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    • MoAbs targeting the tumourigenic pathways

    2021-02-25

    MoAbs targeting the tumourigenic pathways, such as IGF-1R may theoretically have a dual working mechanism. On the one hand they block pathways having an anti-tumour working mechanism, and on the other hand they may also stimulate an immunological response inducing a reaction of the patients own immune system against the tumour cells [80]. Natural killer (NK) cells were found to play an important role in this antibody-dependent cell-mediated cytotoxicity (ADCC) [81]. NK cells can be activated by Fc-receptors (FcR) bound to the target cells by antibodies, thereby being able to lyse the target cells and shred cytokines to activate the adaptive immune system. Several studies show that patients have a different FcR genotype and those with a higher FcR affinity respond better to MoAbs. This finding can also be used as a biomarker and to select patients for the treatment with IGF-1R N1-Methylpseudouridine [82], [83], [84], [85], [86]. This dual working mechanism provides a theoretical advantage of antibody treatment compared to tyrosine kinase inhibitors which lack the ADCC anti-tumour mechanism. Regarding the PARP inhibitors, they have been developed more recently and have been tested with various successes in other tumour types such as breast, lung, prostate, fallopian tube and pancreatic cancer, glioblastoma and haematologic malignancies. So far, only the results of one trial with ES patients were presented and results of monotherapy treatment in this study were unsatisfactory. Different theories about the lack of treatment effect with PARP monotherapy were suggested by the authors of this study, e.g. secondary epigenomic alterations that may render the PARP pathway insignificant [74]. However, the exact mechanism still has to be found. Preclinical models suggest that PARP inhibition may show better results in combination with chemotherapy or radiotherapy [70], [73], [87]. A phase I combination study of the PARP inhibitor olaparib with temozolomide in ES is open for recruitment (NCT01858168) and a phase I study combining olaparib with niraparib, another PARP inhibitor, and temozolomide, an alkylating agent, is also enrolling patients with incurable ES (NCT02044120). To evaluate a possible effect of PARP inhibition as monotherapy versus combined therapy, more clinical studies must be conducted. Measuring the PARP pathway down regulation by recording levels of the PARP pathway caspases before and after the drug exposure in tumour biopsies in different treatment conditions will help to find the optimal dosage and combination schedule. Biomarkers need to be tested in preclinical and clinical studies to identify patient populations with a higher likelihood to respond to certain treatment schedules. Hereby more personalised medicine can be conducted with hopefully better outcome results. IGF-1 was found to be a negative prognostic marker in different types of carcinoma [88], [89]. ES patients with elevated levels of free or total IGF-1 before the treatment had a better overall survival [56]. Another protein which has been found to be overexpressed in various tumour types, like breast, head and neck, colon, pancreas and non-small cell lung cancer, can be used as a biomarker to predict response is Rad51[90], [91], [92], [93], [94], [95], [96], [97]. Rad51 functions as a DNA double strand break repair protein thereby inducing stabilisation of the genome. Overexpression of Rad51 has been found to result in reduced proliferation and a more instable genome [98], [99]. Preclinical testing has to be conducted to determine if these biomarkers are also usable in ES. Hopefully a lesson was learnt from the problems which rose with the development of IGF-1R antibodies in clinical trials, so far the development of PARP inhibitors seems to go more structured. In conclusion, both pathways are interesting potential targets for ES as they either hypothetically interact with the EWSR1-FLI1 or EWSR1-ERG fusion product and/or show promising (pre)clinical data. Therapeutic strategies should therefore definitely be explored further, and we will need to better understand which patients are responding and as a result of which underlying molecular mechanism. Other ways forward may include dual blockade such as with linsitinib and conventional chemotherapy or radiotherapy combined with PARP inhibitors. Both strategies are currently being explored clinically.