in 2017 it was demonstrated that cancer stem cells have more iron and that this is an achille's heel of these cells. targeting iron, particularly by sequestering it in lysosomes, can selectively kill this cell population. a 2018 study identified inhibitors of the aldh1a family of enzymes and showed that they could selectively deplete putative cancer stem cells in several ovarian cancer cell lines. a novel small molecule inhibitor, called compound 974 specifically targets cancer stem cells and inhibits cancer stem cell pathways and genes. this inhibitor also reduced the cancer stem cell frequency in mice. this 2022 study also identified a novel relation between aldh1a1 and senescence. blocking senescence by compound 974, inhibited cancer stemness in ovarian cancer cells. pathways the design of new drugs for targeting cscs requires understanding the cellular mechanisms that regulate cell proliferation. the first advances in this area were made with hematopoietic stem cells (hscs) and their transformed counterparts in leukemia, the disease for which the origin of cscs is best understood. stem cells of many organs share the same cellular pathways as leukemia-derived hscs. a normal stem cell may be transformed into a csc through dysregulation of the proliferation and differentiation pathways controlling it or by inducing oncoprotein activity. bmi-1 the polycomb group transcriptional repressor bmi-1 was discovered as a common oncogene activated in lymphoma and later shown to regulate hscs. the role of bmi-1 has been illustrated in neural stem cells. the pathway appears to be active in cscs of pediatric brain tumors. notch the notch pathway plays a role in controlling stem cell proliferation for several cell types including hematopoietic, neural and mammary scs. components of this pathway have been proposed to act as oncogenes in mammary and other tumors. a branch of the notch signaling pathway that involves the transcription factor hes3 regulates a number of cultured cells with csc characteristics obtained from glioblastoma patients. sonic hedgehog and wnt these developmental pathways are sc regulators. both sonic hedgehog (shh) and wnt pathways are commonly hyperactivated in tumors and are necessary to sustain tumor growth. however, the gli transcription factors that are regulated by shh take their name from gliomas, where they are highly expressed. a degree of crosstalk exists between the two pathways and they are commonly activated together. by contrast, in colon cancer hedgehog signalling appears to antagonise wnt. sonic hedgehog blockers are available, such as cyclopamine. a water-soluble cyclopamine may be more effective in cancer treatment. dmapt, a water-soluble derivative of parthenolide, induces oxidative stress and inhibits nf-κb signaling for aml (leukemia) and possibly myeloma and prostate cancer. telomerase is a study subject in csc physiology. grn163l (imetelstat) was recently started in trials to target myeloma stem cells. wnt signaling can become independent of regular stimuli, through mutations in downstream oncogenes and tumor suppressor genes that become permanently activated even though the normal receptor has not received a signal. β-catenin binds to transcription factors such as the protein tcf4 and in combination the molecules activate the necessary genes. lf3 strongly inhibits this binding in vitro, in cell lines and reduced tumor growth in mouse models. it prevented replication and reduced their ability to migrate, all without affecting healthy cells. no cancer stem cells remained after treatment. the discovery was the product of "rational drug design", involving alphascreens and elisa technologies.