Emerging Molecular-Targeted Therapies in Early-Phase Clinical Trials and Preclinical Models

Abstract

Within the context of modern cooperative group trials, modification of standard cytotoxic chemotherapy has not improved survival in patients with rhabdomyosarcoma (RMS) over the last 30 years. There is need and interest to incorporate novel targeted anticancer agents into the treatment plans for children and adolescents with newly diagnosed RMS; however, targets directly driven by FOXO1 translocation remain elusive, and molecular events driving translocation negative tumors similarly remain ill-defined. Thus, alternate pathways driving the tumors require identification and targeting. Herein, we describe targeted therapies that could be of interest in RMS, but whose inclusion in clinical trials is thus far limited by scientific and regulatory criteria. Sorafenib, pazopanib, crizotinib, TH-302, aurora-kinase inhibitors, and anaplastic lymphoma kinase (ALK)/c-MET inhibitors will be discussed. The current preclinical and clinical data available, as well as limitations and challenges for each, will be outlined.

Use of Antiangiogenic Therapies in Pediatric Solid Tumors

“…Pazopanib is the first FDA-approved drug for metastatic soft sarcoma in adults, as it increases PFS [ 170 , 171 ]. In the PPTP, pazopanib was associated with PFS increase in rhabdomyosarcoma, but no objective responses were seen [ 170 ].…”

“…Pazopanib is the first FDA-approved drug for metastatic soft sarcoma in adults, as it increases PFS [ 170 , 171 ]. In the PPTP, pazopanib was associated with PFS increase in rhabdomyosarcoma, but no objective responses were seen [ 170 ]. However, a phase I clinical trial involving sarcomas, brain tumors, and other refractory solid tumors showed that pazopanib can stabilize alveolar rhabdomyosarcoma [ 97 ], and may even produce complete remission in alveolar rhabdomyosarcoma or partial remission in embryonal rhabdomyosarcoma if combined with vincristine and irinotecan [ 172 ].…”

“…Although, according to PPTP, sorafenib reduces tumor size in xenografts, it had little activity in patients with rhabdomyosarcoma [ 170 ]. Accordingly, a phase II study found no objective response [ 159 ].…”

“…Sunitinib has activity in four out of six rhabdomyosarcoma cell lines of the PPTP [ 127 ], and inhibits tumor growth in xenograft models [ 167 ]. In the case of cabozantinib and imatinib, several studies show that they inhibit the growth and invasion of rhabdomyosarcoma cells [ 167 , 170 , 174 ]. Imatinib also inhibits xenograft growth [ 167 , 174 ], but one third of the mice create resistance [ 174 ].…”

Treatment of generalized infantile myofibromatosis with sorafenib and imatinib: A case report

“…PDGFRB is a receptor tyrosine kinase that can be aberrantly expressed in soft tissue tumors like rhabdomyosarcoma. Sorafenib is a tyrosine kinase inhibitor that has multiple targets including PDGFRB 16 . Regarding our patient, somatic tumor sequencing of the exon regions containing mutations previously identified by Cheung et al and Martignetti et al within PDGFRB and NOTCH3 failed to reveal any mutations.…”