Ludwig Boltzmann Cluster Oncology (LBC ONC): first 10 years and future perspectives

Abstract

In 2008 the Ludwig Boltzmann Cluster Oncology (LBC ONC) was established on the basis of two previous Ludwig Boltzmann Institutes working in the field of hematology and cancer research. The general aim of the LBC ONC is to improve treatment of hematopoietic neoplasms by eradicating cancer-initiating and disease-propagating cells, also known as leukemic stem cells (LSC) in the context of leukemia. In a first phase, the LBC ONC characterized the phenotype and molecular aberration profiles of LSC in various malignancies. The LSC phenotypes were established in acute and chronic myeloid leukemia, in acute lymphoblastic leukemia and in chronic lymphocytic leukemia. In addition, the concept of preleukemic (premalignant) neoplastic stem cells (pre-L-NSC) was coined by the LBC ONC and was tested in myelodysplastic syndromes and myeloproliferative neoplasms. Phenotypic characterization of LSC provided a solid basis for their purification and for the characterization of specific target expression profiles. In a second phase, molecular markers and targets were validated. This second phase is ongoing and should result in the development of new diagnostics parameters and novel, more effective, LSC-eradicating, treatment strategies; however, many issues still remain to be solved, such as sub-clonal evolution, LSC niche interactions, immunologic control of LSC, and LSC resistance. In the forthcoming years, the LBC ONC will concentrate on developing LSC-eradicating strategies, with special focus on LSC resistance, precision medicine and translation of LSC-eradicating concepts into clinical application.

Keywords: Cancer stem cells; Immunotherapy; Leukemic stem cells; Precision medicine; Targeted therapy.

Fig. 1

Evolution of neoplastic disorders and impact of the microenvironment. In an early phase of cancer evolution, normal stem cells acquire early lesions and thereby transform into self-renewing neoplastic stem cells (blue rectangle boxes). These premalignant neoplastic stem cells are slowly cycling or dormant cells that persist and slowly acquire additional pro-oncogenic lesions and hits (color change) in distinct sub-clones. The resulting diversification into many different sub-clones is a constantly ongoing process. In a next step, the stem cells of one or more of these premalignant sub-clones acquire critical combinations of oncogenic hits and thereby an enhanced proliferative potential and the capacity to produce an overt neoplasm. Finally, these stem cells and their sub-clones acquire additional pro-oncogenic lesions and convert into fully malignant neoplastic stem cells (red rectangle boxes) producing an overt cancer. In the context of a solid tumor, these cells are then called cancer stem cells (CSC), and in the context of leukemia, these cells are termed leukemic stem cells (LSC). Cancer/leukemia evolution is triggered by the genetic background, a number of different exogenous factors (viruses, toxins, etc.), epigenetic events, the microenvironment and the immune system. The stem cell-related microenvironment, also called stem cell (SC) niche, has been implicated in stem cell survival, stem cell homing and stem cell resistance. In certain neoplasms, some of the micro-environmental cells may be derived from clonal cells through transdifferentiation. The immune system has been implicated in immunosurveillance; however, in an overt malignancy, neoplastic stem cells have the capacity to escape immunosurveillance