Table 1.
Summary of key clinical evidence for metabolic reprogramming as a therapeutic target for cancer.
| Authors (REF) | Treatment | Inhibitor Target | Methodology | Results |
|---|---|---|---|---|
| DeCensi et al. [119] | Metformin | Insulin-lowering agent. | Meta-analysis combining 11 observational studies and trials (N = 4042) focused on evaluating the effects of metformin on cancer. | A 31% reduction in cancer incidence or mortality was observed in subjects taking metformin compared with other antidiabetics (SRR, 0.69; 95% CI, 0.61–0.79). |
| Andronesi et al. [120] | IDH305 | Mutant-selective allosteric high affinity IDH1 inhibitor. | Phase I clinical trial of IDH305. | A rapid decrease of 2HG levels by 70% (CI 13%, p = 0.019) after 1 week of treatment. Importantly, inhibition of mutant IDH1 may lead to reprogramming of tumor metabolism, suggested by simultaneous changes in glutathione, glutamine, glutamate, and lactate. |
| Basu et al. [121] | AZD2014 | Dual m-TORC 1/2 Inhibitor. | Phase II clinical trial where 56 adults were treated with AZD2014 orally twice daily with doses of 25 to 100 mg. | Two PRs were evidenced in the study. The first was a patient with acinar pancreatic cancer with KRAS, PDGFRA, APC, ERB4, KIT, and FBXW7 mutations. The second to respond was a breast cancer patient with HRAS, NRAS, TP53 and ERBB2 mutations. |
| Graham et al. [122] | MLN0128 | Dual m-TORC 1/2 Inhibitor. | Phase II clinical trial focused on evaluating the efficacy and safety of MLN0128 in mCRPC at a dose of 4 mg for a median time of 11 weeks (range = 3–30) in 9 subjects. | The best response was stable disease. All subjects showed an increase in PSA during treatment (159%) and no decreases in cancer cell counts after treatment. Correlative studies of biopsy samples before and after treatment indicate limited inhibition of AKT phosphorylation, 4EBP1, and eIF4E activity. |
| Mueller et al. [123] | 6-diazo-5-oxo-L-norleucine (DON) | Glutamine antagonist and inhibits irreversibly the purine/pyrimidine synthesis. | Phase IIa multicenter study evaluating the safety and clinical activity of the glutamine-reducing enzyme PEG-PGA in combination with DON in 55 patients treated with 120 IU/m2 of PEG-PGA once a week, and 140 mg/m2 DON twice a week between 1 and 379 days. | After the second infusion, glutamine levels were reduced by 10% and remained reduced in >90% of patients. Among the patients with metastatic colorectal cancer, 1 PR was found, 9 free of progression at 3 months, and 5 free of progression at 5 months. |
| Meric-Bernstam et al. [124] | CB-839 | Glutaminase Inhibitor. | Escalating doses of CB-839 (600–800 mg PO BID) plus Cabo (60 mg PO QD) were evaluated using a 3+3 design. Tumor response was assessed per RECIST 1.1 every 8 weeks. | CB-839 plus Cabo showed encouraging clinical activity and tolerability in heavily pretreated mRCC patients, with response rates (50% ORR, 100% DCR) comparing favorably to historical Cabo monotherapy. |
| Zhou et al. [125] | Crocin | Inhibits the migration, invasion, and epithelial-mesenchymal transition of gastric cancer cells via miR-320/KLF5/HIF-1α signaling. | Preclinical study | Crocin inhibits the EMT, migration, and invasion of gastric cancer cells, and this activity is mediated by miR-320/KLF5/HIF-1α signaling |
| Liu et al. [126] | Ginsenoside 20(S)-Rg3 | Reduces the expression of HIF-1α by activating the ubiquitin-proteasome pathway to promote HIF-1α degradation. | In vivo and in vitro preclinical study | Ginsenoside 20(S)-Rg3 potently blocks hypoxia-induced EMT of ovarian cancer cells |
CI, confidence interval; PR, partial response; mCRPC, metastatic castration resistant prostate cancer; PSA, prostate specific antigen; IDH1, isocitrate dehydrogenase 1; HIF-1α, hypoxia-inducible factor 1α.