Durable tumor regression in highly refractory metastatic
 KIT/PDGFRA
  wild-type GIST following treatment with nivolumab

Schroeder, Brett; Kohli, Karan; O’Malley, Ryan B.; Kim, Teresa S.; Jones, Robin L.; Pierce, Robert H.; Pollack, Seth M.

doi:10.1080/2162402x.2019.1710064

Cited by 11 publications

(7 citation statements)

References 25 publications

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“…For example, the target drugs Imatinib, Sunitinib, Regorafenib and Ripretinib have been successfully used to treat GISTs. 13,14 Additionally, some new drugs, like Avapritinib (BLU-285), also have a very bright application prospect in the treatment of GISTs. 15 The development of laparoscopy has led to its gradual application in the treatment of GISTs.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Endoscopic or Surgical Resection for Patients with 2–5cm Gastric Gastrointestinal Stromal Tumors: A Single-Center 12-Year Experience from China

Lei¹,

Tan²,

Liu³

et al. 2020

CMAR

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The surgical or endoscopic resection is the current treatment modality for 2-5 cm gastric gastrointestinal stromal tumors (GISTs). However, evidence is lacking as to which treatment modality is better. Our objective is to provide a new reference for the standardization of the treatment of 2-5 cm gastric GISTs. Patients and Methods: A retrospective study was conducted on 177 patients who underwent resection for 2-5cm gastric GISTs between January 2007 and July 2019 at Xiangya Hospital of Central South University. The cases were divided into surgical group (n=118) and endoscopic group (n=59). The clinical data, pathological and genetic characteristics, shortand long-term outcomes were compared. Results: Symptoms showed more obvious in the surgical group including abdominal pain and bleeding. In the endoscopic group, tumor size was smaller (p<0.001), and risk classification was lower (p<0.001). Patients in the endoscopic group had shorter anal exhaust time (p<0.001) and lesser hospital cost (p<0.001). However, the incidence rate of complications (25.42 vs 4.20%; p<0.001) and reoperation (22.03 vs 0.00%; p<0.001) in the endoscopic group was relatively higher than these in the surgical group. There was no significant difference in recurrence-free survival or overall survival between two groups. Conclusion: Gastric GISTs of 2-5cm may be suitable to select laparoscopic surgery.

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Section: Discussionmentioning

confidence: 99%

“…Finally, the pathologist (Haiyan Zhou) determined and recorded the location of the GISTs, their maximum diameter and other related data. Gene mutation analysis (C- KIT 9,11,13,17 and PDGFRA 12,18) was performed for the tumor of some patients after the surgery.…”

Section: Pathological Diagnosismentioning

confidence: 99%

Endoscopic or Surgical Resection for Patients with 2–5cm Gastric Gastrointestinal Stromal Tumors: A Single-Center 12-Year Experience from China

Lei¹,

Tan²,

Liu³

et al. 2020

CMAR

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“…Only patients harbouring exon 11 mutation of c-kit are sensitive to imatinib therapy, while other ligand-independent KIT signalling pathways activated by mutations in exon 9, exon 13, exon 17, and others are not blocked by imatinib. Further, primary drug resistance mainly appears in cases without mutation of c-kit [12][13][14]. In addition, long-term imatinib application induces secondary mutations to activate new ligand-independent KIT signalling pathways that are insensitive to imatinib and lead to secondary resistance eventually [15][16].…”

Section: Discussionmentioning

confidence: 99%

“…Although the small-molecule tyrosine kinase inhibitor, imatinib, has shown optimum clinical activity in c-kit-driven GIST patients, the effects are often limited because of intrinsic and acquired resistance resulting in tumour recurrence and progression in most patients [6]. To overcome primary and secondary resistance to imatinib, more effective KIT-targeted therapies are urgently needed.…”

Section: Introductionmentioning

confidence: 99%

A New Monoclonal Antibody that Blocks KIT Dimerisation and Inhibits Gastrointestinal Stromal Tumour Growth

Bai

Qiu

2020

Preprint

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Gastrointestinal stromal tumour (GIST) is the most common sarcoma of the gastrointestinal tract, and arises owing to oncogenic mutations in c-kit that result in constitutive auto-phosphorylation of KIT in the absence of ligand binding. Small-molecule tyrosine kinase inhibitors have shown good clinical activity by inhibiting ATP binding to the receptor. Unfortunately, majority of patients eventually develop drug resistance, which limits the long-term benefits of the tyrosine kinase inhibitors and poses a significant challenge in the clinical management of GIST. Here, we demonstrate c-kit mutation-driven KIT auto-dimerisation prior to tyrosine kinase phosphorylation as same as the procedure in ligand-dependent signalling pathway and describe a monoclonal antibody, KITMAb, with strong affinity to the dimerisation domain of KIT that blocks the important step in both the KIT signalling pathways. Treatment of KIT-dimer-expressing cells with the KITMAb slowed down cell growth. Furthermore, KITMAb reduced the proportion of cells in the proliferative phase (S+G2-M). Finally, we also demonstrate that KITMAb treatment accelerated cell apoptosis. These results indicate that KITMAb strongly inhibits KIT receptor dimerisation-mediated signalling pathway and cell growth responses in vitro. Further, the results suggest that treatment with KITMAb may be potentially therapeutic in imatinib-resistant GIST.

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“…Most GISTs are caused by gain-of-function mutations in c-kit that trigger intrinsic receptor tyrosine kinase activity and downstream signalling cascades including phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathways even in the absence of the binding of its ligand, stem cell factor (SCF) (Hirota et al 1998;Chiao et al 2019;Lennartsson et al 1999;Lev et al 1992;Serve et al 1994). Although the small-molecule tyrosine kinase inhibitor, imatinib, has shown optimum clinical activity in c-kit-driven GIST patients, the effects are often limited because of intrinsic and acquired resistance resulting in tumour recurrence and progression in most patients (Schroeder et al 2020). To Supplementary Information The online version contains supplementary material available at https ://doi.org/10.1007/s0043 2-020-03490 -6. overcome primary and secondary resistance to imatinib, more effective KIT-targeted therapies are urgently needed.…”

Section: Introductionmentioning

confidence: 99%

A new monoclonal antibody that blocks dimerisation and inhibits c-kit mutation-driven tumour growth

Bai

Qiu

2021

J Cancer Res Clin Oncol

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Purpose Imatinib, a small-molecule tyrosine kinase inhibitor, has shown good clinical activity by inhibiting adenosine triphosphate (ATP) binding to the receptor. Unfortunately, majority of patients eventually develop drug resistance, which limits the long-term benefits of the tyrosine kinase inhibitors and poses a significant challenge in the clinical management of GIST. The aim of our study was to explore the feasibility of blocking KIT dimerisation upstream of the phosphorylation in imatinib-resistant GIST. Method KITMAb was prepared using hybridoma technique. The biological function of KITMAb was examined in KIT-dimer-expressing cells constructed by transfecting with liposomes using enzyme linked immunosorbent assay (ELISA), immunohistochemistry, western blot, MTT, Annexin V/FITC, and flow cytometry assay, respectively. Results KIT-dimer was expressed in 293 cells transfected with c-kit mutated-type pcDNA3.1. Treatment of KIT-dimer-expressing cells with the KITMAb significantly decreased the expression of both KIT-dimer and other phosphorylated proteins of KIT downstream signalling pathway. Furthermore, KITMAb slowed down cell growth and reduced the proportion of cells in the proliferative phase (S + G2-M). Finally, we also found that KITMAb treatment accelerated cell apoptosis. These results indicate that KITMAb strongly inhibits KIT receptor dimerisation-mediated signalling pathway and cell growth responses in vitro. Conclusions We demonstrate c-kit mutation-driven KIT auto-dimerisation prior to tyrosine kinase phosphorylation as same as the procedure in ligand-dependent signalling pathway and describe a monoclonal antibody, KITMAb, with strong affinity to the dimerisation domain of KIT that blocks the important step in both the KIT signalling pathways. Further, the results suggest that treatment with KITMAb may be potentially therapeutic in imatinib-resistant GIST.

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Durable tumor regression in highly refractory metastatic KIT/PDGFRA wild-type GIST following treatment with nivolumab

Cited by 11 publications

References 25 publications

<p>Endoscopic or Surgical Resection for Patients with 2–5cm Gastric Gastrointestinal Stromal Tumors: A Single-Center 12-Year Experience from China</p>

<p>Endoscopic or Surgical Resection for Patients with 2–5cm Gastric Gastrointestinal Stromal Tumors: A Single-Center 12-Year Experience from China</p>

A New Monoclonal Antibody that Blocks KIT Dimerisation and Inhibits Gastrointestinal Stromal Tumour Growth

A new monoclonal antibody that blocks dimerisation and inhibits c-kit mutation-driven tumour growth

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