Global Journal of Medical Research, F: Diseases, Volume 23 Issue 2

carbon nanoparticle-mediated hyperthermia allows heating of cancer stem cells to overcome resistance by generating intense localized heat inside these cells which can reach temperatures above 50 ◦ C [53]. Finally, Hh-activated CAF targeting in patient-derived xenografts using smoothened inhibitors (SMOi) can inhibit FGF signaling to suppress CSC populations and overcome chemoresistance [54]. b) Targeted therapy directed toward cancer stem cells Disrupting CAF-CSC crosstalk is an attractive approach to targeting CSCs. Using Stattic, a STAT3 inhibitor, to block IL-6/IL-6R/STAT3 signaling can reduce stemness of BCSCs [55]. Additionally, the STAT3 antisense oligonucleotide AZD9150 exhibits antitumor tumor activity in refractory lymphoma and NSCLC clinical trials [54]. Further, CCL2-neutralizing antibodies and inhibitors of α - and γ -secretases that activate NOTCH have reduced stemness and stopped metastasis of breast cancer cells and glioblastoma cells in preclinical studies [57], [58]. Moreover, using AMD3100 (plerixafor) to block SDF-1/CXCR4 signaling greatly suppresses the CSC population in breast, colon and renal cancers[59]–[61]. However, these interventions have been relatively ineffective in patients with solid tumors [60]–[63]. On the other hand, using BKM120 or Ly294002 to block PI3K/AKT signaling can kill CSCs in can kill colon, prostate and breast cancers [66]–[69], and the PI3K inhibitors PX-866 [73], alpelisib [74], PQR309 [75] and pictilisib [76] were effective in patients with solid tumors [70]–[73]. LGK974, Wnt-C59, and cyclosporin A, which inhibit the WNT/ β -catenin pathway are able to inhibit the proliferation of CSCs in different cancers [74]–[76]. It has also been shown that vismodegib, a Hedgehog inhibitor, inhibits proliferation and triggers apoptosis in breast, colon, and prostate cancers [77]–[79]. Sonidegib, another hedgehog inhibitor, has shown to inhibit CAF activation and reduce the CSC population in triple-negative breast cancer[54]. Another approach is targeting the metabolism of CSCs. One of the most studied strategies that targets metabolism is the use of compounds that block electron transport chain (ETC) complexes, which inhibits mitochondrial respiration[80]. Antidiabetic drugs such as metformin and phenformin can act as ETC inhibitors to impair oxidative phosphorylation in CSCs[80]. In addition, antibiotics like doxycycline, tigecycline and bedaquiline can target mitochondrial translation and biogenesis {cite}. A method for selective drug delivery in mitochondria can be adopted using chemotherapeutics and small drug- conjugated nanocarriers[80]. Targeting lipid metabolism is another pan-CSC strategy. Stearoyl-CoA desaturase 1 (SCD-1) inhibitors have shown to target properties of stemness in cancer models in vitro and in vivo[80]. Statins can also be used to inhibit cholesterol synthesis via the mevalonate pathway[80]. Lipid uptake can be targeted using strategies revolving around inhibition of the transporter CD36 either pharmacologically or using blocking antibodies [80]. Treatment with salinomycin-encapsulated lipid-PLGA nanoparticles conjugated with CD44 antibodies has resulted in improved cytotoxic effects on CD44+ prostate cancer initiating cells with enhanced suppression of tumorsphere formation [81]. Using drugs, antibodies, vaccines, and CAR-T cells to target transcription factors, intracellular signaling pathways such as Hedgehog, Notch, Wnt signaling, extracellular factors, CSC-associated surface markers, apoptotic pathways, and CSC-niche interactions presents several effective ways to target CSCs [39], [82]. Lv et al. showed that vitamin C uptake via sodium-dependent vitamin C transporter 2 (SVCT-2) induced apoptosis in liver cancer stem cells in vitro and in vivo experiments [83]. Furthermore, in a phase II trial, Brown et al. demonstrated that using Metformin as a treatment caused a major reduction in the CSC population, a change in DNA methylation of carcinoma-associated mesenchymal stem cells (CA-MSCs), and elimination of increased chemoresistance caused by CA-MSCs [84]. c) Directing immunotherapy to cancer stem cells A small number of immunotherapyoptions to target CSCs exist to date and include adaptive T- cells, dendritic cell (DC)-based vaccines, and immune checkpoint inhibitors[85], [86].The discovery of ICIs dramatically changed the standard-of-care practice in oncology allowing for the targeting of tumor immunity. CSCs represent a unique subpopulation of tumor cells that initiate and perpetuate tumors. CSCs are recognized as acore cause of drug resistance, cancer relapse, invasion, and migration. CSC self- renewal and immune evasion can be driven by dysregulated FTO(Fat mass and obesity-associated protein)[87]. FTO has been reported to be upregulated in many tumors[87]. Targeting FTO helps to suppress tumor growth, potentiates immunotherapy, and attenuates drug resistance[87]. Inhibition of FTO can dramatically change immune response by suppressing expression of immune checkpoint genes[87]. It has been reported that two potent small-molecule FTO inhibitors exhibit strong anti-tumor effects in multiple types of cancers[87]. This study was conducted using samples from patients with newly diagnosed, after treatment, or relapsed leukemia. Through a series of screening and validation assays the authors discovered that the FTO inhibitors CS1 and CS2 displayed potent anti-leukemic effects in vitro by selectively suppressing FTO activity and signaling leading to the activation of apoptosis. The potent anti-tumor efficacy and minimal side effects of CS1 and CS2 observed in this study suggest a high potential for clinical application. In addition to hematopoietic malignancies, FTO has also been reported to play oncogenic roles in many types of 21 Year 2023 Global Journal of Medical Research Volume XXIII Issue II Version I ( D ) F © 2023 Global Journals Cancer Stem Cells as the Key to Cancer: Special Emphasis on Prostate Cancer