The regulation of the stem cell compartment
The regulation of the stem cell compartment in CML is dynamic, in particular, during disease progression to a blast crisis and might involve a complex cross-regulation of Hh, Wnt, Notch, and hox signaling pathways (). Significant upregulation of Ptch1 and cyclin D1, upon other proteins, marks the blast crisis with Shh-dependent Stat3 activation hypothetically regulating the interconnection between the signaling pathways ().
In light of this complex time- and tissue-dependent regulation, it is not difficult to see why inconsistent data on the role of Smo in malignant hematopoiesis exist. For example, induced AML by transducing whole bone marrow from Smo-null or WT animals with retrovirus harboring the leukemia-associated disease allele MLL-AF9 and could not detect any influence of Smo deficiency on the replating potential of the transduced Probenecid on methylcellulose or on AML development when transplanting these cells into mice ().
T- and B-Cell Malignancies
Outlook The complexity of HH/GLI signal transduction including its context dependence and the various noncanonical variations of GLI regulation by pathway cross talk and signal integration pose challenges in defining the precise role of HH and GLI in cancer, particularly in hematopoietic diseases. The impressive list of highly specific HH pathway inhibitors currently tested in clinical trials (see Table 2.1) raises the hope that targeting HH signaling will mark a leap forward in molecular medicine and oncology, eventually providing a therapeutic benefit to many cancer patients. Results of the first clinical trials with BCC and medulloblastoma patients treated with SMO inhibitors are highly promising while others have been disappointing (; ; ). Whether the failure of SMO inhibition in ovarian or metastatic colorectal cancer has to do with SMO-independent regulation of GLI activator forms remains to be addressed. Also, in HH-dependent medulloblastoma, treatment with SMO inhibitors can cause a dramatic, yet transient response that is rapidly compensated by the development of drug resistance (). SMO inhibitor resistance has been ascribed to the selection for SMO mutants with reduced drug affinity, to amplification of GLI2 and/or parallel activation of PI3K/AKT signaling (; ). In summary, and despite the first successful trials with SMO inhibitors in BCC patients, we propose that the proper combination of therapeutic compounds simultaneously targeting SMO and positively interacting pathways such as PI3K/AKT, RAS/RAF/MEK/ERK, or RTK signaling will eventually turn out to be the most successful strategy. In fact, a number of studies have provided evidence for an increased anticancer effect of such combinations at least in vitro and in preclinical mouse models (; ; ; ). The design of proper therapeutic strategies for GLI-dependent yet SMO-independent malignant diseases such as CLL is likely to be more challenging as transcription factors are generally considered poorly druggable targets. However, the identification of HH pathway inhibitors acting downstream of SMO including GLI antagonists (; ) may open new avenues for novel therapeutic opportunities, although their in vivo anticancer activity still needs rigorous testing. In addition, the discovery that arsenic trioxide (ATO), which is successfully used for the treatment of anaplastic promyelocytic leukemia (de The and Chen, 2010), efficiently reduces survival of CLL cells from patients with poor prognosis (), and directly affects GLI activation and stability (; Kim et al., 2010a, Kim et al., 2010b), represents an important step toward anti-GLI activator-based strategies. In the future, it will therefore be necessary to critically evaluate the therapeutic efficacy of single agent therapies compared to combination regimes with compounds that target SMO, GLI, and GLI activity enhancing signaling pathways. Targeting HH signaling has developed into an exciting field of research, with a realistic chance of identifying novel rationale-based drug combinations that are likely to exceed the therapeutic benefit of current regimens in a variety of human malignancies.