target for cancer therapy due to its crucial role in cell proliferation and survival [67]. Glutamine is a non-essential amino acid that is critical for the growth of cancer cells. Glutamine is converted to glutamate by glutaminase, and glutamate is further metabolized to α-ketoglutarate (α-KG), which feeds into the TCA cycle to generate energy and biosynthetic precursors [68]. In vitro analyses of different cancer cell lines have indicated the glutamine dependency of many SPCs [69]. In SPCs, such as ovarian, colorectal, and gastric cancers, metabolic alterations contribute to the development of chemoresistance and cancer progression. The inhibition of glutamine metabolism has been shown to have antitumor effects in preclinical models of these cancers [70][71]. In ovarian cancer, which frequently metastasizes to the peritoneum, glutamine dependency has been shown to promote chemoresistance [72]. Increased expression of glutaminase and the glutamine transporter SLC1A5/ASCT2 has been observed in cisplatin-resistant ovarian cancer cells, and the inhibition of ASCT2 and glutaminase has been shown to sensitize these cells to cisplatin [73]. Inhibiting ASCT2 has also been shown to reduce the growth and metastasis of pancreatic cancer cells [74]. Several preclinical studies have indicated that a combination therapy with glutaminase inhibitors could provide a survival advantage to cancer patients [69][75]. For instance, it has been observed that treatment with the glutaminase inhibitor 968 along with anti-PD-L1 reduced the intraperitoneal dissemination of ovarian cancers [76]. Glutaminase-1 inhibitor, used in combination with doxorubicin, has been shown to override the doxorubicin resistance of pancreatic adenocarcinoma ascites metastasis cells [77]. Furthermore, inhibiting the glutamine pathway sensitized the cancer cells to gemcitabine therapy in pancreatic cancers [78]. In addition, cisplatin resistance in ovarian cancers has been reported to be overcome by the inhibition of glutamate dehydrogenase, which catalyzes the glutamate to α-KG conversion to fuel the TCA cycle [79][80].
In colorectal cancer, which can also metastasize to the peritoneum, a dynamic metabolic crosstalk involving cancer cells and peritoneal adipocytes that promotes chemoresistance has been observed. Cancer cells override adipocytes for the uptake of glutamine from the PTME, and peritoneal adipocytes enhance endogenous glutamine synthesis to overcome the glutamine shortage. This process is mediated by the epigenetic de-repression of the gene GS, which encodes glutamine synthetase [81]. Increased glutamine levels in the peritoneal adipocytes lead to the release of glutamine to the PTME, replenishing the glutamine pool. Glutamine from the glutamine pools is taken up by the cancer cells for the subsequent utilization in bioenergetic and biosynthetic pathways within the cancer cells [82][83].
Another amino acid metabolic pathway that has been validated as a target for cancer therapy is the methionine metabolic pathway [84]. Methionine is an essential amino acid that is converted to S-adenosylmethionine (SAM), which serves as a methyl donor in numerous cellular processes, including DNA methylation and protein methylation. Methionine metabolism is critical for cancer cells, as it is required for the synthesis of polyamines, which are necessary for cell proliferation [85]. The inhibition of methionine metabolism has been shown to have antitumor effects in multiple preclinical models of different tumors, including the ones that can metastasize into the peritoneum [86][87][88][89]. In addition, it has been shown that the combination of a methionine-restricted diet with chemotherapy had a greater antitumor effect when compared with chemotherapy alone [90]. Arginine metabolism is also emerging as a potential target for cancer therapy [91]. Arginine is an essential amino acid that plays a crucial role in immune function, and its depletion has been shown to impair the growth and survival of cancer cells. Induced depletion of arginine has been shown to inhibit the proliferation and invasive migration of many cancers that reside in the peritoneum such as ovarian, pancreatic, and liver cancers [92]. The metabolic enzyme, arginase, which catalyzes the conversion of arginine to ornithine and urea, is also being targeted for therapeutic strategy [93][91]. Dysregulated expression of arginase resulting in its upregulation is observed in many cancers [93]. Inhibition of arginase has been shown to reduce tumor burden in preclinical models of colorectal, breast, lung, and ovarian cancers as well as hepatocellular carcinoma [93]. Arginine metabolism also involves the synthesis of polycationic polyamines that are considered oncometabolites in colon and colorectal cancers [94][95][96]. Increased levels of polyamines have been correlated with the proliferation and survival of colorectal cancer cells[94][95][96]. However, their role in the context of PPCs and SPCs remains to be established.
Another potential target in amino acid metabolism is the serine-glycine one-carbon metabolism pathway, which plays a critical role in nucleotide synthesis and DNA methylation [97][98]. Inhibition of this pathway has been shown to have anti-tumor effects in several types of cancers, including those of liver, colorectal, breast, and ovarian cancers [99][100][101][102]. Sarcosine or N-methyl glycine is a potential oncometabolite synthesized from glycine. It has been observed that the levels of sarcosine are elevated during metastasis of cancers of extra-peritoneal origin such as gastric and colorectal cancers [103][104]. Though sarcosine upregulation in peritoneal cancers hasn’t been reported yet, its potential role in tumor progression and as a biomarker makes it a potential oncometabolite candidate for peritoneal cancers that could be explored further.

Tryptophan metabolism is another crucial amino acid metabolic pathway that can be targeted for therapy in peritoneal cancers. It generates several oncometabolites that not only promote tumor growth but also contribute to immune suppression [105]. Tryptophan metabolites generated by indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) have been shown to promote tumor growth and immune evasion in peritoneal cancers [106][107]. IDO and TDO catalyze the first step of kynurenine synthesis, resulting in the production of kynurenine and other immunosuppressive metabolites[108][109]. Kynurenine, derived from the activities of IDO and TDO, plays a pivotal role in tumor growth and metastasis by impairing immune surveillance and promoting the recruitment of immunosuppressive cells to the tumor microenvironment [110]. Kynurenine is an immunomodulatory molecule that can suppress T cell activity and foster the differentiation of regulatory T cells as well as myeloid-derived suppressor cells (MDSCs) [111]. In addition, the gut microbiota can modulate tryptophan metabolism and activation of kynurenine pathway, resulting in the production of oncometabolites that promote tumorigenesis and immune suppression. Significantly, it has been demonstrated that gut bacteria promote kynurenine pathway activation and the production of immunosuppressive metabolites in colorectal cancer [112].

Liquid chromatography-mass spectometric (LC-MS) analysis of peritoneal lavage fluid from the peritoneal metastases of gastric cancer patients has identified several upregulated amino acid metabolites including 3-methyl alanine, glutamyl alanine, and α-aminobutyric acid [113]. Among these metabolites, α-aminobutyric acid has been reported to be elevated in diverse cancers, such as ovarian and colorectal cancers, metastasizing to the peritoneum. It has also been associated with oxidative stress-induced glutathione metabolism in peritoneal cancers. Targeting α-aminobutyric acid metabolism has shown promise in reducing tumor growth and metastasis in colorectal cancer models [114]. Inhibiting the synthesis of α-aminobutyric acid metabolism, using 4-aminobutyrate aminotransferase (ABAT), has been shown to reduce the proliferation and migration of colorectal cancer cells [115].
Resistance to chemotherapy is a major challenge in the treatment of peritoneal cancers. One potential mechanism of chemotherapy resistance is the upregulation of amino acid metabolic pathways, which can lead to increased tumor growth and survival. When the expression of amino acid metabolic enzymes was evaluated in samples of peritoneal cancer tissue from patients who had received chemotherapy, it was observed that the expression of glutaminase and methionine adenosyltransferase was significantly higher in patients who had developed resistance to chemotherapy compared to those who had responded to the treatment [116]. Overall, these studies provide evidence for the potential efficacy of targeting amino acid metabolism in peritoneal cancer therapy. While further research is needed to develop effective therapies and identify optimal treatment strategies, targeting amino acid metabolism remains a promising approach for the treatment of peritoneal cancer.
Clinical studies have also identified oncometabolites generated from amino acid metabolism as potential biomarkers for predicting the treatment response and prognosis in peritoneal cancers. For example, elevated levels of 2-HG have been associated with poor prognosis in patients with peritoneal carcinomatosis (PCs) originating from colon and colorectal cancers [30][117]. Similarly, elevated levels of homocysteine have been shown to be a potential biomarker for digestive tract cancer risk [118].

4. Targeting Nucleotide Metabolism

An obvious and clinically utilized example for targeting nucleotide metabolism for chemotherapy is the use of nucleoside analogs that mimic the structure of nucleotides and can be incorporated into DNA or RNA, disrupting their normal function. Several key nodes of nucleotide metabolism have been investigated for their potential as therapeutic targets for peritoneal cancers [119]. The inhibition of thymidylate synthase, involved in the synthesis of thymidine, has been shown to be effective in the treatment of several types of cancers, including colorectal cancer [120][121]. It has been observed that treatment with pemetrexed, an inhibitory analog of folate, elicits significant therapeutic efficacy in recurrent peritoneally metastasized ovarian cancers [122]. Additionally, the combination of pemetrexed with cisplatin resulted in a greater antitumor effect when compared to either of the drugs alone in peritoneal mesothelioma [116][123][124]. Another enzyme involved in nucleotide metabolism that has been proposed as a target for peritoneal cancer therapy is dihydrofolate reductase (DHFR). DHFR is involved in the conversion of dihydrofolate into tetrahydrofolate, a co-factor required for nucleotide synthesis. Inhibition of DHFR has been shown to be effective in the treatment of several types of cancers [125]. It is significant to note that Raltitrexed and Pemetrexed, two DHFR inhibitors, have been clinically approved for colorectal cancer and pleural mesothelioma, respectively [125]. Their clinical efficacy in peritoneal mesothelioma and other peritoneal cancers remains to be evaluated. The inhibition of inosine monophosphate dehydrogenase (IMPDH) is another potential strategy for targeting nucleotide metabolism in cancer therapy [126]. IMPDH is involved in the de novo synthesis of guanine nucleotides, which are necessary for DNA and RNA synthesis. While experimental studies have shown that the inhibition of IMPDH could inhibit the proliferation of cells from multiple cancers, its therapeutic efficacy in SPCs remains to be established [125].
Another potential target in nucleotide metabolism is ribonucleotide reductase (RNR), which catalyzes the conversion of ribonucleotides into deoxyribonucleotides, the building blocks of DNA [127]. It has been observed that the expression of RNR was significantly higher in patients who had developed resistance to chemotherapy when compared with those who had responded to the treatment [128]. Several RNR inhibitors have been clinically approved as single-agent therapy for different cancers including pancreatic cancer [127]. Gemcitabine, an RNR inhibitor, has already been used in a single-agent therapeutic regimen for platinum-resistant ovarian cancers, fallopian tube cancer, and primary peritoneal adenocarcinoma [129]. In addition, gemcitabine has been shown to reverse cisplatin resistance in ovarian and peritoneal carcinomas [130]. Treatment with nucleoside analogs such as gemcitabine and inhibitors of nucleotide metabolism remains the current standard of care for PPCs and SPCs [131]. A phase II clinical trial with a combination therapy involving gemcitabine and the topoisomerase inhibitor, irinotecan, led to a disease control rate of 75% with increased progression-free survival of platinum-refractory ovarian or peritoneal cancer patients [132]. While further research is needed to develop effective therapies and identify optimal treatment strategies, targeting nucleotide metabolism remains a promising approach for the treatment of peritoneal cancers.

This entry is adapted from the peer-reviewed paper 10.3390/metabo13050618

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