Abstract ED01-01: Successes and failures of targeted drug development in adult and pediatric sarcomas
Authors: Verweij Jaap 
Published: March 2020

Abstract
Development of molecularly targeted anticancer agents has seen major successes in the last 2 decades, also in Soft Tissue Sarcomas. But at the same time, many of those agents never made it beyond the stage of initial excitement. Moreover, the rare incidence of soft tissue sarcomas, and the even more rare incidence of its enormously high number of subtypes, frequently with subtype specific molecular aberrations in the malignancy, has led to different levels of evidence for success, if any. The development of Imatinib in c-KIT expressing GIST, does not only exemplify hallmarks of success, but also identifies some features of development failure. In Pediatric GIST for instance, Imatinib is basically ineffective. This was found to be due to the absence of KIT mutations in pediatric GIST, and the likely presence of different tumor growth drivers that are not sensitive to Imatinib. Taken together these features indicate that similar histologies do not necessarily express similar genetic changes in adult vs pediatric sarcomas, and indicate that it is essential to identify changes that represent true driving factors of tumor growth. And likely crucial to genetically analyse the tumor specimens of individual patients prior to treatment- and/or clinical trial selection. Apart from GIST, most of the other interesting suggestions of clinically successful specific targeting are yet based on fairly limited data. And thus, the level of evidence is much less than for Imatinib in adult GIST. These other subtypes and treatments include for instance Imatinib in PDGFR-beta mutant Dermatofibrosarcoma protruberans (DFSP), PLX3397 in colony-stimulating factor 1 (CSF1) expressing (1;2) translocated Tenosynovial Giant Cell Tumors (TGCT), Larotrectinib in TRK mutated Infantile Fibrosarcoma, Sirolimus in TSC1 or TSC2 mutated Perivascular Epitheloid Cell tumors (PEComa) and Crizotinb for ALK mutated Inflammatory Myofibroblastic Tumor (IMT). While the anti-VEGF monoclonal antibody Bevazicumab as a single agent hardly yielded effect in soft tissue sarcoma subsets such as angiosarcomas and hemangioendothelial sarcomas, the effect of multitargeted agents that a.o included VEGF as a target, has been proven effective in diseases such as non-subtype specific soft tissue Sarcomas (Pazopanib), GIST (Sunitinib, Regorafinib) Desmoid tumors (Sorafenib), and Alveolar Soft Part Sarcoma (Cediranib). Yet, given the inability to differentiate one target from the other, it is difficult to ascribe the successful trials to any of them. While for some drugs and targets (such as MDM2 and CDK4/6) the jury is still out, there is a large number of targets and targeted agents that failed the threshold. Among these are the mTOR inhibitors for other soft tissue sarcoma subtypes than PEComa, pPARgamma inhibitors for liposarcomas, EGFR inhibitors in synovial sarcomas, MET inhibitors in soft tissue sarcomas with specific amplifications and translocations, and again most recently the PDGFR-alpha monoclonal antibody Olaratumab. The failure to achieve clinical effect by inhibition of PDGFR will be discussed in somewhat more detail. In conclusion, to increase success rates and reduce failures, it seems important to closely analyze which preclinical biological factors can better predict clinical success and/or failure.
Citation Format: Jaap Verweij. Successes and failures of targeted drug development in adult and pediatric sarcomas [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr ED01-01. doi:10.1158/1535-7163.TARG-19-ED01-01