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Zhao X, Wu G, Tao X, Dong D, Liu J. Targeted mitochondrial therapy for pancreatic cancer. Transl Oncol 2025; 54:102340. [PMID: 40048984 PMCID: PMC11928980 DOI: 10.1016/j.tranon.2025.102340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 01/05/2025] [Accepted: 02/27/2025] [Indexed: 03/18/2025] Open
Abstract
Pancreatic cancer (PC) is a highly invasive tumor characterized by delayed diagnosis, rapid progress, and resistance to chemotherapy. Mitochondria, as the "power chamber" of cells, not only play a central role in energy metabolism but also participate in the production of reactive oxygen species (ROS), calcium signaling, regulation, and differentiation of the cell cycle. The abnormal activity of mitochondria is closely related to the development of PC. In this paper, we discussed the key role of mitochondria in PC, including mitochondrial DNA, mitochondrial biogenesis, mitochondrial dynamics, metabolic regulation, ROS generation, and mitochondrial-dependent apoptosis. We elaborated on the importance of these mitochondrial mechanisms in the development of PC and emphasized the potential of targeted mitochondrial therapy strategies for these mechanisms in the treatment of PC. In addition, this article also reviews the latest developments in innovative drug carriers such as cell-penetrating peptides, nucleic acid aptamers, and nanomaterials, which can achieve precise localization of mitochondria and drug delivery. Therefore, this article comprehensively analyzed the important role of mitochondria in the treatment of PC and clarified the effectiveness and necessity of targeting mitochondria in the treatment of PC.
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Affiliation(s)
- Xinya Zhao
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China; College of Pharmacy, Dalian Medical University, Dalian, 116044, China
| | - Guoyu Wu
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China
| | - Xufeng Tao
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China.
| | - Deshi Dong
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China.
| | - Jing Liu
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
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Marino F, Lorusso G, Gandi C, Ragonese M, Pierconti F, Sacco E. Epithelioid (Histiocytoid) hemangioma of the testis: A case report and literature review of a rare benign tumor. Urologia 2025; 92:169-173. [PMID: 39473270 DOI: 10.1177/03915603241292838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2025]
Abstract
Testicular hemangioma is a rare benign vascular neoplasm originating from the inner layer of the tunica albuginea, predominantly affecting the pediatric population and often associated with hemangiomas in other organs. Histopathologically can be categorized into four types, including capillary, cavernous, papillary endothelial hyperplasia, and epithelioid (histiocytoid). We report a case of a 24-year-old presenting with left inguinal pain, diagnosed with an epithelioid (histiocytoid) hemangioma of the testis. Diagnostic evaluation included scrotal doppler ultrasonography, which revealed a small, hypoechoic formation with evident vascularization. Serum tumor markers were within normal limits. Surgical excision via testis-sparing surgery (TSS) was performed based on frozen section analysis. A literature review underscores the rarity of testicular histiocytoid hemangiomas. Advancements in diagnostic technique have improved the accuracy of diagnosis and allowed for more conservative surgical approaches, preserving fertility and minimizing long-term adverse effects. In conclusion, while testicular hemangiomas may present characteristic features on ultrasound, frozen section examination remains crucial in guiding surgical decision-making. TSS offers significant advantages over traditional excisional surgery, including reduced morbidity and preservation of cancer control, making it an essential option in the management of testicular hemangiomas, particularly in young patients concerned about fertility preservation.
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Affiliation(s)
- Filippo Marino
- Department of Urology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Università Cattolica Del Sacro Cuore, Rome, Italy
- Department of Urology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Giuseppe Lorusso
- Department of Urology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Università Cattolica Del Sacro Cuore, Rome, Italy
- Department of Urology, Ospedale Isola Tiberina - Gemelli Isola, Rome, Italy
| | - Carlo Gandi
- Department of Urology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Università Cattolica Del Sacro Cuore, Rome, Italy
| | - Mauro Ragonese
- Department of Urology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Università Cattolica Del Sacro Cuore, Rome, Italy
| | - Francesco Pierconti
- Università Cattolica Del Sacro Cuore, Rome, Italy
- Department of Anatomic Pathology and Histology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Emilio Sacco
- Università Cattolica Del Sacro Cuore, Rome, Italy
- Department of Urology, Ospedale Isola Tiberina - Gemelli Isola, Rome, Italy
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Khatami F, Reis LO, Ebrahimi M, Nasiri S, Tavangar SM, Pishkuhi MA, Shafiee G, Heshmat R, Aghamir SMK. The role of methylation quantification of circulating tumor DNA (ctDNA) as a diagnostic biomarker of Pheochromocytomas (PCCs) and Paragangliomas (PGLs). J Diabetes Metab Disord 2024; 23:2065-2072. [PMID: 39610555 PMCID: PMC11599490 DOI: 10.1007/s40200-024-01466-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Accepted: 07/02/2024] [Indexed: 07/26/2024]
Abstract
OBJECTIVES Circulating tumor DNAs (ctDNAs) are fragments of malignant tissue DNA that can simply signify the real time genetic change and epigenetic modification of a solid tumor tissue. Pheochromocytomas (PCCs) and Paragangliomas (PGLs) are malinancy of adrenal gland tissue that have the possible diagnosis by ctDNAs. In this study the methylation quanifcation of three target genes RDBP, SDHB, and SDHC in the ctDNA of PCCs/PGLs patients were measured as a diagnostic biomarker. METHODS The biological samples include blood and fresh frozen tissue of twelve PCCs/PGLs patients and blood of 12 non tumoral patients as controls were recruited. Semi quantification methylation status of RDBP, SDHB, and SDHC (two CpG lslands of each gene named 1 and 2) was assesed between PCCs/PGLs patients and controls by Methylation specific-high resolution melting (MS-HRM) technique. RESULTS Between six candidate CpG island of RDBP, SDHB, and SDHC, promoter methylation quantification of SDHC1 and RDBP2 was expressively unsimilar in PCCs/PGLs compare to the controls. SDHC1 was hypermethylated in 49.93% of PCCs/PGLs cases vs. 8.33% of control samples, p-value: 0.026, area under curve AUC = 0.757, and RDBP2 in 74.9% of PCCs/PGLs cases vs. 25.0% of control samples, p-value: 0.032, AUC = 0.750. CONCLUSIONS Our result shows that the ctDNA hypermethylation of SDHC1 and RDBP2 have role in tumorgenesis of adrenal gland and can consider for diagnosis of PCCs/PGLs. SUPPLEMENTARY INFORMATION The online version contains supplementary material available at 10.1007/s40200-024-01466-8.
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Affiliation(s)
- Fatemeh Khatami
- Urology Research Center, Tehran University of Medical Sciences, Sina Hospital, Hassan Abad Sq., Imam Khomeini Ave, Tehran, Iran
| | - Leonardo Oliveira Reis
- UroScience and Department of Surgery (Urology), School of Medical Sciences, University of Campinas, Unicamp, and Pontifical Catholic University of Campinas, PUC-Campinas, Campinas, São Paulo, Brazil
| | - Mehdi Ebrahimi
- Department of Internal Medicine, Faculty of Medicine, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Shirzad Nasiri
- Departments of Surgery, Tehran University of Medical Sciences, Shariati Hospital, Tehran, Iran
| | - Seyed Mohammad Tavangar
- Department of Pathology, Dr. Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahin Ahmadi Pishkuhi
- Urology Research Center, Tehran University of Medical Sciences, Sina Hospital, Hassan Abad Sq., Imam Khomeini Ave, Tehran, Iran
- Pars Advanced and Minimally Invasive Medical Manners Research Center, Pars Hospital, University of Medical Science, Tehran, Iran
| | - Gita Shafiee
- Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ramin Heshmat
- Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Mohammad Kazem Aghamir
- Urology Research Center, Tehran University of Medical Sciences, Sina Hospital, Hassan Abad Sq., Imam Khomeini Ave, Tehran, Iran
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Álvarez-González E, Sierra LM. Tricarboxylic Acid Cycle Relationships with Non-Metabolic Processes: A Short Story with DNA Repair and Its Consequences on Cancer Therapy Resistance. Int J Mol Sci 2024; 25:9054. [PMID: 39201738 PMCID: PMC11355010 DOI: 10.3390/ijms25169054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 08/08/2024] [Accepted: 08/20/2024] [Indexed: 09/03/2024] Open
Abstract
Metabolic changes involving the tricarboxylic acid (TCA) cycle have been linked to different non-metabolic cell processes. Among them, apart from cancer and immunity, emerges the DNA damage response (DDR) and specifically DNA damage repair. The oncometabolites succinate, fumarate and 2-hydroxyglutarate (2HG) increase reactive oxygen species levels and create pseudohypoxia conditions that induce DNA damage and/or inhibit DNA repair. Additionally, by influencing DDR modulation, they establish direct relationships with DNA repair on at least four different pathways. The AlkB pathway deals with the removal of N-alkylation DNA and RNA damage that is inhibited by fumarate and 2HG. The MGMT pathway acts in the removal of O-alkylation DNA damage, and it is inhibited by the silencing of the MGMT gene promoter by 2HG and succinate. The other two pathways deal with the repair of double-strand breaks (DSBs) but with opposite effects: the FH pathway, which uses fumarate to help with the repair of this damage, and the chromatin remodeling pathway, in which oncometabolites inhibit its repair by impairing the homologous recombination repair (HRR) system. Since oncometabolites inhibit DNA repair, their removal from tumor cells will not always generate a positive response in cancer therapy. In fact, their presence contributes to longer survival and/or sensitization against tumor therapy in some cancer patients.
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Affiliation(s)
- Enol Álvarez-González
- Departamento de Biología Funcional, Área de Genética, University of Oviedo, C/Julián Clavería s/n, 33006 Oviedo, Spain;
- Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, 33006 Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias, Avda. HUCA s/n, 33011 Oviedo, Spain
| | - Luisa María Sierra
- Departamento de Biología Funcional, Área de Genética, University of Oviedo, C/Julián Clavería s/n, 33006 Oviedo, Spain;
- Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, 33006 Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias, Avda. HUCA s/n, 33011 Oviedo, Spain
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Giger OT, Ten Hoopen R, Shorthouse D, Abdullahi S, Bulusu VR, Jadhav S, Maher ER, Casey RT. Preferential MGMT hypermethylation in SDH-deficient wild-type GIST. J Clin Pathol 2023; 77:34-39. [PMID: 36198483 PMCID: PMC10804026 DOI: 10.1136/jcp-2022-208462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 09/16/2022] [Indexed: 11/04/2022]
Abstract
AIMS Wild-type gastrointestinal stromal tumours (wtGIST) are frequently caused by inherited pathogenic variants, or somatic alterations in the succinate dehydrogenase subunit genes (SDHx). Succinate dehydrogenase is a key enzyme in the citric acid cycle. SDH deficiency caused by SDHx inactivation leads to an accumulation of succinate, which inhibits DNA and histone demethylase enzymes, resulting in global hypermethylation. Epigenetic silencing of the DNA repair gene MGMT has proven utility as a positive predictor of the therapeutic efficacy of the alklyating drug temozolomide (TMZ) in tumours such as glioblastoma multiforme. The aim of this study was to examine MGMT promoter methylation status in a large cohort of GIST. METHODS MGMT methylation analysis was performed on 65 tumour samples including 47 wtGIST (33 SDH-deficient wtGIST and 11 SDH preserved wtGIST) and 21 tyrosine kinase (TK) mutant GIST. RESULTS MGMT promoter methylation was detected in 8 cases of SDH-deficient (dSDH) GIST but in none of the 14 SDH preserved wild-type GIST or 21 TK mutant GIST samples analysed. Mean MGMT methylation was significantly higher (p 0.0449) and MGMT expression significantly lower (p<0.0001) in dSDH wtGIST compared with TK mutant or SDH preserved GIST. No correlation was identified between SDHx subunit gene mutations or SDHC epimutation status and mean MGMT methylation levels. CONCLUSION MGMT promoter hypermethylation occurs exclusively in a subset of dSDH wtGIST. Data from this study support testing of tumour MGMT promoter methylation in patients with dSDH wtGIST to identify those patients who may benefit from most from TMZ therapy.
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Affiliation(s)
| | | | - David Shorthouse
- Department of Medical Physics and Biomedical Engineering, University College London, London, UK
| | | | | | - Saili Jadhav
- Oncology, University of Cambridge, Cambridge, UK
| | - Eamonn R Maher
- Department of Medical Genetics and Cancer Research, University of Cambridge, Cambridge, UK
| | - Ruth T Casey
- Department of Medical Genetics and Cancer Research, University of Cambridge, Cambridge, UK
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Pierconti F, Rossi ED, Fiorentino V, Bakacs A, Carlino A, Navarra E, Sacco E, Totaro A, Palermo G, Larocca LM, Martini M. Methylation Analysis of Urinary Sample in Non-Muscle-Invasive Bladder Carcinoma: Frequency and Management of Invalid Result. Biomedicines 2023; 11:3288. [PMID: 38137509 PMCID: PMC10741688 DOI: 10.3390/biomedicines11123288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 12/05/2023] [Accepted: 12/07/2023] [Indexed: 12/24/2023] Open
Abstract
BACKGROUND Numerous studies showed that methylation analysis represents a newly developed urinary marker based on DNA methylation changes in a panel of genomic biomarkers and it could represent a valid tool in terms of the diagnosis and prediction of high-grade urothelial carcinoma recurrences. One of the limits of the use of this new molecular method during a follow-up is represented by the number of invalid tests in routine practice. METHOD A total of 782 patients with a diagnosis of non-muscle-invasive high-grade carcinoma (NMIBC) was studied. The Bladder EpiCheck test (BE) was performed together with cytology in all cases within 1 year after the end of treatment. In 402 patients, the urinary samples were voided urine (UV), while, in 380 cases, the samples were collected after bladder washing (IU). For all the patients with invalid BE results, a second BE test was performed following the instructions for use that indicated the test should be repeated with a new urinary sample in the case of an invalid result. RESULTS Analyzing the two different groups (UV and IU), we found the invalid BE results seemed to be not related to urinary samples (p = 0.13 Fisher's exact test), suggesting that the collection method was not relevant in order to reduce the number of invalid tests. CONCLUSIONS In the follow-up for NMIBC, for patients for whom a BE test is planned, a combined approach of cytology and a methylation test is recommended in order to repeat the BE test with an invalid result only in those cases with a cytological diagnosis of atypical urothelial cells (AUC) suspicious for high-grade urothelial carcinoma (SHGUC) and high-grade urothelial carcinoma (HGUC).
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Affiliation(s)
- Francesco Pierconti
- Institute of Pathology, Catholic University of Rome, Fondazione Policlinico Gemelli Roma, 00153 Rome, Italy; (E.D.R.); (A.B.); (E.N.)
| | - E. D. Rossi
- Institute of Pathology, Catholic University of Rome, Fondazione Policlinico Gemelli Roma, 00153 Rome, Italy; (E.D.R.); (A.B.); (E.N.)
| | - V. Fiorentino
- Institute of Pathology, University of Messina, 98125 Messina, Italy; (V.F.); (M.M.)
| | - A. Bakacs
- Institute of Pathology, Catholic University of Rome, Fondazione Policlinico Gemelli Roma, 00153 Rome, Italy; (E.D.R.); (A.B.); (E.N.)
| | - A. Carlino
- Institute of Pathology, UniCamillus Rome, 00131 Rome, Italy; (A.C.); (L.M.L.)
| | - E. Navarra
- Institute of Pathology, Catholic University of Rome, Fondazione Policlinico Gemelli Roma, 00153 Rome, Italy; (E.D.R.); (A.B.); (E.N.)
| | - E. Sacco
- Institute of Urology, Catholic University of Rome, Fondazione Policlinico Gemelli Roma, 00168 Rome, Italy; (E.S.); (A.T.); (G.P.)
| | - A. Totaro
- Institute of Urology, Catholic University of Rome, Fondazione Policlinico Gemelli Roma, 00168 Rome, Italy; (E.S.); (A.T.); (G.P.)
| | - G. Palermo
- Institute of Urology, Catholic University of Rome, Fondazione Policlinico Gemelli Roma, 00168 Rome, Italy; (E.S.); (A.T.); (G.P.)
| | - L. M. Larocca
- Institute of Pathology, UniCamillus Rome, 00131 Rome, Italy; (A.C.); (L.M.L.)
| | - M. Martini
- Institute of Pathology, University of Messina, 98125 Messina, Italy; (V.F.); (M.M.)
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Fiorentino V, Pizzimenti C, Franchina M, Rossi ED, Tralongo P, Carlino A, Larocca LM, Martini M, Fadda G, Pierconti F. Bladder Epicheck Test: A Novel Tool to Support Urothelial Carcinoma Diagnosis in Urine Samples. Int J Mol Sci 2023; 24:12489. [PMID: 37569864 PMCID: PMC10420163 DOI: 10.3390/ijms241512489] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/01/2023] [Accepted: 08/04/2023] [Indexed: 08/13/2023] Open
Abstract
Bladder cancer and upper urothelial tract carcinoma are common diseases with a high risk of recurrence, thus necessitating follow-up after initial treatment. The management of non-muscle invasive bladder carcinoma (NMIBC) after transurethral resection involves surveillance, intravesical therapy, and cytology with cystoscopy. Urinary cytology, cystoscopy, and radiological evaluation of the upper urinary tract are recommended during follow-up in the international urological guidelines. Cystoscopy is the standard examination for the first assessment and follow-up of NMIBC, and urine cytology is a widely used urinary test with high sensitivity for high-grade urothelial carcinoma (HGUC) and carcinoma in situ (CIS). In recent years, various urinary assays, including DNA methylation markers, have been used to detect bladder tumors. Among these, the Bladder EpiCheck test is one of the most widely used and is based on analysis of the methylation profile of urothelial cells to detect bladder neoplasms. This review assesses the importance of methylation analysis and the Bladder EpiCheck test as urinary biomarkers for diagnosing urothelial carcinomas in patients in follow-up for NMIBC, helping cytology and cystoscopy in doubtful cases. A combined approach of cytology and methylation analysis is suggested not only to diagnose HGUC, but also to predict clinical and histological recurrences.
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Affiliation(s)
- Vincenzo Fiorentino
- Department of Human Pathology of the Adult and Developmental Age “G. Barresi”, University of Messina, 98125 Messina, Italy; (M.F.); (G.F.)
| | - Cristina Pizzimenti
- PhD Programme in Translational Molecular Medicine and Surgery, Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, 98125 Messina, Italy;
| | - Mariausilia Franchina
- Department of Human Pathology of the Adult and Developmental Age “G. Barresi”, University of Messina, 98125 Messina, Italy; (M.F.); (G.F.)
| | - Esther Diana Rossi
- Department of Women, Children and Public Health Sciences, Catholic University of the Sacred Heart, Agostino Gemelli IRCCS University Hospital Foundation, 00168 Rome, Italy; (E.D.R.); (P.T.); (A.C.); (F.P.)
| | - Pietro Tralongo
- Department of Women, Children and Public Health Sciences, Catholic University of the Sacred Heart, Agostino Gemelli IRCCS University Hospital Foundation, 00168 Rome, Italy; (E.D.R.); (P.T.); (A.C.); (F.P.)
| | - Angela Carlino
- Department of Women, Children and Public Health Sciences, Catholic University of the Sacred Heart, Agostino Gemelli IRCCS University Hospital Foundation, 00168 Rome, Italy; (E.D.R.); (P.T.); (A.C.); (F.P.)
| | - Luigi Maria Larocca
- Department of Medicine and Surgery, Saint Camillus International University of Health and Medical Sciences (UniCamillus), 00131 Rome, Italy;
| | - Maurizio Martini
- Department of Human Pathology of the Adult and Developmental Age “G. Barresi”, University of Messina, 98125 Messina, Italy; (M.F.); (G.F.)
| | - Guido Fadda
- Department of Human Pathology of the Adult and Developmental Age “G. Barresi”, University of Messina, 98125 Messina, Italy; (M.F.); (G.F.)
| | - Francesco Pierconti
- Department of Women, Children and Public Health Sciences, Catholic University of the Sacred Heart, Agostino Gemelli IRCCS University Hospital Foundation, 00168 Rome, Italy; (E.D.R.); (P.T.); (A.C.); (F.P.)
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Khosroyani HM, Klug LR, Heinrich MC. TKI Treatment Sequencing in Advanced Gastrointestinal Stromal Tumors. Drugs 2023; 83:55-73. [PMID: 36607590 PMCID: PMC10029090 DOI: 10.1007/s40265-022-01820-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/23/2022] [Indexed: 01/07/2023]
Abstract
Prior to the early 2000s, patients with advanced gastrointestinal stromal tumors (GIST) had very poor prognoses owing to a lack of effective therapies. The development of tyrosine kinase inhibitors at the turn of the century significantly improved the overall survival for patients with GIST. The resounding success of imatinib in the first clinical trial of a tyrosine kinase inhibitor to treat GIST led to its approval for first-line therapy for advanced GIST; this study was open to all comers and not restricted to any GIST subtype(s). The trials that led to the approvals of second-, third-, and fourth-line therapy for advanced GIST were also open to all patients with advanced/metastatic GIST. Only in retrospect do we realize the role that the molecular subtypes played in the results observed in these studies. In this review, we discuss the studies that led to the US Food and Drug Administration approval of imatinib (first line), sunitinib (second line), regorafenib (third line), and ripretinib (fourth line) for advanced KIT-mutant GIST. In addition, we review how information about GIST molecular subtypes has been used to accelerate the approval of other targeted therapies for non-KIT mutant GIST, leading to the approval of five additional drugs indicated for the treatment of specific GIST molecular subtypes. We also discuss how our understanding of the molecular subtypes will play a role in the next generation of therapeutic approaches for treating advanced GIST.
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Affiliation(s)
- Homma M Khosroyani
- Portland VA Health Care System and Knight Cancer Institute, Oregon Health & Science University, R&D-19, 3710 SW US Veterans Hospital Road, Portland, OR, 97239, USA
| | - Lillian R Klug
- Portland VA Health Care System and Knight Cancer Institute, Oregon Health & Science University, R&D-19, 3710 SW US Veterans Hospital Road, Portland, OR, 97239, USA
| | - Michael C Heinrich
- Portland VA Health Care System and Knight Cancer Institute, Oregon Health & Science University, R&D-19, 3710 SW US Veterans Hospital Road, Portland, OR, 97239, USA.
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Metastatic SDH-Deficient GIST Diagnosed during Pregnancy: Approach to a Complex Case. Curr Oncol 2022; 29:5933-5941. [PMID: 36005206 PMCID: PMC9406627 DOI: 10.3390/curroncol29080468] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/02/2022] [Accepted: 08/17/2022] [Indexed: 02/07/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) account for 1% of GI neoplasms in adults, and epidemiological data suggest an even lower occurrence in pregnant women. The majority of GISTs are caused by KIT and PDGFRA mutations. This is not the case in women of childbearing age. Some GISTs do not have a KIT/PDGFRA mutation and are classified as wild-type (WT) GISTs. WT-GIST includes many molecular subtypes including SDH deficiencies. In this paper, we present the first case report of a metastatic SDH-deficient GIST in a 23-year-old pregnant patient and the challenges encountered given her concurrent pregnancy. Our patient underwent a surgical tumor resection of her gastric GIST as well as a lymphadenectomy a week after induction of labor at 37 + 1 weeks. She received imatinib, sunitinib as well as regorafenib afterward. These drugs were discontinued because of disease progression despite treatment or after side effects were reported. Hence, she is currently under treatment with ripretinib. Her last FDG-PET showed a stable disease. This case highlights the complexity of GI malignancy care during pregnancy, and the presentation and management particularities of metastatic WT-GISTs. This case also emphasizes the need for a multidisciplinary approach and better clinical guidelines for offering optimal management to women in this specific context.
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10
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Klug LR, Khosroyani HM, Kent JD, Heinrich MC. New treatment strategies for advanced-stage gastrointestinal stromal tumours. Nat Rev Clin Oncol 2022; 19:328-341. [PMID: 35217782 PMCID: PMC11488293 DOI: 10.1038/s41571-022-00606-4] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/08/2022] [Indexed: 02/06/2023]
Abstract
When gastrointestinal stromal tumour (GIST), the most common form of sarcoma, was first recognized as a distinct pathological entity in the 1990s, patients with advanced-stage disease had a very poor prognosis owing to a lack of effective medical therapies. The discovery of KIT mutations as the first and most prevalent drivers of GIST and the subsequent development of the first KIT tyrosine kinase inhibitor (TKI), imatinib, revolutionized the treatment of patients with this disease. We can now identify the driver mutation in 99% of patients with GIST via molecular diagnostic testing, and therapies have been developed to treat many, but not all, molecular subtypes of the disease. At present, seven drugs are approved by the FDA for the treatment of advanced-stage GIST (imatinib, sunitinib, regorafenib, ripretinib, avapritinib, larotrectinib and entrectinib), all of which are TKIs. Although these agents can be very effective for treating certain GIST subtypes, challenges remain and new therapeutic approaches are needed. In this Review, we discuss the molecular subtypes of GIST and the evolution of current treatments, as well as their therapeutic limitations. We also highlight emerging therapeutic approaches that might overcome clinical challenges through novel strategies predicated on the biological features of the distinct GIST molecular subtypes.
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Affiliation(s)
- Lillian R Klug
- Portland VA Health Care System and Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Homma M Khosroyani
- Portland VA Health Care System and Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Jason D Kent
- Portland VA Health Care System and Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Michael C Heinrich
- Portland VA Health Care System and Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
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Abstract
Dysregulation of DNA damage response and repair (DDR) contributes to oncogenesis, yet also generates the potential for targeted cancer therapies by exploiting synthetic lethal interactions. Oncometabolites, small intermediates of metabolism overproduced in certain cancers, have emerged as a new mechanism of DDR modulation through their effects on multiple DNA repair pathways. Increasing evidence suggests that oncometabolite-induced DDR defects may offer the opportunity for tumor-selective chemo- and radio-sensitization. Here we review the biology of oncometabolites and diverse mechanisms by which they impact DDR, with a focus on emerging therapeutic strategies and ongoing clinical trials targeting oncometabolite-induced DDR defects in cancer.
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Affiliation(s)
- Susan E Gueble
- Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT
| | - Ranjit S Bindra
- Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT.
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12
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De Silva M, Rastogi S, Chan D, Angel C, Prall O, Gill A, Guminski A. Succinate dehydrogenase-deficient gastrointestinal stromal tumor: from diagnostic dilemma to novel personalised therapy in 2 case reports. Transl Cancer Res 2021; 10:3588-3599. [PMID: 35116662 PMCID: PMC8797494 DOI: 10.21037/tcr-21-131] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 05/06/2021] [Indexed: 12/29/2022]
Abstract
Succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor (GIST) is a unique and distinctive subtype of gastric GIST. The literature on this subtype from developing countries is exceedingly sparse. Patients with SDH-deficient GIST often experience a lack or delay in genomic profiling, despite stereotypical clinicopathologic features, potentially resulting in sub-optimal management. SDH-deficient GISTs are highly syndromic, typically have more indolent behavior, a prognosis not predicted by size and mitotic rate, a tendency to lymph node metastases, and are insensitive to standard tyrosine kinase inhibitors (TKIs). We report two women with SDH-deficient GIST. In the first case, SDH deficiency was identified late due to lack of awareness and poor access to diagnostic facilities. The patient progressed through TKI therapy, but responded to temozolomide, which is under investigation in clinical trials. In the second case, SDH deficiency was identified at diagnosis, and the patient responded well to 177Lutetium peptide radionuclide receptor therapy (PRRT) after progressing through two lines of TKIs. We aim to highlight the need for more awareness and access to genomic diagnostic facilities for GIST patients, temozolomide as a novel therapy for SDH-deficient GIST, and the potential value of DOTATATE positron emission tomography (PET) and PRRT as a novel imaging modality and therapy for TKI insensitive GIST patients.
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Affiliation(s)
- Madhawa De Silva
- Department of Medical Oncology, Royal North Shore Hospital, Sydney, New South Wales, Australia
| | - Sameer Rastogi
- Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
| | - David Chan
- Department of Medical Oncology, Royal North Shore Hospital, Sydney, New South Wales, Australia
| | - Christopher Angel
- Department of Anatomical Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Owen Prall
- Department of Anatomical Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Anthony Gill
- Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, New South Wales, Australia
| | - Alexander Guminski
- Department of Medical Oncology, Royal North Shore Hospital, Sydney, New South Wales, Australia
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13
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Rosa F, Ricci R, Galiandro F, Cina C, Menghi R, Quero G, Fiorillo C, Longo F, Tortorelli AP, Alfieri S. Laparoscopic vs Open Resection of Gastrointestinal Stromal Tumors (GISTs) from Gastric Origin: different approaches for different diseases. Minerva Surg 2021; 76:372-381. [PMID: 34047528 DOI: 10.23736/s2724-5691.21.08574-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND Although minimally invasive techniques are currently recognized as effective and validated treatment for small gastric gastrointestinal stromal tumors (GISTs), the role of laparoscopy is not yet established. The aim of this study was to evaluate the outcomes of laparoscopic treatment of gastric GISTs compared to the results obtained in a group of patients treated with conventional surgery. METHODS A retrospective analysis was performed, using a prospectively maintained comprehensive database of 100 patients treated for gastric GIST in the period from 2000 to 2015. Thirty-six patients were treated laparoscopically and 64 patients underwent conventional surgery. The analyzed medical data included clinical and pathological features of removed tumors, perioperative parameters as well as short and long-term results of surgical treatment. RESULTS Histopathological examination confirmed radical resection for all patients. No deaths were reported in the 90-day post-operative period. Patients in laparoscopic group had significantly shorter length of hospital stay (5.5 vs. 7 days, p<0.0001), fewer extended and combined surgical procedures (11.2% vs 34.4% and 2.8% vs 39%; p=0.02 and p<0.001, respectively), and a smaller tumor size compared to laparotomic group (3 vs 6 cm, p<0.0001). The median post-operative follow-up for the entire study population was 42 months. During this period, 11 patients died and 4 of them developed a tumor recurrence. None of them was in the laparoscopic group. CONCLUSIONS Laparoscopy in the treatment of gastric GISTs has unquestionable advantages, but its choice is strictly related to tumor features.
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Affiliation(s)
- Fausto Rosa
- Department of Digestive Surgery, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy - .,Università Cattolica del Sacro Cuore, Rome, Italy -
| | - Riccardo Ricci
- Università Cattolica del Sacro Cuore, Rome, Italy.,Department of Pathology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Federica Galiandro
- Department of Digestive Surgery, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Caterina Cina
- Department of Digestive Surgery, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Roberta Menghi
- Department of Digestive Surgery, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Giuseppe Quero
- Department of Digestive Surgery, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Claudio Fiorillo
- Department of Digestive Surgery, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Fabio Longo
- Department of Digestive Surgery, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Antonio P Tortorelli
- Department of Digestive Surgery, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Sergio Alfieri
- Department of Digestive Surgery, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.,Università Cattolica del Sacro Cuore, Rome, Italy
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14
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Lou L, Zhang W, Li J, Wang Y. Abnormal MGMT Promoter Methylation in Gastrointestinal Stromal Tumors: Genetic Susceptibility and Association with Clinical Outcome. Cancer Manag Res 2020; 12:9941-9952. [PMID: 33116851 PMCID: PMC7568426 DOI: 10.2147/cmar.s269388] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 09/25/2020] [Indexed: 01/22/2023] Open
Abstract
Purpose KIT/PDGFRA wild-type (WT) gastrointestinal stromal tumors (GISTs) represent a heterogeneous subgroup of GISTs that lack KIT or PDGFRA mutations and possess distinct genetic alterations and primary resistance to imatinib. Succinate dehydrogenase (SDH)-deficient GISTs comprise the largest subpopulation of WT GISTs that are characterized by loss-of-function of SDH. O6-methylguanine-DNA methyltransferase (MGMT) is a specific DNA repair enzyme that has been identified as a predictor of positive treatment response to alkylating agents in a variety of cancers. The aim of this study was to evaluate the expression of MGMT and the prevalence of MGMT promoter methylation in GISTs and to determine the association between MGMT promoter methylation and clinicopathological characteristics and clinical outcomes. Patients and Methods A heterogeneous cohort of 137 primary GISTs that confirmed by immunohistochemistry and KIT/PDGFRA mutation analysis were retrospectively selected and analyzed for MGMT expression and MGMT promoter methylation using immunohistochemical staining and methylation-specific PCR (MSP). A concordance analysis between MGMT promoter methylation and clinicopathological characteristics and prognosis was also performed. Results A total of 44.5% (65/137) of GIST patients displayed loss of MGMT protein expression, and 10.9% (15/137) of these patients exhibited MGMT promoter methylation. However, no significant correlation was observed between the loss of MGMT protein expression and MGMT promoter methylation. WT GISTs possessing an epithelioid or mixed phenotype, particularly those that were SDH-deficient, displayed a markedly higher prevalence of MGMT promoter methylation compared to that in KIT/PDGFRA mutated GISTs. Moreover, MGMT promoter methylation was identified as a potential independent prognostic factor for OS and DFS in patients with GIST. Conclusion MGMT promoter methylation is particularly frequent in SDH-deficient GISTs and in WT GISTs possessing an epithelioid/mixed phenotype, and knowledge of this methylation status may offer a novel potential therapeutic option for WT GISTs.
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Affiliation(s)
- Liping Lou
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Wendi Zhang
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Jun Li
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Yu Wang
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
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15
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Genomic Study of Chinese Quadruple-negative GISTs Using Next-generation Sequencing Technology. Appl Immunohistochem Mol Morphol 2020; 29:34-41. [PMID: 33002893 DOI: 10.1097/pai.0000000000000842] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
PURPOSE Approximately 10% of gastrointestinal stromal tumors (GISTs) are devoid of KIT, PDGFRA (platelet-derived growth factor-alpha), BRAF, and SDH alterations. The aim of this study was to characterize molecular drivers in Chinese patients with quadruple-negative GISTs. PATIENTS AND METHODS In 1022 Chinese patients with GIST, mutations of KIT and PDGFRA were analyzed by direct sequencing. Of these mutations, 142 KIT/PDGFRA wild-type (WT) GISTs were detected, and succinate dehydrogenase (SDH) deficiency was determined using immunohistochemistry analysis of succinate dehydrogenase B. In 78 KIT/PDGFRA/SDH cases, we performed targeted 425 cancer-related gene analysis using next-generation sequencing. The correlation between molecular findings and clinicopathologic features was also analyzed. RESULTS We defined 72 quadruple-negative GISTs from enrollments. They featured nongastric localization with histologic characteristics of spindle cells and male predilection. An overall 27.78% (20/72) of quadruple-negative tumors carried TP53, and 25.00% (18/72) carried RB1 mutations, which were frequently associated with high mitotic index and large size. TP53 analyses demonstrated coexistence with mutational activation of other oncogenes in 12 of 20 cases. A total of 18 RB1-mutated cases were independent of TP53. Further, no tumors carried NF1 and BRAF mutations. CONCLUSIONS We report the genomic analysis of Chinese quadruple-negative patients. These databases may help advance our understanding of quadruple-negative GISTs' progression. Next-generation sequencing from GISTs is feasible to provide relevant data for guiding individualized therapy.
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16
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Zhao Y, Feng F, Guo QH, Wang YP, Zhao R. Role of succinate dehydrogenase deficiency and oncometabolites in gastrointestinal stromal tumors. World J Gastroenterol 2020; 26:5074-5089. [PMID: 32982110 PMCID: PMC7495036 DOI: 10.3748/wjg.v26.i34.5074] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 06/14/2020] [Accepted: 08/21/2020] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. At the molecular level, GISTs can be categorized into two groups based on the causative oncogenic mutations. Approximately 85% of GISTs are caused by gain-of-function mutations in the tyrosine kinase receptor KIT or platelet-derived growth factor receptor alpha (PDGFRA). The remaining GISTs, referred to as wild-type (WT) GISTs, are often deficient in succinate dehydrogenase complex (SDH), a key metabolic enzyme complex in the tricarboxylic acid (TCA) cycle and electron transport chain. SDH deficiency leads to the accumulation of succinate, a metabolite produced by the TCA cycle. Succinate inhibits α-ketoglutarate-dependent dioxygenase family enzymes, which comprise approximately 60 members and regulate key aspects of tumorigenesis such as DNA and histone demethylation, hypoxia responses, and m6A mRNA modification. For this reason, succinate and metabolites with similar structures, such as D-2-hydroxyglutarate and fumarate, are considered oncometabolites. In this article, we review recent advances in the understanding of how metabolic enzyme mutations and oncometabolites drive human cancer with an emphasis on SDH mutations and succinate in WT GISTs.
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Affiliation(s)
- Yue Zhao
- Department of Gastroenterology, the First Hospital of Lanzhou University, Key Laboratory for Gastrointestinal Disease of Gansu Province, Lanzhou 730000, Gansu Province, China
| | - Fei Feng
- Department of Ultrasound, the First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Qing-Hong Guo
- Department of Gastroenterology, the First Hospital of Lanzhou University, Key Laboratory for Gastrointestinal Disease of Gansu Province, Lanzhou 730000, Gansu Province, China
| | - Yu-Ping Wang
- Department of Gastroenterology, the First Hospital of Lanzhou University, Key Laboratory for Gastrointestinal Disease of Gansu Province, Lanzhou 730000, Gansu Province, China
| | - Rui Zhao
- Department of Biochemistry and Molecular Genetics, School of Medicine, the University of Alabama at Birmingham, Birmingham, AL 35294, United States
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17
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Chen HW, Chen TWW. Genomic-guided precision therapy for soft tissue sarcoma. ESMO Open 2020; 5:e000626. [PMID: 32132106 PMCID: PMC7059546 DOI: 10.1136/esmoopen-2019-000626] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 01/28/2020] [Accepted: 01/29/2020] [Indexed: 12/27/2022] Open
Abstract
Soft tissue sarcoma (STS), although heterogeneous in histopathology presentation, has mostly been treated with chemotherapy agents as one entity. Our understanding of crucial genomic alterations in different STS histologies and the advent of molecular-targeted agents have reshaped the treatment paradigm for advanced STS. Small-molecule inhibitors of c-KIT, plate-derived growth factor receptor alpha, c-MET, BRAF, anaplastic lymphoma kinase, ROS1 and colony-stimulating factor-1 receptor have been successfully validated in clinical studies to yield practice-changing results. Inhibitors of other novel genomic targets including mouse double minute 2 homolog, cyclin-dependent kinase 4/6, mitogen-activated protein kinase and epigenetic regulators are expected to be developed in the near future. Furthermore, with the advancement and accessibility of molecular diagnosis and next-generation sequencing, a genomic-based therapeutic approach should be widely applicable to advanced STS patients. This review will focus on the progress of genomic-guided therapy tailored to each molecular alteration of different STS histologies.
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Affiliation(s)
- Hsing-Wu Chen
- Department of Oncology, National Taiwan University Hospital Yunlin Branch, Douliou, Yunlin, Taiwan
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - Tom Wei-Wu Chen
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
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18
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Djerouni M, Dumont SN. [Wild-type gastroinestinal stromal tumors]. Bull Cancer 2020; 107:499-505. [PMID: 32063345 DOI: 10.1016/j.bulcan.2019.12.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 11/29/2019] [Accepted: 12/05/2019] [Indexed: 02/07/2023]
Abstract
Gastrointestinal stromal tumors (GIST) are the most common non-epithelial tumors of the gastrointestinal tract. Wild-type GISTs (WT-GIST) consist of a rare heterogeneous group characterized by the lack of activating mutations in the tyrosine kinase receptor (Kit) and/or platelet derived growth factor receptor A (PDGFRA). However, WT-GIST is characterized by other genomic alterations, including dehydrogenase succinate (SDH) deficiency or mutations in the Ras pathway. Recent studies have reported many mutations in others genes that may be incriminated in the development of WT-GISTs. Moreover, WT-GIST is frequently associated with hereditary cancer syndromes such as the Carney Triad and Type 1 Neurofibromatosis (NF1). WT-GIST affects usually young and pediatric patients. Most WT-GIST subtypes are insensitive to imatinib; therefore, their therapeutic management is somewhat different from usual GISTs. This review resumes the molecular and therapeutic features of this rare entity.
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Affiliation(s)
- Mohamed Djerouni
- Gustave-Roussy Cancer Campus, département d'oncologie médicale, 114, rue Edouard-Vaillant, 94800 Villejuif, France
| | - Sarah N Dumont
- Gustave-Roussy Cancer Campus, département d'oncologie médicale, 114, rue Edouard-Vaillant, 94800 Villejuif, France.
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19
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Ravegnini G, Ricci R. Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumors: Small Steps Toward Personalized Medicine? Epigenet Insights 2019; 12:2516865719842534. [PMID: 31020269 PMCID: PMC6463228 DOI: 10.1177/2516865719842534] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Accepted: 03/08/2019] [Indexed: 12/12/2022] Open
Abstract
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.
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Affiliation(s)
- Gloria Ravegnini
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Riccardo Ricci
- Department of Pathology, Università Cattolica del Sacro Cuore, Rome, Italy.,UOC di Anatomia Patologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
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