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Stem cells in radiotherapy
Published in Michael C. Joiner, Albert J. van der Kogel, Basic Clinical Radiobiology, 2018
Robert P. Coppes, Michael Baumann, Mechthild Krause, Richard P. Hill
Radiotherapy is a targeted treatment and it has high efficacy to inactivate CSCs, but it is not specific to CSCs. Additional treatment options arise from the potential to develop drugs that specifically target CSCs. Currently, there is not a single drug treatment approved for clinical use that shows an anti-CSC efficacy in the curative range for solid tumours. However, if drugs are combined with irradiation, even inactivation of limited numbers of CSCs should significantly improve local tumour control (6). An example for such treatment approaches is the application of CD44(v6) directed antibodies, loaded with highly cytotoxic drugs (bivatuzumab mertansine). Combination of these antibodies with irradiation led to an improvement of permanent local tumour control, in experimental models of head and neck cancers (22). Other potential targets may be developmental pathways, receptor tyrosine kinases, ROS scavenging, DNA damage signalling, aldehyde metabolism, apoptosis, PI3K/AKT/mTor, hypoxia, CAF, ECM binding and immune responses (14). However, there are major limitations that need to be overcome for successful introduction of targeted drugs into the clinic. One is the specificity of the targeting. If the target is relevant not only in CSCs but also in normal tissue stem cells as may be the case for some of the current surface markers and for targeting of the developmental pathways, such as Hedgehog, Notch or Wnt, that may be aberrantly expressed in some tumours, increased toxicity is to be expected. Another limitation is the diversity of CSCs, not only between different patients, but also within one tumour and even within one CSC clone (reviewed in [10]). The possibility to directly target the CSC niches may also be a useful approach either by direct targeting (radiotherapy dose painting) or with specific drugs. However, it can presently not be judged whether this approach is realistic. Although promising, the translation of cancer stem cell-based therapies to the clinic still has many hurdles before routine use.
Exploiting differential RNA splicing patterns: a potential new group of therapeutic targets in cancer
Published in Expert Opinion on Therapeutic Targets, 2018
Nidhi Jyotsana, Michael Heuser
Neo-oncoproteins which result from alternative splicing may represent valuable targets, which may be exploited for immunotherapies. Cancer-specific splice variants are not only proven as diagnostic biomarkers, but also serve as potential targets for molecules such as isoform-specific antibodies. Interestingly, for many cell membrane proteins, alternative splicing encodes novel epitopes frequently associated with tumorigenesis [146]. For example, the antibody bivatuzumab against the CD44-v6 isoform in head and neck cancer [147] and antibodies targeting the EDB and EDA isoforms of fibronectin as antiangiogenic cancer treatment [148] entered clinical trials. Reported isoforms of the fusion oncogene BCR-ABL in CML and ALL, and splice variants of VEGFA, UGT1A, PXR, CYCLIN D1, BIRC-5, K-RAS, and SOX9 in colorectal cancer [149] represent novel epitopes that may be targeted by therapeutic antibodies.
CD44v6 as innovative sarcoma target for CAR-redirected CIK cells
Published in OncoImmunology, 2018
V. Leuci, M. Casucci, G. Grignani, R. Rotolo, U. Rossotti, E. Vigna, L. Gammaitoni, G. Mesiano, E. Fiorino, C. Donini, A. Pisacane, L. D. ambrosio, Y. Pignochino, M. Aglietta, A. Bondanza, D. Sangiolo
The first clinical trial with an anti-CD44v6 mAb (bivatuzumab) directly conjugated with a potent chemotherapeutic agent (mertansine) raised concerns on potential skin toxicities.52,53 Previous experiments with primary keratinocytes, however, suggested a low level of CD44v6 expression, and relative resistance to CAR-T cell recognition, as compared to hematological tumor cells and monocytes.38 Although in the present study we could not directly study keratinocyte recognition, we confirmed membrane expression of CD44v6 in monocytes, which were readily recognized by CAR-CIK, although with lower efficiency compared with sarcoma cells, suggesting a sufficiently wide therapeutic window also in the case of STS. Moreover, we previously reported that CD44v6 is indeed absent on tissue-macrophages, ruling out potential bystander damages to healthy tissues rich in monocyte-derived cells (e.g. macrophages; liver kupffer cells; microglia). We supported the relevance of the proposed approach by confirming the expression of CD44v6 in about 40% of STS screened. The distribution was not homogenous and we found that it was more frequently expressed by aggressive UPS, Liposarcoma, Fibrosarcoma and Leiomiosarcoma while less present in GIST (2/12).These findings, obtained by flow-cytometry, are consistent with a previous large retrospective immunohistochemistry analysis where CD44v6 was found in 57% of STS cases and associated with worse prognosis and higher risk of relapse.1,3 The expression of CD44v6 across several STS histotypes favorably compares with that of NY-ESO-1, that is a very relevant target for synovial sarcomas6,7 but only rarely expressed by other STS.