Novel therapeutic targets in gastrointestinal stromal tumor

Research output: ThesisDoctoral ThesisCollection of Articles

Abstract

Background: Gastrointestinal stromal tumor (GIST) is one of the most common types of soft tissue sarcoma. The molecular mechanisms of GISTs are incompletely understood though the importance of KIT or platelet-derived growth factor α (PDGFRA) signaling in GIST is evident. The molecular mechanisms beyond KIT and PDGFRA signaling are incompletely understood. Tyrosine kinase inhibitors and especially imatinib, an inhibitor of KIT, PDGFRA and BCL-ABL, revolutionized the systemic treatment of GIST. However, advanced GISTs usually eventually progress on tyrosine kinase inhibitors, often because of secondary KIT mutations. There is a need for novel effective agents for the treatment of patients with GIST. Experimental design: The GIST gene expression profile was investigated in an in silico transcriptome database comprising of human tissue and cancer samples. Two GIST cell lines were screened for sensitivity to 217 anti-cancer compounds. SLUG, ITGA4, PDE3A and PDE3B expression was studied using immunohistochemistry on tissue microarrays (TMA). We used three different clinical cancer patient series: the first was a series that consisted of samples from 630 tumors from the archives of the Department of Pathology, Helsinki University Hospital; the second was a population-based cohort consisting of GIST patients who were treated with surgery in Western Sweden from 1983 through 2000; and the third series consisted of high risk GIST patients who were entered to the Scandinavian Sarcoma Group (SSG) XVIII/Arbeitsgemeinschaft Internistische Onkologie (AIO) adjuvant trial. The effects of SLUG, ITGA4 and PDE3 knockdown and selective ITGA4 and PDE3 inhibitors were investigated in three GIST cells lines. The efficacy of a PDE3 inhibitor, anagrelide, was investigated in patient-derived xenograft mouse models. Results: SLUG was expressed in 25.0 %, ITGA4 in 52.3 %, PDE3A in 90.9 % and PDE3B in 60.0 % of the GISTs investigated. Expression of these proteins were also detected in some other human tumor types, but usually much less frequently. SLUG and ITGA4 expression were associated several factors linked with unfavorable prognosis. SLUG expression was associated significantly also with unfavorable recurrence-free survival both when the patients were treated with surgery alone and when treated with surgery followed by adjuvant imatinib. ITGA4 expression was associated with unfavorable GIST-specific survival and overall survival in a patient population treated with surgery alone. PDE3A and PDE3B expression had no significant associations with the clinicopathological factors studied, RFS or overall survival. SLUG and PDE3 downregulation inhibited cell proliferation and induced apoptosis in GIST cell lines, whereas ITGA4 inhibition decreased GIST cell invasion. Anagrelide reduced or stabilized tumor growth in several GIST xenograft mouse models. Conclusions: SLUG, ITGA4 and PDE3s are frequently expressed in GISTs. They are likely important factors in the molecular pathogenesis of GIST, and may influence their clinical behavior. As ITGA4 and PDE3s can be targeted with specific inhibitors, they could potentially be therapeutic targets in GIST. SLUG may mediate pro-survival signaling in GIST. Some PDE3 inhibitors, such as anagrelide, warrant more study as potential therapeutic agents in GIST.
Original languageEnglish
Supervisors/Advisors
  • Joensuu, Heikki, Supervisor
  • Sihto, Harri, Supervisor
Place of PublicationHelsinki
Publisher
Print ISBNs978-951-51-5206-0
Electronic ISBNs978-951-51-5207-7
Publication statusPublished - 2019
MoE publication typeG5 Doctoral dissertation (article)

Fields of Science

  • Gastrointestinal Stromal Tumors
  • +drug therapy
  • +surgery
  • Quinazolines
  • Biomarkers, Tumor
  • Snail Family Transcription Factors
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • Phosphodiesterase 3 Inhibitors
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Survival
  • Cell Proliferation
  • Neoplasm Invasiveness
  • Mice
  • Down-Regulation
  • Sarcoma
  • Transcriptome
  • Recurrence
  • Imatinib Mesylate
  • Protein-Tyrosine Kinases
  • +antagonists & inhibitors
  • 3122 Cancers

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