Currently, much of the search for novel anticancer therapies has focused on oncogenes that are specific for (e.g., BCR-ABL in CML), or overexpressed in (e.g., c-myc or bcl-2), selected cancers. However, attacking cancer-specific targets has met with variable success, and many of the most effective anticancer therapies, such as rituximab in lymphomas, high-dose cytotoxic therapy, or the allogeneic graft-versus-tumor effect, show limited or even no tumor selectivity. Targeting a cancer-specific pathway could fail for several reasons. It is likely that many cancers have already acquired multiple oncogenic mutations, even at initial diagnosis, capable of driving tumor growth; in such cases, targeting only one oncogene might be expected to generate limited activity. Further, even when the initiating oncogenic event is targeted as with imatinib in CML, inherent properties of stem cells may make the target inaccessible or irrelevant. For example, stem cells’ quiescence and high expression of ABC transporters may limit a drug’s access to a target; moreover, inhibiting an oncogene would not be expected to eradicate cells that are already long-lived in the absence of the oncogene [13
Properties shared with normal stem cells not only appear to be responsible for CSC resistance to many anticancer agents [11
], they may also lead to the development of novel therapies active across many malignancies. In fact, prospective targets shared with normal stem cells may have particularly strong anticancer potential since their conserved expression suggests a critical function retained by the CSC. Several signaling pathways that are important for the generation and maintenance of normal stem cells during embryonic development, (e.g., Notch, Wnt, and Hedgehog) [30
] and/or postnatally (e.g., telomerase [31
]) also appear to be important for the growth of many cancers. Preliminary data suggest that inhibition of these pathways, even when they are not mutated or overexpressed, may produce potent antitumor activity across a range of malignancies, possibly because of the key roles these pathways play in stem cell maintenance and growth [32
While toxicity from lack of tumor-specificity is an obvious concern for shared stem cell targets, there are several potential differences between normal and CSC that may provide a therapeutic ratio for shared targets. Normal stem cells have normal cell cycle checkpoints that are likely to protect them from cellular damage or crisis. The stage of differentiation at which cancers arise may also provide a therapeutic ratio for approaches targeting cancer. Although many cancers may arise from tissue stem cells, they may not be the most primitive tissue stem cells as exemplified by CML which appears to arise from myeloid or low-quality stem cells [3
]. Accordingly, if a therapy equally eliminated both CML stem cells and their normal counter-parts, the existence of more primitive normal HSC should replenish the normal progenitor pool [29
Another example of a shared stem cell target potentially providing tumor selectivity is telomerase, where differences between CSC and their normal counterparts in the interplay of telomere length and telomerase may provide a therapeutic ratio. Normal stem cells require telomerase to prevent telomere shortening leading to replicative senescence. However, even in the absence of telomerase, normal stem cells can maintain replicative capacity for some period of time because of their relatively long telomeres. Accordingly, telomerase knockout mice show a phenotype only after four to six generations [33
]. In addition, the major cause of death in dyskeratosis congenita, a congenital disease that results from loss of function mutations in telomerase components, is bone marrow failure, but this usually does not manifest until the second or third decade of life [34
]. In contrast, uninterrupted telomerase activity may be absolutely required for the maintenance and growth of most malignancies, in order to stabilize the short telomeres that have been hypothesized to characterize CSC [35
]. In fact, crossing telomerase knock-out mice with INK4a−/−
] or APCmin
] mice predisposed to cancer, significantly lowered the development of cancers in these mice. Thus, the differential in telomere length between normal (long) and cancer (short) stem cells could provide telomerase inhibition selectivity toward cancer.
The rarity of many CSC (often <1% of the total tumor cells) has both limited their study and potentially masked CSC responses to treatment. Any therapeutic impact on the rare CSC may be imperceptible, hidden by the bulk of differentiated cells (). Current detection methods are insufficient to resolve differences in the size of the minute CSC population with treatment. Hence, as discussed above, therapies which are effective against only the differentiated cells (but inactive against CSC) may appear overly promising, while highly active agents against CSC may appear falsely ineffective if they have little impact on the differentiated leukemic bulk.
Because of the difficulty assessing the effects of therapies on the rare CSC responsible for relapse, the development of such approaches requires new clinical paradigms and methodologies [6
]. We believe these new paradigms should rely heavily on preclinical modeling, employ nontraditional measures of clinical response as trial endpoints, and utilize novel preclinical assays to evaluate the fate of CSC. Preclinical studies should assess the effects of therapies on both CSC and differentiated cancer cell populations. Using suitable preclinical models, it may be possible to develop a detailed understanding of the mechanisms of action of new treatments, as well as strategies for optimizing activity; this could potentially allow a fully developed new approach to be taken directly from the “bench to the bedside”. However, effective preclinical models for CSC may ease the task of clinical trial development, but will not eliminate the need for new clinical paradigms. Evaluating the efficacy of treatments against CSC should be possible by utilizing these treatments after debulking the differentiated cells that constitute the majority of the tumor. In cancers where clinical debulking is successful (i.e., complete remissions are common but transient), studying therapies after induction of remission should permit using duration of remission as a measure of activity against the CSC. The fate of CSC could also be assessed as correlative laboratory endpoints using newly developed preclinical assays.