Novel Small Molecule Inhibitors of Cancer Stem Cell Signaling Pathways
The main aim of oncologists worldwide is to understand and then intervene in the primary tumor initiation and propagation mechanisms. This is essential to allow targeted elimination of cancer cells without altering normal mitotic cells. Currently, there are two main rival theories describing the process of tumorigenesis. According to the Stochastic Model, potentially any cell, once defunct, is capable of initiating carcinogenesis. Alternatively the Cancer Stem Cell (CSC) Model posits that only a small fraction of undifferentiated tumor cells are capable of triggering carcinogenesis. Like healthy stem cells, CSCs are also characterized by a capacity for self-renewal and the ability to generate differentiated progeny, possibly mediating treatment resistance, thus leading to tumor recurrence and metastasis. Moreover, molecular signaling profiles are similar between CSCs and normal stem cells, including Wnt, Notch and Hedgehog pathways. Therefore, development of novel chemotherapeutic agents and proteins (e.g., enzymes and antibodies) specifically targeting CSCs are attractive pharmaceutical candidates. This article describes small molecule inhibitors of stem cell pathways Wnt, Notch and Hedgehog, and their recent chemotherapy clinical trials.
KeywordsCancer Stem cells Inhibitor Wnt Notch Hedgehog Signaling pathway
Authors are thankful for financial support provided through the grant “Analysis of gene expression for different stages of colorectal cancer” (‘Programme-targeted funding 2014–2017’; Government of Republic of Kazakhstan).
All authors equally contributed to the design, literature analysis and writing of the manuscript.
Disclosure of Interest
The authors have no commercial, proprietary, or financial interest in the products or companies described in this article.
- 10.Wang, W. K., Quan, Y., Fu, Q. B., et al. (2014). Dynamics between Cancer Cell Subpopulations Reveals a Model Coordinating with Both Hierarchical and Stochastic Concepts. PLoS One, 9, 1.Google Scholar
- 30.Boon, E. M., Keller, J. J., Wormhoudt, T. A., Giardiello, F. M., Offerhaus, G. J., van der Neut, R., & Pals, S. T. (2004). Sulindac targets nuclear beta-catenin accumulation and Wnt signalling in adenomas of patients with familial adenomatous polyposis and in human colorectal cancer cell lines. British Journal of Cancer, 90, 224–9.PubMedCentralCrossRefPubMedGoogle Scholar
- 36.LoRusso, P. M., Rudin, C. M., Borad, M. J., et al. (2008). A first-in-human, first-in-class, phase (ph) I study of systemic Hedgehog (Hh) pathway antagonist, GDC-0449, in patients (pts) with advanced solid tumors. Journal of Clinical Oncology, 26, 15.Google Scholar
- 37.Stein, A., & Bokemeyer, C. (2014). How to select the optimal treatment for first line metastatic colorectal cancer. World J Gastroenterol, 20(4), 899–907.Google Scholar
- 38.Lin, T. L., & Matsui, W. (2012). Hedgehog pathway as a drug target: smoothened inhibitors in development. OncoTargets and Therapy, 5, 47–58.Google Scholar
- 39.Jamieson, C., Cortes, J. E., Oehler, V., et al. (2011). Phase 1 dose-escalation study of PF-04449913, an oral hedgehog (Hh) inhibitor, in patients with select hematologic malignancies. Blood, 118, 195–6.Google Scholar
- 40.Artavanis-Tsakonas, S., Rand, M., & Lake, R. (1999). Notch signaling: cell fate control and signal integration in development. Science, 284, 770–6.Google Scholar
- 41.Reedijk, M., Odorcic, S., Zhang, H., et al. (2008). Activation of Notch signaling in human colon adenocarcinoma. International Journal of Oncology, 33, 1223–9.Google Scholar
- 42.Meng, R. D., Shelton, C. C., Li, Y. M., Qin, L. X., Notterman, D., Paty, P. B., & Schwartz, G. K. (2009). gamma-Secretase inhibitors abrogate oxaliplatin-induced activation of the Notch-1 signaling pathway in colon cancer cells resulting in enhanced chemosensitivity. Cancer Research, 69, 573–82.Google Scholar
- 43.Huynh, C., Poliseno, L., Segura, M. F., et al. (2011). The Novel Gamma Secretase Inhibitor RO4929097 Reduces the Tumor Initiating Potential of Melanoma. PLoS One, 6(9), e25264.Google Scholar
- 44.Deangelo, D. J., Stone, R. M., Silverman, L. B., et al. (2006). A phase I clinical trial of the notch inhibitor MK-0752 in patients with T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) and other leukemias. Journal of Clinical Oncology, 24, 357s-s.Google Scholar
- 47.Rudge, J. S., Thurston, G., Davis, S., Papadopoulos, N., Gale, N., Wiegand, S. J., & Yancopoulos, G. D. (2005). VEGF trap as a novel antiangiogenic treatment currently in clinical trials for cancer and eye diseases, and VelociGene- based discovery of the next generation of angiogenesis targets. Cold Spring Harbor Symposia on Quantitative Biology, 70, 411–8.CrossRefPubMedGoogle Scholar
- 55.Shiras, A., Chettiar, S. T., Shepal, V., Rajendran, G., Prasad, G. R., & Shastry, P. (2007). Spontaneous transformation of human adult nontumorigenic stem cells to cancer stem cells is driven by genomic instability in a human model of glioblastoma. Stem Cells, 25, 1478–89.CrossRefPubMedGoogle Scholar
- 58.Gajjar, A., Stewart, C. F., Ellison, D. W., et al. (2013). Phase I study of vismodegib in children with recurrent or refractory medulloblastoma: a pediatric brain tumor consortium study. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 19, 6305–12.CrossRefGoogle Scholar
- 59.LoRusso, P. (2009). Targeting the hedgehog pathway in medulloblastoma and advanced basal cell cancer therapy. Cancer Biology & Therapy, 8, v-vi.Google Scholar
- 64.Rodon, J., Tawbi, H. A., Thomas, A. L., et al. (2014). A phase I, multicenter, open-label, first-in-human, dose-escalation study of the oral smoothened inhibitor Sonidegib (LDE225) in patients with advanced solid tumors. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 20, 1900–9.CrossRefGoogle Scholar
- 67.Diaz-Padilla, I., Wilson, M. K., Clarke, B. A., et al. (2015). A phase II study of single-agent RO4929097, a gamma-secretase inhibitor of Notch signaling, in patients with recurrent platinum-resistant epithelial ovarian cancer: a study of the Princess Margaret, Chicago and California phase II consortia. Gynecologic oncology.Google Scholar
- 70.Tolcher, A. W., Messersmith, W. A., Mikulski, S. M., et al. (2012). Phase I study of RO4929097, a gamma secretase inhibitor of Notch signaling, in patients with refractory metastatic or locally advanced solid tumors. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 30, 2348–53.CrossRefGoogle Scholar
- 74.Tong, G., Wang, J. S., Sverdlov, O., et al. (2012). Multicenter, randomized, double-blind, placebo-controlled, single-ascending dose study of the oral gamma-secretase inhibitor BMS-708163 (Avagacestat): tolerability profile, pharmacokinetic parameters, and pharmacodynamic markers. Clinical Therapeutics, 34, 654–67.CrossRefPubMedGoogle Scholar
- 75.Gurney, A., Axelrod, F., Bond, C. J., et al. (2012). Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors. Proceedings of the National Academy of Sciences of the United States of America, 109, 11717–22.PubMedCentralCrossRefPubMedGoogle Scholar
- 77.Messersmith, W. A., Shapiro, G. I., Cleary, J. M., et al. (2015). A Phase I, dose-finding study in patients with advanced solid malignancies of the oral gamma-secretase inhibitor PF-03084014. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 21, 60–7.CrossRefGoogle Scholar
- 78.Smith, D. C., Eisenberg, P. D., Manikhas, G., et al. (2014). A phase I dose escalation and expansion study of the anticancer stem cell agent demcizumab (anti-DLL4) in patients with previously treated solid tumors. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 20, 6295–303.CrossRefGoogle Scholar
- 79.Zemskova, M., Wechter, W., Bashkirova, S., Chen, C. S., Reiter, R., & Lilly, M. B. (2006). Gene expression profiling in R-flurbiprofen-treated prostate cancer: R-Flurbiprofen regulates prostate stem cell antigen through activation of AKT kinase. Biochemical Pharmacology, 72, 1257–67.CrossRefPubMedGoogle Scholar