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N. Watkins

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    MS 12 - NSCLC Stems Cells: Are They a Real Target? (ID 30)

    • Event: WCLC 2015
    • Type: Mini Symposium
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      MS12.01 - Biology of Cancer Stem Cells (ID 1900)

      14:15 - 15:45  |  Author(s): N. Watkins

      • Abstract
      • Presentation

      There is general agreement amongst biomedical researchers that stem cells exist in multicellular organisms. The most well characterized model of adult somatic stem cells is the bone marrow, in which serial transplantation in both immunocompetent and immunodeficient mice have clearly identified the hematopoietic stem cell (HSC). Using the same models, it is now generally accepted, even amongst cancer stem cell (CSC) sceptics, that most forms of myeloid leukemia are maintained by a self-renewing, transplantable HSC-like cell, even though the initial transformation event may have occurred in a committed progenitor. Given that nature tends to conserve processes across evolution, it is logical to hypothesize that a similar functional hierarchy exists in solid tumors. Over two decades, numerous papers have reported the presence of a functionally distinct, rare population of cells within solid tumors with stem-like properties based on the same criteria used to define the HSC and leukemic CSC. However, the idea that CSCs exist solid tumors remains controversial at best. The difficulties in reproducing results in highly complex models systems, and questions over the validity of CSC surface markers in solid tumors, have clearly contributed to these, often heated, arguments. If we assume for a moment that CSCs do not exist in solid tumors, they would constitute the only multicellular entity in nature without a hierarchical organisation based on self-renewal and differentiation. If this were true, then solid tumors would behave like colonies of bacteria or yeast, in which all cells were identical, where the capacity to self-renew in the face of an environmental challenge would be entirely determined by random genetic variants. In the setting of acquired resistance to targeted therapies, there is convincing evidence for such a “rare clone” hypothesis. For example, the source of acquired resistance to tyrosine kinase inhibitor (TKI) therapy in EGRF-mutant adenocarcinoma seems to be pre-existing clones that already possess a point mutation that confers resistance. But, can this genetic model explain other stemness phenotypes in non-small cell lung cancer (NSCLC)? In clinical terms, a pressing question is whether random genetic events can explain the rapid regeneration of NSCLC tumors after a long period of dormancy following curative surgery. Equally, can the “rare clone” hypothesis explain innate the innate chemoresistance of quiescent CSC-like NSCLC cells that have a greatly enhanced capacity for self-renewal. If the answer to either of questions is “not always”, then targeting CSCs based on function rather than genome remains a potential avenue for improving outcomes in NSCLC patients. The characterization of NSCLC CSCs is made difficult by the phenotypic and genomic heterogeneity of the disease, problems identifying robust surface markers, and in defining what experimental endpoints constitute CSC function. In addition, there is no general agreement on which markers are associated with CSC in NSCLC, although several studies suggest that the surface markers CD44 and CD133 can prospectively identify such cells. In therapeutic terms, elimination of CSCs in NSCLC would require such markers be reproducible and robust, but can also be therapeutically targeted in humans. An alternative approach is to target embryonic signaling pathways known to regulate self-renewal in development. This idea is the driving force behind clinical trials of Notch and Hedgehog inhibitors in several cancer types. Unfortunately, most of these clinical trials add the experimental agent along side standard-of-care chemotherapy rather than delivering the experimental agent following treatment in order to determine whether stem-cell targeting can “burn out” quiescent, undifferentiated residual disease. One promising candidate marker in NSCLC is ALDH1. In most published studies, expression of ALDH1 or ALDH1A correlates with reduced overall survival, consistent with the presence of enhanced regenerative capacity and innate chemoresistance in NSCLC. Moreover, experimental evidence supports the notion that expression of the ALDH1 protein, and its enzymatic activity, is associated with enhanced CSC functions in vitro and in vivo. Since secondary prevention studies in advanced NSCLC are impractical, it may be possible strengthen the case for targeting NSCLC, using ALDH1 as an example, using more practical preclinical and clinical approaches. Such an approach might be: 1. Concentrate on one subgroup of NSCLC- for example KRAS mutant lung adenocarcinoma. 2. Show that rare, single ALDH1+ cells give rise to tumors with the same ratio of ALDH1+ to ALDH1- cells as was seen in the parent tumor. 3. Using single cell genomics, determine whether ALDH1+ and ALDH1- cells share the same genotype. 4. In lung cancer patients treated with neoadjuvant chemotherapy, show that the percentage of ALDH1+ cells increases in the residual tumor removed at surgery. 5. In lung cancer patients with recurrent disease following surgery, show that the recurrent tumor contains the same ratio of ALDH1+ to ALDH1- cells as was seen in the parent tumor. References: Jordan CT. Cancer stem cells: controversial or just misunderstood? Cell Stem Cell, 2009; 4:203-5. Alamgeer M, Peacock CD, Matsui W, Ganju V, Watkins DN. Cancer stem cells in lung cancer: Evidence and controversies. Respirology, 2013; 18:757-764 Sullivan JP, Spinola M, Dodge M, Raso MG, Behrens C, Gao B, Schuster K, Shao C, Larsen JE, Sullivan LA, Honorio S, Xie Y, Scaglioni PP, DiMaio JM, Gazdar AF, Shay J, Wistuba II, Minna JD. Aldehyde Dehydrogenase Activity Selects for Lung Adenocarcinoma Stem Cells Dependent on Notch Signaling. Cancer Res, 2010; 70:9937-48. Shao C, Sullivan JP, Girard L, Augustyn A, Yenerall P, Rodriguez-Canales J, Behrens C, Shay JW, Wistuba II, Minna JD. Essential Role of Aldehyde Dehydrogenase 1A3 for the Maintenance of Non–Small Cell Lung Cancer Stem Cells Is Associated with the STAT3 Pathway. Clin Cancer Res; 2014; 20:4154–66. Alamgeer M, Ganju V, Szczepny A, Russell PA, Prodanovic Z, Kumar B, Wainer Z, Brown T, Schneider-Kosky M, Conron M, Wright G, Watkins DN. The prognostic significance of ALDEHYDE DEHYDROGENASE 1A1 (ALDH1A1) and CD133 expression in early-stage non-small cell lung cancer. Thorax, 2013; 68(12):1095-104. Alamgeer M, Ganju V, Kumar B, Fox J, Hart S, White M, Harris M, Stuckey J, Prodanovic Z, Schneider M, Watkins DN. Changes in ALDEHYDE DEHYDROGENASE-1 (ALDH1) expression during neoadjuvant chemotherapy predict outcome in locally advanced breast cancer. Breast Cancer Res, 2014; 16:R44.

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