Identifying Targets in Gastrointestinal Stromal Tumors

Gastrointestinal (GI) stromal tumors are a rare form of soft tissue sarcoma of the digestive system, primarily affecting the stomach and small intestine. In the US, approximately 6000 new cases of GI stromal tumors are diagnosed each year.¹ Despite their rarity, these tumors are the most prevalent mesenchymal tumors of the GI tract.²

Surgery is the first line of treatment for GI stromal tumors, with neoadjuvants used for patients with large tumors or those which had infiltrated other organs.³ In the case of high-risk GI stromal tumors, the widely accepted standard treatment involves the use of tyrosine kinase inhibitor (TKI) imatinib.⁴ However, the emergence of acquired resistance to these TKIs remains a concern. Consequently, the complete eradication of GI stromal tumors can be difficult, and recurrence or metastasis can occur even after treatment.

Ongoing research aims to develop better therapies and discover a potential cure. Novel treatment strategies are being explored to improve outcomes and increase long-term remission prospects for individuals with GI stromal tumors.

There is a need for novel treatment alternatives for patients with GI stromal tumors who are resistant to current therapies. Causaly facilitates the rapid identification of potential drug targets by leveraging causal relationships within diseases. Using Causaly, over 400 targets for this disease were identified. Here we have prioritized targets being investigated in clinical trials, as well as focusing on emerging targets and targets studied in animal models.

CD117 (Proto-Oncogene Protein c-kit) is a transmembrane tyrosine kinase receptor being investigated in clinical trials associated with GI stromal tumors. An observational study aiming to identify patterns of care and outcomes of patients with metastatic GI stromal tumors, is recruiting participants.⁵ This includes evaluating patient outcomes to treatment with imatinib, a TKI which targets CD117.⁵ A phase II study of imatinib revealed that small bowel GI stromal tumors may be associated with KIT exon 9 mutations.⁶

TGFB2 (transforming growth factor beta 2), a cytokine involved in cell proliferation and migration, was uncovered as an emerging target for GI stromal tumors. The upregulation of TGF-β expression in gastrointestinal tumors has been associated with poor prognosis, particularly at advanced tumor stages.⁷ A recent study showed that secretion of TGFB2 by mesenchymal stromal cells via paracrine signalling may trigger resistance against TKIs in GI stromal tumors.⁸ This study suggests that TGFB2 could promote GI stromal tumor growth by activating signalling pathways downstream of KIT and PDGFRA, thereby preventing direct inhibition of KIT and PDGFRA activity through targeted therapy.⁸

PDGFRA (Platelet-derived growth factor receptor alpha) was identified as an important target for GI stromal tumors studied in animal models. It is a receptor tyrosine kinase which, upon activation, initiates downstream signalling cascade leading to cell growth and proliferation. Mutations in PDGFRA specially in exon 18 causes constitutive activation of this receptor leading to uncontrolled growth of cancer cells.⁹ Recently, it was reported that cancer-associated fibroblasts secrete PDGFC, promoting GI stromal tumor growth and metastasis through PDGFRA activation.¹⁰

The pursuit of therapeutic targets in GI stromal tumors continues to drive research efforts. Despite advancements in disease management, challenges such as disease recurrence and acquired resistance to current therapies persist. Here we have used Causaly to identify potential targets for GI stromal tumors, including CD117 in clinical trials, PDGFRA in animal models, and TGFB2 protein as an emerging target. These findings represent crucial steps towards developing more effective therapies and improving outcomes for individuals affected by GI stromal tumors.

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