scholarly journals Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumors: Small Steps Toward Personalized Medicine?

2019 ◽  
Vol 12 ◽  
pp. 251686571984253 ◽  
Author(s):  
Gloria Ravegnini ◽  
Riccardo Ricci
Keyword(s):  
Succinate Dehydrogenase ◽  
Gastrointestinal Stromal Tumors ◽  
Dna Methyltransferase ◽  
Kinase Inhibitors ◽  
Alkylating Agents ◽  
Mgmt Methylation ◽  
Wild Type ◽  
Stromal Tumors ◽  
Methylguanine Dna Methyltransferase ◽  
Specific Alternative

Various molecular triggers define heterogeneous subsets of gastrointestinal stromal tumors (GISTs), differing in clinical behavior and drug sensitivity. KIT/PDGFRA-wild-type GISTs, including those succinate dehydrogenase (SDH)-deficient, are overall unresponsive to the tyrosine kinase inhibitors commonly used, fostering the development of specific alternative therapeutic strategies. Epigenetic inactivation of O6-methylguanine-DNA methyltransferase (MGMT) through promoter methylation leads to effectiveness of alkylating agents in several human cancers. SDH-deficient GISTs typically feature widespread DNA methylation. However, the actual occurrence of MGMT methylation in these tumors, potentially predisposing them to respond to alkylating drugs, has not been investigated so far. Here we discuss the recent findings concerning the occurrence of MGMT methylation in different GIST subgroups, including SDH-deficient ones, as a premise for a possible reappraisal of alkylating agents specifically targeting these small, otherwise overall chemorefractory, GIST subgroups.

Expression of IGF-1 receptor in KIT/PDGF receptor-α wild-type gastrointestinal stromal tumors with succinate dehydrogenase complex dysfunction

2013 ◽  
Vol 9 (1) ◽  
pp. 121-126 ◽  
Author(s):  
Margherita Nannini ◽  
Annalisa Astolfi ◽  
Paola Paterini ◽  
Milena Urbini ◽  
Donatella Santini ◽  
...  
Keyword(s):  
Succinate Dehydrogenase ◽  
Gastrointestinal Stromal Tumors ◽  
Pdgf Receptor ◽  
Wild Type ◽  
Stromal Tumors ◽  
Succinate Dehydrogenase Complex ◽  
Dehydrogenase Complex

scholarly journals Evaluation of MGMT gene methylation in neuroendocrine neoplasms

2021 ◽  
Author(s):  
Rosa Della Monica ◽  
Mariella Cuomo ◽  
Roberta Visconti ◽  
Annabella di Mauro ◽  
Michela Buonaiuto ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Alkylating Agents ◽  
Methylation Status ◽  
Neuroendocrine Neoplasms ◽  
Mgmt Methylation ◽  
Gene Methylation ◽  
Mgmt Gene ◽  
Methylguanine Dna Methyltransferase ◽  
Specific Pcr ◽  
Well Differentiated

Unresectable neuroendocrine neoplasms (NENs) often poorly respond to standard therapeutic approaches. Alkylating agents, in particular temozolomide, commonly used to treat high-grade brain tumors including glioblastomas, have recently been tested in advanced or metastatic NENs, where they showed promising response rates. In glioblastomas, prediction of response to temozolomide is based on the assessment of the methylation status of the MGMT gene, as its product, O-6-methylguanine-DNA methyltransferase, may counteract the damaging effects of the alkylating agent. However, in NENs, such a biomarker has not been validated yet. Thus, we have investigated MGMT methylation in 42 NENs of different grades and from various sites of origin by two different approaches: in contrast to methylation-specific PCR (MSP), which is commonly used in glioblastoma management, amplicon bisulfite sequencing (ABS) is based on high resolution next-generation sequencing and interrogates several additional CpG sites compared to those covered by MSP. Overall, we found MGMT methylation in 74% (31/42) of the NENs investigated. A higher methylation degree was observed in well-differentiated tumors and in tumors originating in the gastrointestinal tract. Comparing MSP and ABS results, we demonstrate that the region analyzed by the MSP test is sufficiently informative of the MGMT methylation status in NENs, suggesting that this predictive parameter could routinely be interrogated also in NENs

The c-KIT mutation causing human mastocytosis is resistant to STI571 and other KIT kinase inhibitors; kinases with enzymatic site mutations show different inhibitor sensitivity profiles than wild-type kinases and those with regulatory-type mutations

Blood ◽  
2002 ◽  
Vol 99 (5) ◽  
pp. 1741-1744 ◽  
Author(s):  
Yongsheng Ma ◽  
Shan Zeng ◽  
Dean D. Metcalfe ◽  
Cem Akin ◽  
Sasa Dimitrijevic ◽  
...  
Keyword(s):  
Cell Line ◽  
Gastrointestinal Stromal Tumors ◽  
Kinase Inhibitors ◽  
Wild Type ◽  
Kit Mutation ◽  
Stromal Tumors ◽  
Activating Mutations ◽  
Natural Ligand ◽  
Mast Cell Line ◽  
Regulatory Type

Mutations of c-KIT causing spontaneous activation of the KIT receptor kinase are associated with sporadic adult human mastocytosis (SAHM) and with human gastrointestinal stromal tumors. We have classified KIT-activating mutations as either “enzymatic site” type (EST) mutations, affecting the structure of the catalytic portion of the kinase, or as “regulatory” type (RT) mutations, affecting regulation of an otherwise normal catalytic site. Using COS cells expressing wild-type or mutant KIT, 2 compounds, STI571 and SU9529, inhibited wild-type and RT mutant KIT at 0.1 to 1 μM but did not significantly inhibit the Asp816Val EST mutant associated with SAHM, even at 10 μM. Using 2 subclones of the HMC1 mast cell line, which both express KIT with an identical RT mutation but which differ in that one also expresses the Asp816Val EST mutation, both compounds inhibited the RT mutant KIT, thereby suppressing proliferation and producing apoptosis in the RT mutant-only cell line. Neither compound suppressed activation of Asp816Val EST mutant KIT, and neither produced apoptosis or significantly suppressed proliferation of the cell line expressing the Asp816Val mutation. These studies suggest that currently available KIT inhibitors may be useful in treating neoplastic cells expressing KIT activated by its natural ligand or by RT activating mutations such as gastrointestinal stromal tumors but that neither compound is likely to be effective against SAHM. Furthermore, these results help establish a general paradigm whereby classification of mutations affecting oncogenic enzymes as RT or EST may be useful in predicting tumor sensitivity or resistance to inhibitory drugs.

Succinate dehydrogenase in KIT/PDGFRA wild-type gastrointestinal stromal tumors.

2010 ◽  
Vol 28 (15_suppl) ◽  
pp. 10008-10008 ◽  
Author(s):  
K. A. Janeway ◽  
S. Kim ◽  
M. Lodish ◽  
V. Nose ◽  
P. Dahia ◽  
...  
Keyword(s):  
Succinate Dehydrogenase ◽  
Gastrointestinal Stromal Tumors ◽  
Wild Type ◽  
Stromal Tumors

scholarly journals Gastrointestinal Stromal Tumors (GISTs): Novel Therapeutic Strategies with Immunotherapy and Small Molecules

2021 ◽  
Vol 22 (2) ◽  
pp. 493
Author(s):  
Christos Vallilas ◽  
Panagiotis Sarantis ◽  
Anastasios Kyriazoglou ◽  
Evangelos Koustas ◽  
Stamatios Theocharis ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Gastrointestinal Stromal Tumors ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Survival Rates ◽  
Cancer Therapeutics ◽  
Gastrointestinal Neoplasms ◽  
Mesenchymal Tumors ◽  
Stromal Tumors

Gastrointestinal stromal tumors (GISTs) are the most common types of malignant mesenchymal tumors in the gastrointestinal tract, with an estimated incidence of 1.5/100.000 per year and 1–2% of gastrointestinal neoplasms. About 75–80% of patients have mutations in the KIT gene in exons 9, 11, 13, 14, 17, and 5–10% of patients have mutations in the platelet-derived growth factor receptor a (PDGFRA) gene in exons 12, 14, 18. Moreover, 10–15% of patients have no mutations and are classified as wild type GIST. The treatment for metastatic or unresectable GISTs includes imatinib, sunitinib, and regorafenib. So far, GIST therapies have raised great expectations and offered patients a better quality of life, but increased pharmacological resistance to tyrosine kinase inhibitors is often observed. New treatment options have emerged, with ripretinib, avapritinib, and cabozantinib getting approvals for these tumors. Nowadays, immune checkpoint inhibitors form a new landscape in cancer therapeutics and have already shown remarkable responses in various tumors. Studies in melanoma, non-small-cell lung cancer, and renal cell carcinoma are very encouraging as these inhibitors have increased survival rates. The purpose of this review is to present alternative approaches for the treatment of the GIST patients, such as combinations of immunotherapy and novel inhibitors with traditional therapies (tyrosine kinase inhibitors).

scholarly journals Prognostic value of TP53 expression and MGMT methylation in glioblastoma patients treated with temozolomide combined with other chemotherapies

2021 ◽  
Vol 152 (3) ◽  
pp. 541-549
Author(s):  
Maher Kurdi ◽  
Nadeem Shafique Butt ◽  
Saleh Baeesa ◽  
Badrah Alghamdi ◽  
Yazid Maghrabi ◽  
...  
Keyword(s):  
Prognostic Value ◽  
Dna Methyltransferase ◽  
Chemotherapeutic Agents ◽  
Recurrence Interval ◽  
Mgmt Methylation ◽  
Conventional Radiotherapy ◽  
Methylguanine Dna Methyltransferase ◽  
Kaplan Meier ◽  
Significant Difference ◽  
Temozolomide Chemotherapy

Abstract Objective To assess the recurrence interval and predictive significance of TP53 expression and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation in glioblastomas treated with radiotherapy and combined chemotherapies, including temozolomide, lomustine, procarbazine and bevacizumab. Method We reviewed the clinical outcomes of 52 totally resected glioblastoma patients, who received conventional radiotherapy and temozolomide with other chemotherapeutic agents. Correlation of TP53 expression and MGMT promotor methylation with recurrence interval was analyzed using Kaplan Meier estimates. Results No significant association was found between MGMT promotor methylation and TP53 expression in glioblastomas (P-value = 0.158). Patients with non-methylated MGMT who received temozolomide chemotherapy with other chemotherapeutic agents showed significantly later recurrence (P-value = 0.007) compared with patients with non-methylated MGMT who received temozolomide alone. No significant difference was found in recurrence interval among glioblastoma patients with methylated MGMT who received temozolomide alone or with other chemotherapies (P-value = 0.667). Moreover, patients with non-TP53-expressing tumors who received temozolomide with other chemotherapies had significantly later recurrence (P-value = 0.04) compared with patients who received temozolomide alone. Conclusion Totally resected glioblastoma patients, with non-methylated MGMT or non-TP53-expressing tumors treated with radiotherapy and combined chemotherapies had a reduced chance of tumor recurrence and a more favorable outcome. Furthermore, both MGMT and TP53 are independent prognostic factors for glioblastoma.

scholarly journals Prognostic value of Onodera’s nutritional index for intermediate- and high-risk gastrointestinal stromal tumors treated with or without tyrosine kinase inhibitors

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Feng Wang ◽  
Tingting Tao ◽  
Heng Yu ◽  
Yingying Xu ◽  
Zhi Yang ◽  
...  
Keyword(s):  
Propensity Score ◽  
Propensity Score Matching ◽  
Prognostic Marker ◽  
Gastrointestinal Stromal Tumors ◽  
Prognostic Value ◽  
Kinase Inhibitors ◽  
Rank Test ◽  
Stromal Tumors ◽  
Lymphocyte Ratio ◽  
Nutritional Index

Abstract Background Immunoinflammatory and nutritional markers, such as the peripheral blood neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and Onodera’s prognostic nutritional index (OPNI), have gained considerable attention and have been preliminarily revealed as prognostic markers of gastrointestinal stromal tumors (GISTs). Methods In this study, we first investigated the prognostic value of OPNI in GISTs treated with or without TKIs based on the propensity score matching (PSM) method. All of the patients had received surgical resection for primary GIST, and data from 2010 to 2018 were initially and retrospectively identified from our gastrointestinal center. Recurrence-free survival (RFS) was calculated by the Kaplan–Meier method and compared by the log-rank test. Results The patients were divided into groups treated and not treated with TKIs, and we used the propensity score matching method to homogenize their baseline data. Multivariate Cox proportional hazard regression models were applied to identify associations with outcome variables. A total of 563 GISTs were initially chosen, and 280 of them were included for analysis under the inclusion criteria. After PSM, there were 200 patients included. Multivariate analyses identified OPNI as an independent prognostic marker that was associated with primary site, tumor size, mitotic index, tumor rupture, necrosis, and modified NIH risk classification. Low OPNI (< 42.6; HR 0.409; P < 0.001) was associated with worse RFS. Conclusions Preoperative OPNI is a novel and useful prognostic marker for GISTs both treated and not treated with TKIs. Higher NLR and PLR have negative effects on RFS.

Sign in / Sign up

Export Citation Format

Share Document