Table 2.
Therapeutic attempts to target TNBC metabolism.
| Target | Drug | Preclinical Results | Clinical Trial Status and Results |
|---|---|---|---|
| Glycolysis inhibitors | |||
| HK2 | Metformin | A systemic glycolysis inhibitor; it suppresses TNBC stem cells and reduces the tumor-initiating potential in TNBC xenografts [137,153]. | Phase III -NCT02201381: The trial is currently recruiting cancer patients; overall survival is the primary outcome measure. |
| HL010183 | A metformin derivative; it inhibits proliferation and invasion of TNBC cells and reduces tumor growth in MDA-MB-231 xenografts [139]. | Preclinical | |
| Benserazide | FDA-approved drug for Parkinson’s disease. It reduces anaerobic glycolysis in breast cancer cells and inhibits tumor growth [140]. | Preclinical | |
| PKM2 | TLN-232 | It has anti-proliferative effects on diverse cancer cells [154,155]. | Phase II -NCT00422786: The trial has been completed in patients with refractory metastatic renal cell carcinoma, but the results have not yet been reported. -NCT00735332): The trial was conducted in recurring metastatic melanoma patients, but it was stopped because of license termination. |
| PDK1 | DCA | It inhibits metastatic breast cancer cell growth in vitro and in vivo [142]. | Phase II -NCT01029925: The trial was conducted in patients with metastatic breast cancer or with lung cancer, but it was terminated early due to higher than expected risk/safety concerns. |
| AR-12 (OSU-03012) | It reduces proliferation and induces apoptosis of MDA-MB-231 cells in vitro and in vivo. Additionally, it sensitizes MDA-MB-231 cells to tamoxifen [156]. | Phase I -NCT00978523: The trial was conducted in patients with advanced or recurrent solid tumors or with lymphoma. |
|
| BX795/BX912 | It reduces the cell viability of MYC-expressing TNBC cells (MDA-MB-231, SUM159PT, Hs578T) but does not affect non-TNBC cells (BT474 and T47D). In addition, it attenuates the CD44+/CD24- population in MDA-MB-231 cells [95,157]. | Preclinical | |
| OXPHOS inhibitors | |||
| Mitochondrial complex I |
IACS-010759 | It reduces cell growth and viability across a panel of cancer cell lines, including TNBC without affecting normal cells [147]. | Phase I -NCT03291938: The trial is currently recruiting patients with advanced cancer. -NCT02882321: The trial is currently recruiting subjects with relapsed or refractory acute myeloid leukemia. |
| ME-344 | It sensitizes breast tumors to tyrosine kinase inhibitors in mouse mammary tumor virus-polyoma middle tumor-antigen (MMTV-PyMT) mouse model [158,159,160]. | Phase I -NCT02100007: The trial was terminated because of the lack of efficacy in solid tumor patients as a combinatory agent with Hycamtin® -NCT01544322: The trial was completed in patients with refractory solid cancer; however, the results have not yet been released. -NCT02806817: The trial was recruiting HER2-negative breast cancer patients with antiangiogenic-induced mitochondrial metabolism, but the trial status has not been verified in over two years. |
|
| FAO inhibitors | |||
| CPT1 | Etomoxir | It reduces the ATP production in MYC-expressing TNBC cells, thus leads to tumor regression in vitro and in vivo. Moreover, it reduces the CSC proliferation and their self-renewing activity in TNBC cells [116,117]. | Preclinical |
| Perhexiline | It reduces tumor growth, CSC population, and Sox2 expression in MMTV-PyMT tumors. Additionally, it restores the efficacy of paclitaxel in the paclitaxel-resistant MDA-MB-231 cells [117]. | Phase II and III -NCT00845364: The trial was conducted to assess whether an anti-anginal agent could protect the myocardium in patients undergoing coronary artery surgery (CASPER). The role of perhexiline in cardiac surgery is limited [161]. |
|
| Other molecules linked to TNBC metabolism | |||
| GSTP1 | LAS17 | It reduces survival in TNBC cells and tumor growth in TNBC xenografts [152]. | Preclinical |