Drug Repurposing Identifies a Synergistic Combination Therapy with Imatinib Mesylate for Gastrointestinal Stromal Tumor

Abstract

Gastrointestinal Stromal Tumor (GIST) is a rare and therefore often neglected disease. Introduction of the kinase inhibitor, imatinib mesylate (IM) radically improved the clinical response of patients with GIST; however, its effects are often short-lived, with GISTs demonstrating a median time to progression of approximately two years. Although many investigational drugs, approved first for other cancers, have been subsequently evaluated for the management of GIST, few have greatly impacted the overall survival of patients with advanced disease. We employed a novel, focused, drug repurposing effort for GIST including IM-resistant GIST evaluating a large library of FDA-approved drugs regardless of current indication. As a result of the drug repurposing screen, we identified eight FDA-approved drugs including fludarabine phosphate (F-AMP) that showed synergy with and/or overcame resistance to IM. F-AMP induces DNA damage, annexin V and caspase 3/7 activities as the cytotoxic effects on GIST cells, including IM-resistant GIST cells. F-AMP and IM combination treatment showed greater inhibition of GIST cell proliferation when compared to IM alone and F-AMP alone. Successful in vivo experiments confirmed the combination of IM with F-AMP enhanced the antitumor effects compared to IM alone. Our results identified F-AMP as a promising, repurposed drug therapy for the treatment of GISTs, with potential to be administered in combination with IM or for treatment of IM-refractory tumors.

Beyond standard therapy: drugs under investigation for the treatment of gastrointestinal stromal tumor

“…These strategies represent an opportunity to rapidly advance and deliver new drug therapies to GIST patients by capitalizing on data readily available. Based on the recent recognition of drug repurposing by Dr. Francis Collins, NIH Director, as a key strategy to accelerate translational research for orphan diseases [134, 135], we and others initiated studies using a dual drug repurposing and rediscovery strategy to provide additional therapeutic options for GIST patients which are proceeding to the clinic [136-138]. In a drug-repurposing screen, we evaluated a library of 796 FDA-approved drugs to determine any potential activity against GIST cell lines [137].…”

“…It was found to inhibit the activity of thioredoxin reductase (TrxR) and increase the levels of reactive oxygen species (ROS) leading to the death of GIST cells regardless of the IM resistance status. A subsequent study by our group showed that fludarabine phosphate (F-AMP) exhibits synergy with and/or decreases resistance to IM in IM-resistant GIST cell lines [136]. To confirm the combination's efficacy, an in vivo study was carried out and showed enhanced antitumor activity of the combination compared to IM alone, which makes F-AMP a promising repurposed drug.…”

Establishment of the Clone of Gastrointestinal Stromal Tumor Cells with the Signs of Multiple Drug Resistance and Assessment of Its Properties

“…Boichuk Despite a long existing point of view about the low efficacy of chemotherapy for patients with gastrointestinal stromal tumors (GISTs) [1,2], recent data indicates GISTs sensitivity to the certain types of chemotherapeutic drugs. For example, it was shown rather good perspectives of some chemotherapeutic drugs to manage the patients with metastatic and inoperable forms of GIST [3,4]. The results obtained by our research group also demonstrate that some GIST cell lines are sensitive to the topoisomerase type II inhibitors in vitro and in vivo [5,6].…”

The adrenergic receptor antagonists propranolol and carvedilol decrease bone sarcoma cell viability and sustained carvedilol reduces clonogenic survival and increases radiosensitivity in canine osteosarcoma cells

“…Treatment of human osteosarcoma and Ewing sarcoma is complicated, in part due to the lack of prospective, randomized trials beyond first‐line therapy, and there is a clear need for the development of new approaches to improve clinical outcomes . The costs of new drug discovery efforts, particularly for paediatric tumours like osteosarcoma, are often prohibitive, leading to an interest in repurposing existing FDA‐approved drugs if they demonstrate anticancer activity …”