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Jiménez-Labaig P, Lorini L, Gurizzan C, Kinloch E, Burton S, Forster MD, Metcalf R, Ferrarotto R, Bossi P, O Leary B, Hanna G, Felip E, Garcia IB, Harrington KJ. Clinical trials for patients with salivary gland cancers: A systematic review of worldwide registers and an evaluation of current challenges. Crit Rev Oncol Hematol 2025; 211:104747. [PMID: 40294876 DOI: 10.1016/j.critrevonc.2025.104747] [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: 12/02/2024] [Revised: 04/21/2025] [Accepted: 04/25/2025] [Indexed: 04/30/2025] Open
Abstract
BACKGROUND Clinical trials (CT) are crucial for generating scientific evidence and improving clinical outcomes, but they can be challenging in the context of rare cancers. Salivary gland cancers (SGC) are rare and heterogeneous tumors, without standard-of-care approved systemic therapies. We analyzed completed and ongoing CTs to assess the current state of clinical research activity in the field. METHODS ClinicalTrials.gov, WHO-ICTRP, HealthCanadaCT were searched for antineoplastic pharmacological and interventional CT involving patients with SGC from the trials database creation until August 6th, 2024. CT characteristics and status were collected. RESULTS 134 clinical trials met inclusion criteria. Of these, 78 % were sponsored by non-industry entities. 49 % were conducted at only one site, and 61 % at up to five centers. Only 25 trials (19 %) were multinational, being 15 industry-sponsored, a significantly higher proportion compared to non-industry-sponsored trials(p < 0.01). 16 % CTs were umbrella or basket, and 6 % were randomized, again predominantly industry-sponsored(p < 0.01). Regarding SGC-specific trials, 32 % were open to all patients with SGC, regardless of specific histology. Patients with adenoid cystic, salivary duct, and mucoepidermoid carcinoma had access to 92 %, 66 % and 62 % of trials, respectively. 88 % CT targeted palliative setting, and 38 % incorporated predictive biomarkers. Tyrosine kinase inhibitors were the most studied therapy(26 %), followed by immunotherapy(15 %), chemotherapy and antibody-drug conjugate(12 % each) and androgen-blockade(8 %), among others. CONCLUSION Clinical research for patients with SGC relies mainly in non-industry organisations, most of them limited to run trials in one to five sites, in a single country. Further collaboration between investigators is needed, as well as reconsidering inclusion criteria and trial designs.
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Affiliation(s)
- Pablo Jiménez-Labaig
- Head and Neck Unit. The Royal Marsden NHS Foundation Trust, London, United Kingdom; The Institute of Cancer Research, Division of Radiotherapy and Imaging, London, United Kingdom; Universidad Autónoma de Barcelona, Barcelona, Spain.
| | - Luigi Lorini
- Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Rozzano, MI, Italy
| | - Cristina Gurizzan
- Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Rozzano, MI, Italy
| | - Emma Kinloch
- Salivary Gland Cancer UK, London, United Kingdom
| | - Sarah Burton
- Head and Neck Unit. The Royal Marsden NHS Foundation Trust, London, United Kingdom; The International Centre for Recurrent Head and Neck Cancer, United Kingdom
| | - Martin D Forster
- UCL Cancer Institute, London, United Kingdom; University College London Hospitals NHS Foundation Trust, London, United Kingdom
| | - Robert Metcalf
- Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom; The Cancer Research UK Manchester Institute, United Kingdom
| | - Renata Ferrarotto
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, United States
| | - Paolo Bossi
- Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Rozzano, MI, Italy; Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, Milan 20072, Italy
| | - Ben O Leary
- Head and Neck Unit. The Royal Marsden NHS Foundation Trust, London, United Kingdom; The Institute of Cancer Research, Division of Radiotherapy and Imaging, London, United Kingdom
| | - Glenn Hanna
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
| | - Enriqueta Felip
- Lung and Head & Neck Tumors Unit. Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain; Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Irene Braña Garcia
- Lung and Head & Neck Tumors Unit. Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain; Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Kevin J Harrington
- Head and Neck Unit. The Royal Marsden NHS Foundation Trust, London, United Kingdom; The Institute of Cancer Research, Division of Radiotherapy and Imaging, London, United Kingdom
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Zhao Z, Jing Y, Xu Z, Zhao H, He X, Lu T, Bai J, Qin W, Yang L. The mechanism of histone modifications in regulating enzalutamide sensitivity in advanced prostate cancer. Int J Biol Sci 2025; 21:2880-2890. [PMID: 40303302 PMCID: PMC12035886 DOI: 10.7150/ijbs.109638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Accepted: 03/23/2025] [Indexed: 05/02/2025] Open
Abstract
Prostate cancer (PCa) is the second most common malignant tumor in men worldwide, particularly castration-resistant prostate cancer (CRPC), for which enzalutamide (Enz) resistance is of particular concern. Modifications to histone methylation and acetylation patterns are closely associated with resistance to Enz in these patients. As PCa progresses, cancer cells alter their histone modification patterns, leading to a reduction in Enz treatment efficacy. Signaling pathways in the tumor microenvironment regulate gene expression by affecting the activity of histone-modifying enzymes, further affecting the efficacy of Enz. This review summarizes recent research about changes in histone modification patterns that occur in drug resistance-related genes at different stages of PCa and explores the potential use of combination therapies for reversing this process, providing insights into novel treatment strategies to improve the clinical efficacy of Enz.
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Affiliation(s)
- Zhite Zhao
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Yuming Jing
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Zhicheng Xu
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Hongfan Zhao
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Xinglin He
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
- The Second Clinical Medical College, Shaanxi University of Chinese Medicine, Xi'an, Shaanxi 710000, China
| | - Tong Lu
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Jianhui Bai
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
- Department of Urology, Joint Logistics Support Force, Hospital 987, Baoji, China
| | - Weijun Qin
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Lijun Yang
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
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Chae YK, Duan R, Chung LI, Oh Y, Alexiev B, Shin S, Kim S, Helenowski I, Matsangou M, Villaflor V, Mahalingam D. Phase II Study of Nivolumab and Ipilimumab for Treatment of Metastatic/Recurrent Adenoid Cystic Carcinoma (ACC) of all Anatomic Sites of Origin and Other Malignant Salivary Gland Tumors. Cancer Med 2025; 14:e70724. [PMID: 40166913 PMCID: PMC11959299 DOI: 10.1002/cam4.70724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Revised: 02/11/2025] [Accepted: 02/13/2025] [Indexed: 04/02/2025] Open
Abstract
OBJECTIVE Dual checkpoint inhibitor therapy with nivolumab and ipilimumab has been FDA approved for a number of cancer sites. However, its role in the treatment of ACC and non-ACC salivary gland carcinomas (non-ACC SGC) is not well established. METHODS AND ANALYSIS We performed Simon's two-stage prospective single-institution Phase II clinical trial of nivolumab with ipilimumab. Two cohorts were analyzed: patients with metastatic/recurrent ACC and patients with non-ACC SGC. The primary endpoint was median progression-free survival (PFS); secondary endpoints were overall response rate (ORR), overall survival (OS), and toxicity. RESULTS Patient enrollment was prematurely terminated due to funding constraints. In total, 19 patients with ACC and 5 patients with non-ACC SGC were enrolled. The patients with ACC had a median OS of 30.0 months (95% CI 15.3-NR months), a median PFS of 8.3 months (95% CI 5.5-30.0 months), and a disease control rate (DCR) of 53% (10/19). The ORR in the ACC group was 5% (CR 0%, n = 0; confirmed PR 5%, n = 1), with one patient having continued stable disease at the time of trial conclusion. The patients with non-ACC SGC had a median OS of 10.4 months (95% CI 6.21-NR months), a median PFS of 6.21 months (95% CI 2.83-NR months), and a DCR of 40% (2/5). The ORR in this cohort was 0%. CONCLUSION In patients with recurrent or metastatic ACC and non-ACC SGC, the combination of nivolumab with ipilimumab resulted in moderate disease control. Further studies are warranted to validate our findings. TRIAL NUMBER NCT03146650.
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Affiliation(s)
- Young Kwang Chae
- Department of Hematology and OncologyNorthwestern UniversityChicagoIllinoisUSA
- Feinberg School of MedicineNorthwestern UniversityChicagoIllinoisUSA
| | - Richard Duan
- Feinberg School of MedicineNorthwestern UniversityChicagoIllinoisUSA
| | | | - Youjin Oh
- Feinberg School of MedicineNorthwestern UniversityChicagoIllinoisUSA
| | - Borislav Alexiev
- Department of Surgical PathologyNorthwestern UniversityChicagoIllinoisUSA
| | | | | | - Irene Helenowski
- Feinberg School of MedicineNorthwestern UniversityChicagoIllinoisUSA
| | | | | | - Devalingam Mahalingam
- Department of Hematology and OncologyNorthwestern UniversityChicagoIllinoisUSA
- Feinberg School of MedicineNorthwestern UniversityChicagoIllinoisUSA
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Sun J, Huai J, Zhang W, Zhao T, Shi R, Wang X, Li M, Jiao X, Zhou X. Therapeutic strategies for adrenocortical carcinoma: integrating genomic insights, molecular targeting, and immunotherapy. Front Immunol 2025; 16:1545012. [PMID: 40145087 PMCID: PMC11937102 DOI: 10.3389/fimmu.2025.1545012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 02/21/2025] [Indexed: 03/28/2025] Open
Abstract
Adrenocortical carcinoma (ACC) is an uncommon and highly aggressive cancer originating in the adrenal cortex, characterized by a high likelihood of recurrence and unfavorable survival rates, particularly in the advanced disease stages. This review discusses the complex molecular pathogenesis of ACC, focusing on critical pathways implicated in the tumorigenesis and providing potential targets for therapy: the Wnt/β-catenin signaling pathway, the IGF2/IGF1R axis, and the apoptosis pathway regulated by p53. Current treatment strategies include surgical resection and mitotane, the sole adrenolytic agent approved by the FDA; however, its effects in advanced disease are suboptimal. Cytotoxic chemotherapy combined with mitotane may be applied, but survival benefits are limited so far. In the following review, we outline emerging targeted therapies, such as mTOR inhibitors and tyrosine kinase inhibitors (TKIs), which show favorable preclinical and clinical data, especially in treatment-resistant ACC. We also emphasize the possible role of immune checkpoint inhibitors (ICIs) in the management of ACC, although their effectiveness is still under study. Upcoming trends in treatment involve forms of personalized medicine, where molecular profiling is integrated to identify actionable biomarkers for administered therapies. This review will attempt to provide a comprehensive framework on how recent breakthroughs in the genomics of ACC, coupled with advances in targeted therapies and immunotherapy, can improve management.
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Affiliation(s)
- Jing Sun
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- The First School of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jiaxuan Huai
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Wenhui Zhang
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Tianyu Zhao
- Institute and Clinic for Occupational, Social and Environmental Medicine, Ludwig Maximilians University (LMU) University Hospital Munich, Munich, Germany
| | - Run Shi
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xuanbin Wang
- Laboratory of Chinese Herbal Pharmacology, Department of Pharmacology, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Minglun Li
- Department of Radiation Oncology, Lueneburg Hospital, Lueneburg, Germany
| | - Xuehua Jiao
- Department of Endocrinology, Suzhou Ninth People’s Hospital, Suzhou Ninth Hospital Affiliated to Soochow University, Suzhou, China
| | - Xiqiao Zhou
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
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Zhang L, Yang HN, Wang Y, Li D, Lei Z, Yang MQ, Liu YC, He J, Wu YZ, Sui JD. The effectiveness of targeted therapy for recurrence or metastasis adenoid cystic carcinoma: a systematic review and meta-analysis. Ann Med 2024; 56:2399867. [PMID: 39258959 PMCID: PMC11391875 DOI: 10.1080/07853890.2024.2399867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Revised: 05/07/2024] [Accepted: 08/07/2024] [Indexed: 09/12/2024] Open
Abstract
BACKGROUND AND PURPOSE Several clinical studies have demonstrated the potential of molecular-targeted agents for the treatment of recurrent or metastatic adenoid cystic carcinoma (R/M ACC). However, there is currently no consensus regarding the efficacy of molecular-targeted agents for patients with R/M ACC. This study aimed to evaluate the therapeutic efficacy and safety of molecular-targeted agents in patients with R/M ACC and provide insights to guide clinical decision-making. MATERIALS AND METHODS Five databases (PubMed, Embase, Cochrane, ProQuest, and Scopus) were searched based on the search strategy and selection criteria. Primary endpoints were objective response rate (ORR) and progression-free survival (PFS). The secondary endpoints were disease control rate (DCR), overall survival (OS), metastatic sites, and adverse events (AE). Pooled estimates were calculated using a random-effects meta-analysis. RESULTS Finally, 28 studies, involving 849 patients, were included. The most common metastatic sites were the lungs, bones, liver, lymph nodes, and kidneys. The pooled ORR was 4.0% (95% CI, 0.7-8.8%), the pooled DCR was 80.5% (95% CI, 72.2%-87.7%). Compared with other-target drugs, multiple kinase inhibitors (MKIs) improved the ORR (pooled ORR for single-target drugs vs. MKIs: 5.9% vs. 0%). The combination of MKIs and immune checkpoint inhibitors (ICIs) had a significantly higher ORR (17.9% in the axitinib + avelumab group). The pooled median PFS and OS were 8.35 and 25.62 months, respectively. MKIs improved the median PFS compared to other-target drugs (9.43 months vs 5.06 months). In addition, the most common adverse events (AEs) were fatigue (51.6%), hypertension (44.2%), and nausea (40.0%), followed by hand-foot skin syndrome (36.8%), diarrhoea (34.4%), weight loss (34.2%), anorexia (31.8%), rash (31.7%), and headache (29.0%). CONCLUSION The findings of this study suggest that MKIs have a better therapeutic efficacy than single-target drugs in patients with R/M ACC. Future studies are warranted to verify the synergistic role of the combination strategy of MKIs plus ICIs, given the limited number of studies on this topic conducted and published to date.
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Affiliation(s)
- Lu Zhang
- College of Medicine, Chongqing University, Chongqing, China
- Radiation Oncology Center, Chongqing University Cancer Hospital, Chongqing, China
| | - Hao-Nan Yang
- College of Medicine, Chongqing University, Chongqing, China
- Radiation Oncology Center, Chongqing University Cancer Hospital, Chongqing, China
- College of Bioengineering, Chongqing University, Chongqing, China
| | - Ying Wang
- College of Medicine, Chongqing University, Chongqing, China
- Radiation Oncology Center, Chongqing University Cancer Hospital, Chongqing, China
| | - Dan Li
- Radiation Oncology Center, Chongqing University Cancer Hospital, Chongqing, China
| | - Zheng Lei
- College of Medicine, Chongqing University, Chongqing, China
- Radiation Oncology Center, Chongqing University Cancer Hospital, Chongqing, China
| | - Meng-Qi Yang
- Radiation Oncology Center, Chongqing University Cancer Hospital, Chongqing, China
| | - Yun-Chang Liu
- College of Medicine, Chongqing University, Chongqing, China
- Radiation Oncology Center, Chongqing University Cancer Hospital, Chongqing, China
- College of Bioengineering, Chongqing University, Chongqing, China
| | - Jiang He
- Radiation Oncology Center, Chongqing University Cancer Hospital, Chongqing, China
- College of Bioengineering, Chongqing University, Chongqing, China
| | - Yong-Zhong Wu
- College of Medicine, Chongqing University, Chongqing, China
- Radiation Oncology Center, Chongqing University Cancer Hospital, Chongqing, China
| | - Jiang-Dong Sui
- College of Medicine, Chongqing University, Chongqing, China
- Radiation Oncology Center, Chongqing University Cancer Hospital, Chongqing, China
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Bin Sumaida A, Shanbhag NM, AlKaabi K, Hasnain SM, Balaraj K. Outcomes in Adenoid Cystic Carcinoma: A 14-Year Analysis. Cureus 2024; 16:e75222. [PMID: 39759714 PMCID: PMC11700538 DOI: 10.7759/cureus.75222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Accepted: 12/06/2024] [Indexed: 01/07/2025] Open
Abstract
Background Adenoid cystic carcinoma (ACC) is a rare malignancy characterized by slow progression, local recurrence, and distant metastases. This study aims to evaluate the demographic patterns, clinical presentations, outcomes, and survival trends of patients with ACC. Methods A retrospective analysis of 14 patients diagnosed with ACC from 2010 to 2024 at a tertiary cancer center in the United Arab Emirates was conducted. Data on demographics, presenting symptoms, clinical outcomes, tumor characteristics, recurrence patterns, and survival were analyzed. Kaplan-Meier survival analysis was performed to evaluate survival trends. Results The cohort was predominantly male (64.3%, n=9) with a mean age of 38.9 years. An enlarging mass in the neck (50%, n=7) was the most common presenting symptom. Local recurrence and distant metastases were observed in 42.9% (n=6) of patients each, with the lungs being the most frequent site of metastases (83.3%, n=5). Advanced-stage disease (Stage III/IV) was common (64.3%, n=9). Overall survival was 85.7% (n=12) over a mean follow-up of 4.3 years. Smoking was associated with poorer survival trends, though not statistically significant (HR=7.0, p=0.083). Conclusion ACC predominantly affects middle-aged individuals and is associated with high rates of local recurrence and distant metastases, especially to the lungs. Although survival trends varied by gender, smoking, and metastases, these differences were not statistically significant, underscoring the need for larger studies to better elucidate prognostic factors.
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Affiliation(s)
| | - Nandan M Shanbhag
- Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, ARE
- Radiation Oncology: Palliative Care, Tawam Hospital, Al Ain, ARE
| | - Khalifa AlKaabi
- Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, ARE
- Radiation Oncology, Tawam Hospital, Al Ain, ARE
| | | | - Khalid Balaraj
- Oncology: Radiation Oncology, Tawam Hospital, Al Ain, ARE
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Zhou J, Zhao G, Wang S, Li N. Systemic therapy in the management of metastatic or locally recurrent adenoid cystic carcinoma of the salivary glands: a systematic review of the last decade. Br J Cancer 2024; 131:1021-1031. [PMID: 39097677 PMCID: PMC11405853 DOI: 10.1038/s41416-024-02795-4] [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: 12/18/2023] [Revised: 07/04/2024] [Accepted: 07/08/2024] [Indexed: 08/05/2024] Open
Abstract
IMPORTANCE Recurrent/metastatic adenoid cystic carcinoma (R/M AdCC) presents a clinical challenge with limited treatment options, particularly in the face of unsatisfactory efficacy from current therapeutic approaches. This review underscores the unmet clinical needs in managing R/M AdCC, emphasising the imperative for novel therapeutic strategies to address this critical gap. OBJECTIVE The primary objective of this review is to comprehensively analyse and assess trials investigating therapeutic approaches for R/M AdCC. Emphasis is placed on endpoints such as tumour response rates and progression-free survival. The specific interventions, populations, and outcomes examined in these trials will be detailed to provide a focused and informative systematic review. EVIDENCE REVIEW The systematic search spanned databases, including PubMed, EMBASE, and the Cochrane database of systematic reviews. Employing terms like "Carcinoma, Adenoid Cystic" and "trial," the search focused on English full-text articles from April 1, 2010, to August 9, 2023. Inclusion criteria encompassed studies with patients having R/M AdCC, involving drug interventions. Study quality was assessed using the Newcastle-Ottawa Scale for retrospective studies, Cochrane ROBINS-I tool for non-randomised trials, and the ROB-2 tool for randomised controlled trials. FINDINGS A total of 46 trials involving 1244 patients are included in this review, encompassing a variety of therapeutic approaches for R/M AdCC. Targeted therapies, particularly Apatinib at 500 mg, exhibit efficacy with a 47.1% objective response rate (ORR). Conversely, immunotherapeutic agents demonstrate suboptimal performance, with an overall ORR ranging from 0 to 18%. While Apatinib shows promise, the review underscores the imperative for a thorough exploration of drugs targeting unique mechanisms in the immunologically cold nature of R/M AdCC. CONCLUSIONS AND RELEVANCE Substantial progress in systemic therapy for R/M AdCC is evident, driven by early-phase clinical trials, particularly with promising outcomes in VEGF-2 inhibitors. However, challenges persist, notably in immunotherapy due to the cancer's immunologically cold nature. Ongoing research, prioritising early-stage trials, is crucial, emphasising exploration of emerging therapies like cell therapy and antibody-drug conjugates. Transitioning to Phase III trials is essential for more precise therapeutic insights. Collaborative efforts and a focus on personalised precision medicine are vital for overcoming challenges and advancing our understanding of treatment efficacy in this rare cancer.
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Affiliation(s)
- Jiawei Zhou
- Clinical Cancer Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Guo Zhao
- Clinical Cancer Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shuhang Wang
- Clinical Cancer Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Ning Li
- Clinical Cancer Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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Piórek A, Płużański A, Knetki-Wróblewska M, Winiarczyk K, Tabor S, Kowalski DM, Krzakowski M. Tracheal Tumors: Clinical Practice Guidelines for Palliative Treatment and Follow-Up. Oncol Rev 2024; 18:1451247. [PMID: 39360235 PMCID: PMC11445028 DOI: 10.3389/or.2024.1451247] [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: 06/18/2024] [Accepted: 08/23/2024] [Indexed: 10/04/2024] Open
Abstract
A substantial portion of patients with advanced cancer cannot be cured, regardless of the therapeutic methods employed. Hence, rational palliative causal treatment becomes crucial. Representative studies specifically addressing the exclusive palliative treatment of patients diagnosed with tracheal cancers have not been identified. In most studies, patients treated palliatively constituted a subset of the overall evaluated group. A thorough literature review was conducted, focusing on three types of palliative treatment: palliative radiotherapy, palliative surgical procedures, and systemic treatment for advanced disease. This review uniquely fills a significant gap in the existing literature by providing the first comprehensive and updated clinical practice guidelines specifically focused on the palliative treatment of tracheal tumors. The proposed guidelines emphasize the unique clinical challenges and treatment strategies pertinent to palliative care in tracheal tumors, which are not adequately covered in existing guidelines for other thoracic malignancies.
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Affiliation(s)
- Aleksandra Piórek
- Department of Lung Cancer and Thoracic Tumors, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Adam Płużański
- Department of Lung Cancer and Thoracic Tumors, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Magdalena Knetki-Wróblewska
- Department of Lung Cancer and Thoracic Tumors, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Kinga Winiarczyk
- Department of Lung Cancer and Thoracic Tumors, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Sylwia Tabor
- Department of Lung Cancer and Thoracic Tumors, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Dariusz M Kowalski
- Department of Lung Cancer and Thoracic Tumors, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Maciej Krzakowski
- Department of Lung Cancer and Thoracic Tumors, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
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Biersack B, Höpfner M. Emerging role of MYB transcription factors in cancer drug resistance. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2024; 7:15. [PMID: 38835346 PMCID: PMC11149108 DOI: 10.20517/cdr.2023.158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 03/19/2024] [Accepted: 04/04/2024] [Indexed: 06/06/2024]
Abstract
Decades ago, the viral myeloblastosis oncogene v-myb was identified as a gene responsible for the development of avian leukemia. However, the relevance of MYB proteins for human cancer diseases, in particular for solid tumors, remained basically unrecognized for a very long time. The human family of MYB transcription factors comprises MYB (c-MYB), MYBL2 (b-MYB), and MYBL1 (a-MYB), which are overexpressed in several cancers and are associated with cancer progression and resistance to anticancer drugs. In addition to overexpression, the presence of activated MYB-fusion proteins as tumor drivers was described in certain cancers. The identification of anticancer drug resistance mediated by MYB proteins and their underlying mechanisms are of great importance in understanding failures of current therapies and establishing new and more efficient therapy regimens. In addition, new drug candidates targeting MYB transcription factor activity and signaling have emerged as a promising class of potential anticancer therapeutics that could tackle MYB-dependent drug-resistant cancers in a more selective way. This review describes the correlation of MYB transcription factors with the formation and persistence of cancer resistance to various approved and investigational anticancer drugs.
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Affiliation(s)
- Bernhard Biersack
- Organic Chemistry Laboratory, University of Bayreuth, Bayreuth 95440, Germany
| | - Michael Höpfner
- Institute for Physiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin 10117, Germany
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Horio Y, Kuroda H, Masago K, Matsushita H, Sasaki E, Fujiwara Y. Current diagnosis and treatment of salivary gland-type tumors of the lung. Jpn J Clin Oncol 2024; 54:229-247. [PMID: 38018262 DOI: 10.1093/jjco/hyad160] [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] [Received: 09/13/2023] [Accepted: 11/02/2023] [Indexed: 11/30/2023] Open
Abstract
Salivary gland-type tumors of the lung are thought to originate from the submucosal exocrine glands of the large airways. Due to their rare occurrence, reports of their study are limited to small-scale or case reports. Therefore, daily clinical practices often require a search for previous reports. In the last 20 years, several genetic rearrangements have been identified, such as MYB::NF1B rearrangements in adenoid cystic carcinoma, CRTC1::MAML2 rearrangements in mucoepidermoid carcinoma, EWSR1::ATF1 rearrangements in hyalinizing clear cell carcinoma and rearrangements of the EWSR1 locus or FUS (TLS) locus in myoepithelioma and myoepithelial carcinoma. These molecular alterations have been useful in diagnosing these tumors, although they have not yet been linked to molecularly targeted therapies. The morphologic, immunophenotypic, and molecular characteristics of these tumors are similar to those of their counterparts of extrapulmonary origin, so clinical and radiologic differential diagnosis is required to distinguish between primary and metastatic disease of other primary sites. However, these molecular alterations can be useful in differentiating them from other primary lung cancer histologic types. The management of these tumors requires broad knowledge of the latest diagnostics, surgery, radiotherapy, bronchoscopic interventions, chemotherapy, immunotherapy as well as therapeutic agents in development, including molecularly targeted agents. This review provides a comprehensive overview of the current diagnosis and treatment of pulmonary salivary gland tumors, with a focus on adenoid cystic carcinoma and mucoepidermoid carcinoma, which are the two most common subtypes.
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Affiliation(s)
- Yoshitsugu Horio
- Department of Outpatient Services, Aichi Cancer Center Hospital, Nagoya, Japan
- Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Hiroaki Kuroda
- Department of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya, Japan
- Department of Thoracic Surgery, Teikyo University Hospital, Mizonokuchi, Kanagawa-prefecture, Japan
| | - Katsuhiro Masago
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Hirokazu Matsushita
- Division of Translational Oncoimmunology, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Eiichi Sasaki
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Yutaka Fujiwara
- Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
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11
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Silva LC, Pérez-de-Oliveira ME, Pedroso CM, Leite AA, Santos-Silva AR, Lopes MA, Junior GD, Martins MD, Wagner VP, Kowalski LP, Squarize CH, Castilho RM, Vargas PA. Systemic therapies for salivary gland carcinomas: an overview of published clinical trials. Med Oral Patol Oral Cir Bucal 2024; 29:e280-e287. [PMID: 38150606 PMCID: PMC10945875 DOI: 10.4317/medoral.26264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 11/20/2023] [Indexed: 12/29/2023] Open
Abstract
BACKGROUND There is no consensus about effective systemic therapy for salivary gland carcinomas (sgcs). Our aim was summarized the clinical trials assessing the systemic therapies (ST) on sgcs. MATERIAL AND METHODS Electronic searches were carried out through MEDLINE/pubmed, EMBASE, Scopus, Web of Science, and the Cochrane Library databases, and gray literature. RESULTS Seventeen different drugs were evaluated, and the most frequent histological subtype was adenoid cystic carcinoma (n=195, 45.5%). Stable disease, observed in 11 ST, achieved the highest rate in adenoid cystic carcinoma treated with sunitinib. The highest complete (11.1%) and partial response (30.5%) rates were seen in androgen receptor-positive tumors treated with leuprorelin acetate. CONCLUSIONS Despite all the advances in this field, there is yet no effective evidence-based regimen of ST, with all the clinical trials identified showing low rates of complete and partial responses. Further, translational studies are urgently required to characterize molecular targets and effective ST.
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Affiliation(s)
- L-C Silva
- Department of Oral Diagnosis Piracicaba Dental School, University of Campinas Av Limeira, 901, Postal code:13414-016, Piracicaba, São Paulo, Brasil
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12
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Ferrarotto R, Swiecicki PL, Zandberg DP, Baiocchi RA, Wesolowski R, Rodriguez CP, McKean M, Kang H, Monga V, Nath R, Palmisiano N, Babbar N, Sun W, Hanna GJ. PRT543, a protein arginine methyltransferase 5 inhibitor, in patients with advanced adenoid cystic carcinoma: An open-label, phase I dose-expansion study. Oral Oncol 2024; 149:106634. [PMID: 38118249 DOI: 10.1016/j.oraloncology.2023.106634] [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] [Received: 07/31/2023] [Revised: 11/02/2023] [Accepted: 11/15/2023] [Indexed: 12/22/2023]
Abstract
OBJECTIVES Currently, no systemic treatments are approved for patients with recurrent and/or metastatic (R/M) adenoid cystic carcinoma (ACC). PRT543, a protein arginine methyltransferase 5 inhibitor that downregulates NOTCH1 and MYB signalling in tumours, is a potential candidate for R/M ACC treatment. We report the safety, tolerability and preliminary efficacy of PRT543 in a dose-expansion cohort of patients with R/M ACC. MATERIALS AND METHODS This phase I multicentre, open-label, sequential-cohort, dose-escalation and dose-expansion study (NCT03886831) enrolled patients with advanced solid tumours and select haematologic malignancies. Dose-escalation study design and results were reported previously. In the dose expansion, patients with R/M ACC received recommended phase II doses of 35 or 45 mg PRT543 orally on days 1-5 of each week. Primary objectives were to establish the safety and tolerability of PRT543. Secondary objectives included efficacy. RESULTS Between February 2019 and May 2022, 56 patients with ACC were enrolled across 23 US sites and received either 35 mg (n = 28) or 45 mg (n = 28) of PRT543. Overall, 23% of patients experienced a grade 3 treatment-related adverse event, most commonly anaemia (16%) and thrombocytopaenia (9%). No grade 4/5 treatment-emergent adverse events were reported. Median progression-free survival was 5.9 months (95% CI: 3.8-8.3). The clinical benefit rate was 57% (95% CI: 43-70). Overall response rate (per Response Evaluation Criteria in Solid Tumours v1.1) was 2%, with 70% of patients having stable disease. CONCLUSION In this analysis, PRT543 was tolerable, and the observed efficacy was limited in patients with R/M ACC.
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Affiliation(s)
- Renata Ferrarotto
- Department of Thoracic/Head and Neck Medical, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
| | - Paul L Swiecicki
- Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA
| | - Dan P Zandberg
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Robert A Baiocchi
- Department of Medicine, Division of Hematology, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Robert Wesolowski
- Department of Medicine, Division of Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | | | - Meredith McKean
- Sarah Cannon Research Institute, Tennessee Oncology, Nashville, TN, USA
| | - Hyunseok Kang
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Varun Monga
- Department of Medicine, Division of Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
| | | | - Neil Palmisiano
- Department of Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Naveen Babbar
- Prelude Therapeutics, Research and Development, Wilmington, DE, USA
| | - William Sun
- Prelude Therapeutics, Research and Development, Wilmington, DE, USA
| | - Glenn J Hanna
- Center for Head and Neck Oncology, Center for Salivary and Rare Head and Neck Cancers, Dana-Farber Cancer Institute, Boston, MA, USA
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13
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Silva LC, Leite AA, Borgato GB, Wagner VP, Martins MD, Loureiro FJA, Lopes MA, Santos-Silva AR, Sperandio M, de Castro Junior G, Kowalski LP, Squarize CH, Castilho RM, Vargas PA. Oral squamous cell carcinoma cancer stem cells have different drug sensitive to pharmacological NFκB and histone deacetylation inhibition. Am J Cancer Res 2023; 13:6038-6050. [PMID: 38187064 PMCID: PMC10767341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 11/06/2023] [Indexed: 01/09/2024] Open
Abstract
Despite many progresses in the development of new systemic therapies for oral squamous cell carcinoma (OSCC), the five-year survival rate of OSCC is low. The traditional chemotherapies approach (cisplatin - CDDP) shows some limitations like drug toxicity, limited efficacy, and drug resistance. Promising studies suggested OSCC cancer stem cells (CSC) presented resistance to CDDP. We have previously studied many targets, and we extensively showed the efficacy of the NFκB signaling and the role of histones acetylation, on different malignant tumors, including adenoid cystic carcinoma and mucoepidermoid carcinoma, but until then the effects of the NFkB inhibitor and histone deacetylase (HDAC) inhibitor on the biology of OSCC were not evaluated. Here we assessed the pharmacological inhibitor of NFκB emetine and HDAC inhibitor SAHA on the behavior of CSC derived from OSCC. Our data suggested that CDDP administration resulted in reduced viability of bulk OSCC cells and increased CSC. A single and isolated shot of emetine and SAHA were able to disrupt CSC by inhibiting the NFκB pathway and increasing the histone acetylation levels, respectively. Further, the combined administration of emetine and SAHA presented the same CSC disruption as seen in emetine alone.
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Affiliation(s)
- Luan César Silva
- Department of Oral Diagnosis, Piracicaba Dental School, University of CampinasPiracicaba, SP, Brazil
- Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan School of DentistryAnn Arbor, MI, USA
| | - Amanda Almeida Leite
- Department of Oral Diagnosis, Piracicaba Dental School, University of CampinasPiracicaba, SP, Brazil
| | | | - Vivian Petersen Wagner
- Academic Unit of Oral and Maxillofacial Medicine and Pathology, Department of Clinical Dentistry, University of SheffieldSheffield, SY, UK
| | - Manoela Domingues Martins
- Department of Oral Diagnosis, Piracicaba Dental School, University of CampinasPiracicaba, SP, Brazil
- Department of Oral Pathology, School of Dentistry, Federal University of Rio Grande do SulPorto Alegre, Brazil
| | | | - Márcio Ajudarte Lopes
- Department of Oral Diagnosis, Piracicaba Dental School, University of CampinasPiracicaba, SP, Brazil
| | - Alan Roger Santos-Silva
- Department of Oral Diagnosis, Piracicaba Dental School, University of CampinasPiracicaba, SP, Brazil
| | - Marcelo Sperandio
- Department of Oral Pathology & Medicine, Sao Leopoldo Mandic Dental Institute and Research CenterCampinas, SP, Brazil
| | - Gilberto de Castro Junior
- Serviço de Oncologia Clínica, Instituto do Câncer do Estado de São Paulo, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São PauloSão Paulo, SP, Brazil
| | - Luiz Paulo Kowalski
- Department of Head and Neck Surgery, University of Sao Paulo Medical School and Head and Neck Surgery and Otorhinolaryngology Department, AC Camargo Cancer CenterSão Paulo, SP, Brazil
| | - Cristiane H Squarize
- Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan School of DentistryAnn Arbor, MI, USA
| | - Rogerio Moraes Castilho
- Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan School of DentistryAnn Arbor, MI, USA
| | - Pablo Agustin Vargas
- Department of Oral Diagnosis, Piracicaba Dental School, University of CampinasPiracicaba, SP, Brazil
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14
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Malarkey M, Toscano AP, Bagheri MH, Solomon J, Machado LB, LoRusso P, Chen A, Folio LR, Goncalves PH. A pilot study of volumetric and density tumor analysis of ACC patients treated with vorinostat in a phase II clinical trial. Heliyon 2023; 9:e18680. [PMID: 37593628 PMCID: PMC10428039 DOI: 10.1016/j.heliyon.2023.e18680] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 06/23/2023] [Accepted: 07/25/2023] [Indexed: 08/19/2023] Open
Abstract
Rationale and objectives Adenoid cystic carcinoma (ACC) is a rare salivary gland cancer. The vast majority of clinical trials evaluating systemic therapy efficacy in solid tumors use the Response Evaluation Criteria in Solid Tumors (RECIST) to measure response that is limited to 2 dimensional only evaluations, not taking volume or density into account. The indolent behavior ACC represents a challenge toward an appropriate evaluation of therapy response. Objectives: 1) To describe and contrast volumetric and density changes at each time-point, including changes noted from baseline to best response, to currently used 2 dimensional-only criteria (RECIST) and 2) To report the coefficient of variation in volume measurement among three reviewers on a subset of ACC patients. Materials and methods We retrospectively assessed a cohort of 18 prospectively treated patients with ACC in a phase 2 trial with vorinostat using a volumetric (viable tumor volume, VTV) and density criteria. Three independent and blinded observers segmented target lesions across a sample of randomly selected computed tomography (CT) exams to examine inter-observer variation. Results We found that the average coefficient of variation among observers for all target lesions was 16.1%, with lung lesions displaying a smaller variation at 14.0% (p-value >0.17). We describe examples of decrease in volume and density in several lesions despite stable disease by RECIST. Conclusion This pilot study demonstrates that two-dimensional criteria such as RECIST may not be the best criteria to assess response to therapy, especially with evolving tools within picture archiving and communication system (PACS) that can assess volumetric size, density and texture, however, this should be prospectively studied.
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Affiliation(s)
- Molly Malarkey
- National Institutes of Health, 10 Center Drive, Building 10, Room 1C 340, Bethesda, MD, 20892, USA
| | - Alex P. Toscano
- National Institutes of Health, 10 Center Drive, Building 10, Room 1C 340, Bethesda, MD, 20892, USA
| | - Mohammad Hadi Bagheri
- Radiology and Imaging Sciences Clinical Center, National Institutes of Health, 10 Center Drive, Bldg. 10, Room 1C342, Bethesda, MD, 20892, USA
| | - Jeffrey Solomon
- Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA
| | - Laura B. Machado
- Department of Radiology, Division of Body Imaging, Hospital of the University of Pennsylvania, 3400 Spruce St, Philadelphia PA 19104, USA
| | - Patricia LoRusso
- Yale University, 333 Cedar Street, WWW217, New Haven, CT, 06510, USA
| | - Alice Chen
- Early Clinical Trials Development Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, 31 Center Blvd, 3A44, Bethesda, MD, 20892, USA
| | - Les R. Folio
- Acting Associate Chief Medical Informatics Officer, Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, FL 33612, USA
- Senior Member, Department of Machine Learning, Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, FL 33612, USA
- Professor, Department of Oncologic Sciences, University of South Florida Morsani College of Medicine, 560 Channelside Dr, Tampa, FL 33602, USA
| | - Priscila H. Goncalves
- HIV and AIDS Malignancy Branch, National Institutes of Health, Bethesda, MD, 20892, USA
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15
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Manou M, Kanakoglou DS, Loupis T, Vrachnos DM, Theocharis S, Papavassiliou AG, Piperi C. Role of Histone Deacetylases in the Pathogenesis of Salivary Gland Tumors and Therapeutic Targeting Options. Int J Mol Sci 2023; 24:10038. [PMID: 37373187 PMCID: PMC10298439 DOI: 10.3390/ijms241210038] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 06/09/2023] [Accepted: 06/10/2023] [Indexed: 06/29/2023] Open
Abstract
Salivary gland tumors (SGTs) comprise a rare and heterogenous category of benign/malignant neoplasms with progressively increasing knowledge of the molecular mechanisms underpinning their pathogenesis, poor prognosis, and therapeutic treatment efficacy. Emerging data are pointing toward an interplay of genetic and epigenetic factors contributing to their heterogeneity and diverse clinical phenotypes. Post-translational histone modifications such as histone acetylation/deacetylation have been shown to actively participate in the pathobiology of SGTs, further suggesting that histone deacetylating factors (HDACs), selective or pan-HDAC inhibitors (HDACis), might present effective treatment options for these neoplasms. Herein, we describe the molecular and epigenetic mechanisms underlying the pathology of the different types of SGTs, focusing on histone acetylation/deacetylation effects on gene expression as well as the progress of HDACis in SGT therapy and the current status of relevant clinical trials.
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Affiliation(s)
- Maria Manou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.M.); (D.S.K.)
| | - Dimitrios S. Kanakoglou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.M.); (D.S.K.)
| | - Theodoros Loupis
- Haematology Research Laboratory, Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation, Academy of Athens, 11527 Athens, Greece; (T.L.); (D.M.V.)
| | - Dimitrios M. Vrachnos
- Haematology Research Laboratory, Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation, Academy of Athens, 11527 Athens, Greece; (T.L.); (D.M.V.)
| | - Stamatios Theocharis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Athanasios G. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.M.); (D.S.K.)
| | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.M.); (D.S.K.)
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16
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Wagner VP, Ferrarotto R, Vargas PA, Martins MD, Bingle CD, Bingle L. Drug-based therapy for advanced adenoid cystic carcinoma: Current landscape and challenges based on an overview of registered clinical trials. Crit Rev Oncol Hematol 2023; 181:103886. [PMID: 36427771 DOI: 10.1016/j.critrevonc.2022.103886] [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: 08/16/2022] [Revised: 11/01/2022] [Accepted: 11/21/2022] [Indexed: 11/27/2022] Open
Abstract
Adenoid cystic carcinoma (ACC) has a significant patient-population in need of effective systemic therapy, as no drug is currently approved by the FDA for its management. We critically reviewed ACC-clinical trials (CT) registered on the ClinicalTrials.gov website using "ACC" under condition or disease. Trials specifically designed to test a drug-based therapy for ACC (n = 33) were analyzed with most being one-arm phase II trials enrolling advanced, recurrent/metastatic, incurable ACC cases. Site restriction, maximum ECOG status, and period of disease progression varied as inclusion criteria. Small-molecule inhibitors were those most commonly investigated with Apatinib, Axitinib and Lenvatinib showing the best results in association with rigid enrollment criteria. The overall median time to progression remains modest and more efforts are urgently needed in this field. CTs designed to test drugs that act on key pathways associated with ACC aggressiveness are being conducted and represent a promising pathway if efficacy is proved.
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Affiliation(s)
- Vivian Petersen Wagner
- Academic Unit of Oral and Maxillofacial Medicine and Pathology, Department of Clinical Dentistry, University of Sheffield, Sheffield, UK.
| | - Renata Ferrarotto
- Department of Thoracic Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Pablo Agustin Vargas
- Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas, Piracicaba, São Paulo, Brazil
| | - Manoela Domingues Martins
- Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas, Piracicaba, São Paulo, Brazil; Oral Pathology Department, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Colin D Bingle
- Academic Unit of Respiratory Medicine, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK
| | - Lynne Bingle
- Academic Unit of Oral and Maxillofacial Medicine and Pathology, Department of Clinical Dentistry, University of Sheffield, Sheffield, UK
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17
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Cleymaet R, Vermassen T, Coopman R, Vermeersch H, De Keukeleire S, Rottey S. The Therapeutic Landscape of Salivary Gland Malignancies-Where Are We Now? Int J Mol Sci 2022; 23:ijms232314891. [PMID: 36499216 PMCID: PMC9740091 DOI: 10.3390/ijms232314891] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 11/23/2022] [Accepted: 11/25/2022] [Indexed: 11/29/2022] Open
Abstract
Salivary gland malignancies (SGMs) account for less than 5% of new diagnoses in head and neck tumors. If feasible, surgery is the preferred treatment modality. Nevertheless, some malignancies have a tendency of recurrence, with possible distant metastasis. Alternative treatment strategies, such as primary radiation or chemotherapeutics, often present low response rates. As a result, there is an unmet need for novel therapeutic approaches. Nowadays, target-based therapies (e.g., small inhibitors and immunotherapy) are used by the medical oncologist for possible treatment of advanced SGMs. Based on recent published trials, some novel treatments may provide additional disease control for some patients. However, sample sizes are small, the general findings are unsatisfactory, and a lot of uncertainties remain to be elucidated. Nevertheless, research shows that patients do not benefit from blind administration of systemic treatments and therefore a more personalized approach is highly needed. The aim of this review paper is to summarize the most recent advances in the biological understanding and molecular pathways of salivary gland cancers, the association of these pathways with the current treatments used and their implications for more personalized targeted-based therapies.
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Affiliation(s)
- Robbert Cleymaet
- Department of Oromaxillofacial and Plastic Surgery, Ghent University Hospital, 9000 Ghent, Belgium
| | - Tijl Vermassen
- Department Medical Oncology, University Hospital Ghent, 9000 Ghent, Belgium
- Department Basic and Applied Medical Sciences, Ghent University, 9000 Ghent, Belgium
- Cancer Research Institute Ghent, 9000 Ghent, Belgium
- Correspondence: ; Tel.: +32-9-332-26-92
| | - Renaat Coopman
- Department of Oromaxillofacial and Plastic Surgery, Ghent University Hospital, 9000 Ghent, Belgium
- Cancer Research Institute Ghent, 9000 Ghent, Belgium
| | - Hubert Vermeersch
- Department of Oromaxillofacial and Plastic Surgery, Ghent University Hospital, 9000 Ghent, Belgium
| | - Stijn De Keukeleire
- Department Internal Medicine, University Hospital Brussels, 1090 Brussels, Belgium
| | - Sylvie Rottey
- Department Medical Oncology, University Hospital Ghent, 9000 Ghent, Belgium
- Department Basic and Applied Medical Sciences, Ghent University, 9000 Ghent, Belgium
- Cancer Research Institute Ghent, 9000 Ghent, Belgium
- Drug Research Unit Ghent, University Hospital Ghent, 9000 Ghent, Belgium
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18
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Lee RH, Wai KC, Chan JW, Ha PK, Kang H. Approaches to the Management of Metastatic Adenoid Cystic Carcinoma. Cancers (Basel) 2022; 14:5698. [PMID: 36428790 PMCID: PMC9688467 DOI: 10.3390/cancers14225698] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 11/16/2022] [Accepted: 11/17/2022] [Indexed: 11/22/2022] Open
Abstract
High rates of recurrence and distant metastasis are a foremost challenge in the management of adenoid cystic carcinoma (ACC), occurring in approximately 40% of all ACC patients. Despite the morbidity and mortality resulting from recurrent/metastatic (R/M) disease, there are no FDA-approved systemic agents for these patients. In this review, we summarize pertinent ACC pathophysiology and its implications for different systemic treatment regimens in R/M ACC. We review the evidence for the most widely used systemic agents - cytotoxic chemotherapy and tyrosine kinase inhibitors (TKIs) targeting VEGFR - in addition to immune checkpoint inhibitors and non-TKI biologic agents. Exciting emerging targets for R/M ACC, including inhibitors of Notch signaling, stemness, PRMT5, and Axl, are also discussed. Lastly, we review local therapies for small-volume lung disease in patients with oligometastatic ACC, specifically pulmonary metastasectomy and stereotactic body radiation therapy (SBRT). Future development of targeted molecular agents which exploit the underlying biology of this disease may yield novel therapeutic options to improve clinical outcomes in patients with R/M ACC.
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Affiliation(s)
- Rex H. Lee
- Department of Otolaryngology-Head and Neck Surgery, University of California San Francisco, San Francisco, CA 94143, USA
| | - Katherine C. Wai
- Department of Otolaryngology-Head and Neck Surgery, Stanford University, Palo Alto, CA 94304, USA
| | - Jason W. Chan
- Department of Radiation Oncology, University of California San Francisco, San Francisco, CA 94143, USA
| | - Patrick K. Ha
- Department of Otolaryngology-Head and Neck Surgery, University of California San Francisco, San Francisco, CA 94143, USA
| | - Hyunseok Kang
- Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA
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19
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Lam-Ubol A, Phattarataratip E. Distinct histone H3 modification profiles correlate with aggressive characteristics of salivary gland neoplasms. Sci Rep 2022; 12:15063. [PMID: 36064736 PMCID: PMC9445049 DOI: 10.1038/s41598-022-19174-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 08/25/2022] [Indexed: 11/09/2022] Open
Abstract
Post-translational modification of histones is the crucial event that affect many tumor-specific traits. A diverse type of histone modifications had been reported in different cancers with prognostic implications. This study aimed to examine the degree of histone H3 modifications in salivary gland neoplasms and their associations with tumor pathologic characteristics and proliferative activity. The expression of H3K9Ac, H3K18Ac, H3K9Me3 and Ki-67 in 70 specimens of salivary gland neoplasms, consisting of 30 mucoepidermoid carcinoma (MEC), 20 adenoid cystic carcinoma (ACC) and 20 pleomorphic adenoma (PA), were investigated immunohistochemically. The immunohistochemical scoring of 3 histone modification types and Ki-67 labeling index were determined. Overall, MEC demonstrated elevated H3K9Ac level compared with benign PA. Increased H3K9Me3 in MEC was positively correlated with small nest invasion at tumor front, advanced pathologic grade, and elevated proliferative index. In addition, the significant upregulation of all 3 types of histone H3 modification was noted in solid subtype of ACC and associated with increased cell proliferation. This study indicates that salivary gland neoplasms differentially acquire distinct patterns of histone H3 modification, which impact prognostically relevant cancer phenotypes. The hyperacetylation and methylation of histone H3 could be underpinning the prognostically worsen solid type of ACC, and the trimethylation of H3K9 may be involved in aggressive characteristics of MEC.
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Affiliation(s)
- Aroonwan Lam-Ubol
- Department of Oral Surgery and Oral Medicine, Faculty of Dentistry, Srinakharinwirot University, 114 Sukhumvit 23 Wattana, Bangkok, 10110, Thailand
| | - Ekarat Phattarataratip
- Department of Oral Pathology, Faculty of Dentistry, Chulalongkorn University, Henri-Dunant Road, Pathumwan, Bangkok, 10330, Thailand.
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20
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de Sousa LG, Jovanovic K, Ferrarotto R. Metastatic Adenoid Cystic Carcinoma: Genomic Landscape and Emerging Treatments. Curr Treat Options Oncol 2022; 23:1135-1150. [PMID: 35854180 DOI: 10.1007/s11864-022-01001-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/29/2022] [Indexed: 11/03/2022]
Abstract
OPINION STATEMENT Adenoid cystic carcinoma (ACC) is a heterogeneous cancer that commonly develops in the salivary glands. Approximately 40 to 50% of patients with ACC develop recurrence and/or metastasis. Although most patients with ACC have slow-growing disease, a subset experiences aggressive disease with early visceral and/or bone metastasis. Thus far, there is no consensus on the best time to start palliative treatment in patients with indolent disease. The only systemic therapies available for recurrent or metastatic ACC are cytotoxic agents and multikinase inhibitors targeting vascular endothelial growth factor receptor, and both types of therapy have modest activity. Studies integrating proteomics, genomics, and clinical data have revealed distinct molecular ACC subtypes, ACC-I and ACC-II, with ACC-I generally associated with more aggressive disease biology. ACC-I tumors were enriched for NOTCH1-activating mutation and upregulation of MYC and MYC targets, while ACC-II tumors exhibited upregulation of TP63 and receptor tyrosine kinases. These findings highlight the importance of patient selection for surveillance and targeted therapy development in ACC. In recent clinical trials of targeted therapy in ACC, patients are being selected according to tumor molecular profile (e.g., presence of NOTCH-activating mutations), which represents a major advance in the field. Ongoing collaborative research focusing on the development of novel therapeutic strategies for ACC patients based on disease biology will increase the drug armamentarium and improve survival outcomes for these patients in dire need.
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Affiliation(s)
- Luana Guimaraes de Sousa
- Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, PO Box 432, Houston, TX, 77030, USA
| | - Katarina Jovanovic
- Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, PO Box 432, Houston, TX, 77030, USA
| | - Renata Ferrarotto
- Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, PO Box 432, Houston, TX, 77030, USA.
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21
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Zhang D, Chai Y, Wei Y, Qi F, Dong M. Survival and prognosis of metastatic head and neck adenoid cystic carcinoma. Head Neck 2022; 44:2407-2416. [PMID: 35822446 DOI: 10.1002/hed.27143] [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: 04/02/2022] [Revised: 06/16/2022] [Accepted: 06/28/2022] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND To investigate the clinical characteristics, treatment, and prognosis of patients with metastatic head and neck adenoid cystic carcinoma (HNACC). METHOD The clinical data of metastatic HNACC from 1999 to 2020 at the National Cancer Center of China were retrospectively collected. RESULTS One hundred seventy-four patients with metastatic HNACC were enrolled and median overall survival (OS) was 45.6 months. Univariate analysis indicated that smoking history, disease-free interval (DFI), number and sites of metastases, and systemic therapy were associated with OS. In the multivariate analysis, non-smokers, DFI ≥3 years, and lung metastasis were prognostic factors. Local therapy for localized disease could prolong survival in patients with both recurrent and metastatic disease. CONCLUSION No smoking history, DFI ≥3 years, and lung metastasis were favorable prognostic factors. Local therapy for metastases could not provide survival benefits, but local therapy for localized disease may prolong survival. Whether initial systemic therapy could improve prognosis needs further exploration.
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Affiliation(s)
- Di Zhang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yue Chai
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuce Wei
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fei Qi
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Lymphoma, Peking University Cancer Hospital & Institute, Beijing, China
| | - Mei Dong
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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22
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Savarese T, Abate A, Basnet RM, Lorini L, Gurizzan C, Tomasoni M, Lombardi D, Tomasini D, Zizioli D, Memo M, Berruti A, Bonini SA, Sigala S, Bossi P. Cytotoxic effects of targeted agent alone or with chemotherapy in the treatment of adenoid cystic carcinoma: a preclinical study. Sci Rep 2022; 12:9951. [PMID: 35705678 PMCID: PMC9200834 DOI: 10.1038/s41598-022-14197-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 06/02/2022] [Indexed: 11/24/2022] Open
Abstract
Adenoid cystic carcinoma (ACC) is a rare malignancy characterized by high incidence of relapse. When relapsing, ACC has an indolent but relentless behaviour, thus leading to a poor long-term prognosis. The treatment of choice of relapsing ACC remains surgery followed by radiotherapy, whenever feasible. Therapeutic weapons are limited to systemic drugs. The most widely used chemotherapy regimen is the combination of cisplatin and doxorubicin, however with low response rate and not long lasting; there is also a lack of alternatives for second line therapies in case of disease progression. Therefore, a more comprehensive strategy aimed at identifying at preclinical level the most promising drugs or combination is clearly needed. In this study, the cytotoxic effects of two standard chemotherapy drugs, cisplatin and doxorubicin, and of five targeted therapy-drugs was tested in vitro, on an h-TERT immortalized ACC cell line, and in vivo, on zebrafish embryos with ACC tumoral cell xenograft. Then, combinations of one standard chemotherapy drug plus one targeted therapy drug were also evaluated, in order to find the best treatment strategy for ACC. Data obtained demonstrated that both vorinostat and olaparib significantly increased the standard chemotherapy cytotoxic effects, suggesting new interesting therapeutic options for ACC.
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Affiliation(s)
- Teresa Savarese
- Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy
| | - Andrea Abate
- Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy
| | - Ram Manohar Basnet
- Section of Biotechnology, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy
| | - Luigi Lorini
- Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia and ASST Spedali Civili, Piazzale Spedali Civili 1, 25123, Brescia, Italy
| | - Cristina Gurizzan
- Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia and ASST Spedali Civili, Piazzale Spedali Civili 1, 25123, Brescia, Italy
| | - Michele Tomasoni
- Unit of Otorhinolaryngology-Head and Neck Surgery, ASST Spedali Civili di Brescia, Department of Medical and Surgical Specialties, Radiologic Sciences, and Public Health, University of Brescia, Piazzale Spedali Civili 1, 25123, Brescia, Italy
| | - Davide Lombardi
- Unit of Otorhinolaryngology-Head and Neck Surgery, ASST Spedali Civili di Brescia, Department of Medical and Surgical Specialties, Radiologic Sciences, and Public Health, University of Brescia, Piazzale Spedali Civili 1, 25123, Brescia, Italy
| | - Davide Tomasini
- Radiation Oncology Unit, Department of Medical and Surgical Specialties, Radiological Science and Public Health, ASST Spedali Civili of Brescia, University of Brescia, Piazzale Spedali Civili 1, 25123, Brescia, Italy
| | - Daniela Zizioli
- Section of Biotechnology, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy
| | - Maurizio Memo
- Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy
| | - Alfredo Berruti
- Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia and ASST Spedali Civili, Piazzale Spedali Civili 1, 25123, Brescia, Italy
| | - Sara A Bonini
- Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy.
| | - Sandra Sigala
- Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy
| | - Paolo Bossi
- Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia and ASST Spedali Civili, Piazzale Spedali Civili 1, 25123, Brescia, Italy
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23
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Atallah S, Marc M, Schernberg A, Huguet F, Wagner I, Mäkitie A, Baujat B. Beyond Surgical Treatment in Adenoid Cystic Carcinoma of the Head and Neck: A Literature Review. Cancer Manag Res 2022; 14:1879-1890. [PMID: 35693117 PMCID: PMC9176735 DOI: 10.2147/cmar.s355663] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 04/24/2022] [Indexed: 12/16/2022] Open
Abstract
Introduction Adenoid cystic carcinoma (AdCC) is a rare tumour as it accounts for about 10% of all salivary gland neoplasms. It occurs in all age groups with a predominance of women, but no risk factors have been identified to date. Although AdCC behaves as a slow-growing tumour, it is characterized by multiple and late recurrences. Therefore, we aim to update the knowledge of the treatment options in advanced and recurrent cases. Materials and Methods We performed a systematic literature review to provide a synthesis of the practical knowledge required for AdCC non-surgical management. Altogether, 99 out of the 1208 available publications were selected for analysis. Results AdCC is described as a basaloid tumour consisting of epithelial and myoepithelial cells. Immunohistochemistry is useful for diagnosis (PS100, Vimentin, CD117, CKit, muscle actin, p63) and for prognosis (Ki67). Identified mutations could lead to therapeutic opportunities (MYB-NFIB, Notch 1). The work-up is mainly based on neck and chest CT scan and MRI, and PET-CT with 18-FDG or PSMA can be considered. Surgical treatment remains the gold standard in resectable cases. Post-operative intensity modulated radiotherapy is the standard of care, but hadron therapy may be used in specific situations. Based on the available literature, no standard chemotherapy regimen can be recommended. Conclusion There is currently no consensus on the use of chemotherapy in AdCC, either concomitantly to RT in a postoperative setting or at a metastatic stage. Further, the available targeted therapies do not yet provide significant tumour response.
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Affiliation(s)
- Sarah Atallah
- Department of Otorhinolaryngology–Head and Neck Surgery, Sorbonne University, Tenon Hospital, AP-HP, Paris, France
- Doctoral School of Public Health, University of Paris Sud, CESP, INSERM U1018, University of Paris-Saclay, UVSQ, Villejuif, France
- Correspondence: Sarah Atallah, Hôpital Tenon, AP-HP, 4 rue de la Chine, Paris, 75020, France, Tel +33 156016417, Email
| | - Morgane Marc
- Department of Otorhinolaryngology–Head and Neck Surgery, Sorbonne University, Tenon Hospital, AP-HP, Paris, France
| | - Antoine Schernberg
- Department of Radiotherapy, Sorbonne University, Tenon Hospital, AP-HP, Paris, France
| | - Florence Huguet
- Department of Radiotherapy, Sorbonne University, Tenon Hospital, AP-HP, Paris, France
| | - Isabelle Wagner
- Department of Otorhinolaryngology–Head and Neck Surgery, Sorbonne University, Tenon Hospital, AP-HP, Paris, France
| | - Antti Mäkitie
- Department of Otorhinolaryngology - Head and Neck Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Bertrand Baujat
- Department of Otorhinolaryngology–Head and Neck Surgery, Sorbonne University, Tenon Hospital, AP-HP, Paris, France
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24
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de Sousa LG, Neto FL, Lin J, Ferrarotto R. Treatment of Recurrent or Metastatic Adenoid Cystic Carcinoma. Curr Oncol Rep 2022; 24:621-631. [PMID: 35212920 DOI: 10.1007/s11912-022-01233-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/27/2021] [Indexed: 12/24/2022]
Abstract
PURPOSE OF REVIEW Adenoid cystic carcinoma (ACC) is a rare and heterogeneous malignancy of secretory glands. Recurrence after curative-intent treatment is common, and approximately 40% of patients develop metastatic disease, for which consensus is lacking regarding therapeutic approaches. Here, we review the available therapies for recurrent/metastatic (R/M) ACC and offer our perspectives on future treatment options. RECENT FINDINGS Proteogenomic studies of ACC revealed two molecular subtypes with therapeutic implications: ACC-I (37% of cases) and ACC-II (63%); each has distinct disease biology and prognosis. Molecular drivers, such as NOTCH1, have emerged as potential therapeutic targets for ACC-I and are being explored in clinical trials. Despite its biological heterogeneity, treatment for R/M ACC is not personalized and limited to cytotoxic agents and VEGFR inhibitors, which produce modest responses and significant toxicity. The increasing understanding of ACC's molecular biology might guide the development of biomarkers for patient selection and new therapies development.
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Affiliation(s)
- Luana Guimaraes de Sousa
- Departments of a Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, PO Box 432, Houston, TX, 77030, USA
| | - Felippe Lazar Neto
- Departments of a Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, PO Box 432, Houston, TX, 77030, USA
| | - Jessica Lin
- Departments of a Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, PO Box 432, Houston, TX, 77030, USA
| | - Renata Ferrarotto
- Departments of a Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, PO Box 432, Houston, TX, 77030, USA.
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25
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Imamura Y, Kiyota N, Tahara M, Hanai N, Asakage T, Matsuura K, Ota I, Saito Y, Sano D, Kodaira T, Motegi A, Yasuda K, Takahashi S, Yokota T, Okano S, Tanaka K, Onoe T, Ariizumi Y, Homma A. Systemic therapy for salivary gland malignancy: current status and future perspectives. Jpn J Clin Oncol 2022; 52:293-302. [PMID: 35134985 DOI: 10.1093/jjco/hyac008] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 01/14/2022] [Indexed: 12/15/2022] Open
Abstract
Salivary gland malignancies are rare neoplasms that have a broad histological spectrum and a variety of biologic behaviors. Salivary gland malignancies are known as chemo-resistant tumors, which render optimal treatment challenging. This review summarizes the role of systemic therapy for salivary gland malignancies. To date, the advantage of adding concurrent chemotherapy has remained undefined for both postoperative and inoperable locally advanced salivary gland malignancy patients undergoing radiotherapy. For recurrent/metastatic disease, local and/or systemic treatment options should be discussed in a multidisciplinary setting with consideration to both patient needs and tumor factors. For symptomatic patients or those who may compromise organ function, palliative systemic therapy can be a reasonable option based on the results of phase II studies. Platinum combination regimens as first-line therapy have been widely accepted. Personalized therapies have become established options, particularly for androgen receptor-positive, HER2-positive and NTRK fusion-positive salivary gland malignancies (i.e. androgen receptor and HER2 in salivary duct carcinoma and NTRK3 in secretory carcinoma). For patients with adenoid cystic carcinoma, multi-targeted tyrosine kinase inhibitors have also been developed. Anti-PD1 checkpoint inhibitors have shown limited activity to date. Investigation of active systemic treatments for salivary gland malignancy remains a significant unmet need. Future directions might include a more comprehensive genomic screening approach (usually next-generation sequencing-based) and combination strategies using immune checkpoint inhibitors. These are rare malignancies that require ongoing effort in the conduct of high-quality clinical trials.
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Affiliation(s)
- Yoshinori Imamura
- Department of Medical Oncology and Hematology, Kobe University Hospital, Kobe, Japan
| | - Naomi Kiyota
- Department of Medical Oncology and Hematology, Kobe University Hospital, Kobe, Japan.,Cancer Center, Kobe University Hospital, Kobe, Japan
| | - Makoto Tahara
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Nobuhiro Hanai
- Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Takahiro Asakage
- Department of Head and Neck Surgery, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kazuto Matsuura
- Department of Head and Neck Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Ichiro Ota
- Department of Otolaryngology-Head and Neck Surgery, Nara Medical University, Kashihara, Japan
| | - Yuki Saito
- Department of Otolaryngology and Head and Neck Surgery, University of Tokyo, Tokyo, Japan
| | - Daisuke Sano
- Department of Otorhinolaryngology, Head and Neck Surgery, Yokohama City University School of Medicine, Yokohama, Japan
| | - Takeshi Kodaira
- Department of Radiation Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Atsushi Motegi
- Department of Radiation Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Koichi Yasuda
- Department of Radiation Oncology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Shunji Takahashi
- Department of Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Tomoya Yokota
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Sunto-gun, Japan
| | - Susumu Okano
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Kaoru Tanaka
- Department of Medical Oncology, Kindai University Faculty of Medicine Hospital, Osaka-Sayama, Japan
| | - Takuma Onoe
- Department of Medical Oncology, Hyogo Cancer Center, Akashi, Japan
| | - Yosuke Ariizumi
- Department of Head and Neck Surgery, Tokyo Medical and Dental University, Tokyo, Japan
| | - Akihiro Homma
- Department of Otolaryngology-Head and Neck Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
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26
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Witte HM, Gebauer N, Steinestel K. Mutational and immunologic Landscape in malignant Salivary Gland Tumors harbor the potential for novel therapeutic strategies. Crit Rev Oncol Hematol 2022; 170:103592. [PMID: 35026433 DOI: 10.1016/j.critrevonc.2022.103592] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 11/24/2021] [Accepted: 01/06/2022] [Indexed: 12/18/2022] Open
Abstract
Salivary gland carcinomas (SGC) are rare (3-6 % of all head and neck cancers) and show biological heterogeneity depending on the respective histological subtype. While complete surgical resection is the standard treatment for localized disease, chemotherapy or radiation therapy are frequently insufficient for the treatment of unresectable or metastasized SGC. Therefore, new therapeutic approaches such as molecularly targeted therapy or the application of immune checkpoint inhibition enhance the treatment repertoire. Accordingly, comprehensive analyses of the genomic landscape and the tumor-microenvironment (TME) are of crucial importance in order to optimize and individualize SGC treatment. This manuscript combines the current scientific knowledge of the composition of the mutational landscape and the TME in SGCs harboring the potential for novel (immune-) targeted therapeutic strategies.
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Affiliation(s)
- Hanno M Witte
- Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, Campus Luebeck, 23538, Luebeck, Germany; Department of Hematology and Oncology, Federal Armed Forces Hospital Ulm, Oberer Eselsberg 40, 89081, Ulm, Germany; Institute of Pathology and Molecular Pathology, Federal Armed Forces Hospital Ulm, Oberer Eselsberg 40, 89081, Ulm, Germany.
| | - Niklas Gebauer
- Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, Campus Luebeck, 23538, Luebeck, Germany
| | - Konrad Steinestel
- Institute of Pathology and Molecular Pathology, Federal Armed Forces Hospital Ulm, Oberer Eselsberg 40, 89081, Ulm, Germany
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27
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Sahara S, Herzog AE, Nör JE. Systemic therapies for salivary gland adenoid cystic carcinoma. Am J Cancer Res 2021; 11:4092-4110. [PMID: 34659878 PMCID: PMC8493384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/09/2021] [Indexed: 06/13/2023] Open
Abstract
Adenoid cystic carcinoma (ACC) is a slow growing, but relentless cancer. Due to its rarity and lack of understanding of its molecular etiology, no standard chemotherapy for ACC currently exists and many patients suffer from recurrent and/or metastatic disease. As such, development of safe and effective therapies is imperative. To describe and summarize existing clinical trial studies and preclinical discoveries, we surveyed the PubMed on developmental therapeutics for ACC. Objective response rates to monotherapy with cytotoxic agents were approximately 10% with cisplatin, 5-FU, gemcitabine, mitoxantrone, epirubicin, vinorelbine and paclitaxel. The most studied combination therapies were cyclophosphamide-doxorubicin-cisplatin (CAP) and cisplatin-vinorelbine, with an objective response rate of 18-31%. Among molecularly targeted drugs, the most studied drugs are inhibitors targeting the vascular endothelial growth factor receptor (VEGFR) to inhibit tumor angiogenesis. Among those, lenvatinib and axitinib showed a relatively high objective response rate of 11-16% and 9-17%, respectively. Given high recurrence rates and chemoresistance of ACC, treatments targeting cancer stem cells (CSC), which function as tumor-initiating cells and drive chemoresistance, may be particularly valuable. CSC have been shown to be targetable via MYB, Notch1, p53 and epigenetic mechanisms. Myb overexpression is characteristic in ACC but was previously thought to present a difficult target due to its nature as a transcription factor. However, due to the development Myb-targeted inhibitors and an ongoing clinical trial of MYB-targeted cancer vaccine therapy, MYB is becoming an increasingly attractive therapeutic target. Drugs targeting NOTCH signaling demonstrated 5-17% response rate in phase I clinical trials. Within the field of epigenetics, treatment with PRMT5 inhibitors has shown 21% partial response rate in phase I clinical trial. Immunotherapies, such as PD-1 inhibitors, are also associated with CSC, but have not been effective against ACC. However, clinical trials of cancer vaccine therapies are actively being conducted. In addition to conventional chemotherapies and inhibitors of angiogenesis, the emergence of new therapies such as immunotherapy and those targeting cancer stemness is expected to bring clinical benefits to patients in the future.
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Affiliation(s)
- Sosuke Sahara
- Department of Cariology, Restorative Sciences, and Endodontics, University of Michigan School of DentistryAnn Arbor, Michigan 48109-1078, USA
- Department of Otorhinolaryngology/Head and Neck Surgery, Hamamatsu University School of MedicineHamamatsu 431-3192, Japan
| | - Alexandra E Herzog
- Department of Cariology, Restorative Sciences, and Endodontics, University of Michigan School of DentistryAnn Arbor, Michigan 48109-1078, USA
| | - Jacques E Nör
- Department of Cariology, Restorative Sciences, and Endodontics, University of Michigan School of DentistryAnn Arbor, Michigan 48109-1078, USA
- Department of Otolaryngology-Head & Neck Surgery, University of Michigan School of MedicineAnn Arbor, Michigan 48109-1078, USA
- Department of Biomedical Engineering, University of Michigan College of EngineeringAnn Arbor, Michigan 48109, USA
- University of Michigan Rogel Cancer CenterAnn Arbor, Michigan 48109, USA
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28
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Abstract
Salivary gland carcinomas are a rare and heterogenous group of cancers with varying underlying biology and clinical behavior. A quickly evolving body of data has advanced the understanding of these tumors, leading to effective therapeutics for several histologic subtypes. Biologically rational clinical trials have developed from an understanding of MYB and NOTCH signaling in adenoid cystic carcinoma. The recognition of androgen receptor signaling and HER2-targeted therapy has offered therapeutic options in non-ACC salivary cancers. The use of TRK inhibitors in salivary secretory carcinoma has led to exceptional responses. Immunotherapy is an exciting new therapeutic avenue that requires further exploration.
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Affiliation(s)
- Vatche Tchekmedyian
- Tufts University School of Medicine, MaineHealth Cancer Care, 265 Western Avenue, Suite 2, South Portland, ME 04106, USA.
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29
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Hanna GJ, ONeill A, Cutler JM, Flynn M, Vijaykumar T, Clark JR, Wirth LJ, Lorch JH, Park JC, Mito JK, Lohr JG, Kaufman J, Burr NS, Zon LI, Haddad RI. A phase II trial of all-trans retinoic acid (ATRA) in advanced adenoid cystic carcinoma. Oral Oncol 2021; 119:105366. [PMID: 34091189 DOI: 10.1016/j.oraloncology.2021.105366] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/23/2021] [Accepted: 05/24/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND Effective therapies are lacking for recurrent, metastatic adenoid cystic carcinoma (R/M ACC) and preclinical models suggest retinoic acid agonists inhibit ACC growth. This phase II trial evaluated all-trans retinoic acid (ATRA) as a novel therapy for ACC. METHODS Patients with R/M ACC (any site) with clinical and/or radiographic progression ≤12 months prior to study entry were eligible. Cohort 1 (CH1) received ATRA 45 mg/m2 split oral daily dosing on days 1-14 of a 28-day cycle; Cohort 2 (CH2) received the same dosing continuously. Primary endpoint was best overall response rate (CR + PR) (RECIST v1.1). Secondary endpoints: safety and progression-free survival (PFS). Exploratory analyses: ATRA impact on MYB expression and genomic predictors of response. RESULTS Eighteen patients enrolled. There were no responses, but 61% (11/18) had stable disease (SD) and 28% (5/18) progression as best response; 11% (2/18) unevaluable. Median duration of stability: 3.7 months (95%CI, 1.9-3.9). One patient (CH1) remains on drug with SD approaching 1 year. Half of those who received prior VEGFR therapy achieved SD (4/8). At median follow up of 7.9 months, median PFS was 3.2 months (95%CI, 1.8-3.9). N = 1 required dose adjustment; N = 1 came off drug for toxicity. There were no grade 3-4 adverse events. NOTCH1 and PI3K pathway alterations were most frequent. Low MYB protein expression was associated with longer duration of stability on ATRA (P < 0.01). CONCLUSION(S) While the trial did not meet its prespecified response endpoint, ATRA alone or in combination may be a low toxicity treatment for disease growth stabilization in R/M ACC.
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Affiliation(s)
- Glenn J Hanna
- Department of Medical Oncology, Center for Head & Neck Oncology, Center for Salivary and Rare Head and Neck Cancers, Dana-Farber Cancer Institute, Boston, USA.
| | - Anne ONeill
- Department of Data Science, Dana-Farber Cancer Institute, Boston, USA
| | - Jennifer M Cutler
- Department of Medical Oncology, Center for Head & Neck Oncology, Center for Salivary and Rare Head and Neck Cancers, Dana-Farber Cancer Institute, Boston, USA
| | - Michelle Flynn
- Department of Medical Oncology, Center for Head & Neck Oncology, Center for Salivary and Rare Head and Neck Cancers, Dana-Farber Cancer Institute, Boston, USA
| | - Tushara Vijaykumar
- Center for Hematologic Oncology, Dana-Farber Cancer Institute, Boston, USA
| | - John R Clark
- Center for Head and Neck Cancers, Massachusetts General Hospital, Boston, USA
| | - Lori J Wirth
- Center for Head and Neck Cancers, Massachusetts General Hospital, Boston, USA
| | - Jochen H Lorch
- Department of Medical Oncology, Center for Head & Neck Oncology, Center for Salivary and Rare Head and Neck Cancers, Dana-Farber Cancer Institute, Boston, USA
| | - Jong C Park
- Center for Head and Neck Cancers, Massachusetts General Hospital, Boston, USA
| | - Jeffrey K Mito
- Department of Pathology, Brigham & Women's Hospital, Boston, USA
| | - Jens G Lohr
- Center for Hematologic Oncology, Dana-Farber Cancer Institute, Boston, USA
| | | | | | - Leonard I Zon
- Department of Stem Cell and Regenerative Biology, Boston Children's Hospital and Harvard Medical School, Boston, USA
| | - Robert I Haddad
- Department of Medical Oncology, Center for Head & Neck Oncology, Center for Salivary and Rare Head and Neck Cancers, Dana-Farber Cancer Institute, Boston, USA
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30
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Abstract
Despite aggressive initial interventions, recurrent/metastatic salivary gland cancer is not uncommon. Standard chemotherapy has not been shown to have durable clinical benefits. Several potential molecular markers have been identified in different histologic subtypes of salivary cancers. The objective of this review is to highlight the molecular markers that have been targeted in clinical trials for salivary gland cancers.
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Affiliation(s)
- Katherine C Wai
- Department of Otolaryngology-Head and Neck Surgery, University of California San Francisco 550 16th Street, 6th floor, UCSF Box 3213, San Francisco, CA 94158, USA
| | - Hyunseok Kang
- Department of Hematology and Oncology, University of California San Francisco, 1825 4th Street, San Francisco, CA 94158, USA
| | - Patrick K Ha
- Department of Otolaryngology-Head and Neck Surgery, University of California San Francisco 550 16th Street, 6th floor, UCSF Box 3213, San Francisco, CA 94158, USA.
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31
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Geiger JL, Ismaila N, Beadle B, Caudell JJ, Chau N, Deschler D, Glastonbury C, Kaufman M, Lamarre E, Lau HY, Licitra L, Moore MG, Rodriguez C, Roshal A, Seethala R, Swiecicki P, Ha P. Management of Salivary Gland Malignancy: ASCO Guideline. J Clin Oncol 2021; 39:1909-1941. [PMID: 33900808 DOI: 10.1200/jco.21.00449] [Citation(s) in RCA: 216] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
PURPOSE To provide evidence-based recommendations for practicing physicians and other healthcare providers on the management of salivary gland malignancy. METHODS ASCO convened an Expert Panel of medical oncology, surgical oncology, radiation oncology, neuroradiology, pathology, and patient advocacy experts to conduct a literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 2000 through 2020. Outcomes of interest included survival, diagnostic accuracy, disease recurrence, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS The literature search identified 293 relevant studies to inform the evidence base for this guideline. Six main clinical questions were addressed, which included subquestions on preoperative evaluations, surgical diagnostic and therapeutic procedures, appropriate radiotherapy techniques, the role of systemic therapy, and follow-up evaluations. RECOMMENDATIONS When possible, evidence-based recommendations were developed to address the diagnosis and appropriate preoperative evaluations for patients with a salivary gland malignancy, therapeutic procedures, and appropriate treatment options in various salivary gland histologies.Additional information is available at www.asco.org/head-neck-cancer-guidelines.
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Affiliation(s)
| | | | | | | | | | | | | | - Marnie Kaufman
- Adenoid Cystic Carcinoma Research Foundation, Needham, MA
| | | | | | - Lisa Licitra
- Istituto Nazionale Tumori, Milan, Italy.,University of Milan, Milan, Italy
| | | | | | | | | | | | - Patrick Ha
- University of California San Francisco, San Francisco, CA
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32
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Jin N, George TL, Otterson GA, Verschraegen C, Wen H, Carbone D, Herman J, Bertino EM, He K. Advances in epigenetic therapeutics with focus on solid tumors. Clin Epigenetics 2021; 13:83. [PMID: 33879235 PMCID: PMC8056722 DOI: 10.1186/s13148-021-01069-7] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 04/04/2021] [Indexed: 02/06/2023] Open
Abstract
Epigenetic ("above genetics") modifications can alter the gene expression without altering the DNA sequence. Aberrant epigenetic regulations in cancer include DNA methylation, histone methylation, histone acetylation, non-coding RNA, and mRNA methylation. Epigenetic-targeted agents have demonstrated clinical activities in hematological malignancies and therapeutic potential in solid tumors. In this review, we describe mechanisms of various epigenetic modifications, discuss the Food and Drug Administration-approved epigenetic agents, and focus on the current clinical investigations of novel epigenetic monotherapies and combination therapies in solid tumors.
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Affiliation(s)
- Ning Jin
- The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA
| | - Tiffany L George
- The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA
| | - Gregory A Otterson
- The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA
| | - Claire Verschraegen
- The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA
| | - Haitao Wen
- The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA
| | - David Carbone
- The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA
| | - James Herman
- Department of Medicine, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Erin M Bertino
- The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA.
| | - Kai He
- The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA.
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Tang Z, Lin F, Xiao J, Du X, Zhang J, Li S, Tang G, Chen C, Li J. Case Report: Efficacy of Pyrotinib in ERBB2 Amplification Pulmonary Adenoid Cystic Carcinoma. Front Oncol 2021; 11:605658. [PMID: 33816237 PMCID: PMC8012760 DOI: 10.3389/fonc.2021.605658] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Accepted: 02/24/2021] [Indexed: 02/05/2023] Open
Abstract
Primary pulmonary adenoid cystic carcinomas are salivary tumors that are low-grade malignant and prone to recurrence and metastasis. Surgery is currently the main treatment, but there is no standard with regard to postoperative adjuvant therapy. Adenoid cystic carcinoma is more sensitive to radiotherapy and patients benefit less from chemotherapy, but few studies have focused on targeted therapy, and their conclusions are inconsistent. With respect to primary pulmonary adenoid cystic carcinoma, large-scale studies cannot be conducted due to its low incidence, and studies on the targeted therapy of it are very scarce. A few case reports indicate that targeted therapy can be effective however, suggesting that it may be a good option. The current report is the first on the occurrence of human epidermal growth factor receptor 2 amplification in pulmonary adenoid cystic carcinoma. The patient was treated with pyrotinib for 6 months and achieved stable disease.
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Affiliation(s)
- Zhongben Tang
- Department of Thoracic, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Feng Lin
- Department of Thoracic, West China Hospital of Sichuan University, Chengdu, China
| | - Jiarong Xiao
- Department of Thoracic, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Xiaojun Du
- Department of Thoracic, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Jian Zhang
- Department of Thoracic, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Sini Li
- Department of Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences Peking Union Medical College, Beijing, China
| | - Gongshun Tang
- Department of Nuclear Medicine, West China Hospital of Sichuan University, Chengdu, China
| | - Chen Chen
- Department of Thoracic, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Jian Li
- Department of Thoracic, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
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A Drosophila platform identifies a novel, personalized therapy for a patient with adenoid cystic carcinoma. iScience 2021; 24:102212. [PMID: 33733072 PMCID: PMC7940980 DOI: 10.1016/j.isci.2021.102212] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 01/25/2021] [Accepted: 02/17/2021] [Indexed: 02/07/2023] Open
Abstract
Adenoid cystic carcinoma (ACC) is a rare cancer type that originates in the salivary glands. Tumors commonly invade along nerve tracks in the head and neck, making surgery challenging. Follow-up treatments for recurrence or metastasis including chemotherapy and targeted therapies have shown limited efficacy, emphasizing the need for new therapies. Here, we report a Drosophila-based therapeutic approach for a patient with advanced ACC disease. A patient-specific Drosophila transgenic line was developed to model the five major variants associated with the patient's disease. Robotics-based screening identified a three-drug cocktail—vorinostat, pindolol, tofacitinib—that rescued transgene-mediated lethality in the Drosophila patient-specific line. Patient treatment led to a sustained stabilization and a partial metabolic response of 12 months. Subsequent resistance was associated with new genomic amplifications and deletions. Given the lack of options for patients with ACC, our data suggest that this approach may prove useful for identifying novel therapeutic candidates.
Personalized therapy was developed for patient with Adenoid Cystic Carcinoma Genomics analysis was leveraged to establish a Drosophila ‘personalized patient avatar’ A robotics-based screen identified a novel three drug therapeutic cocktail 12 months response was followed by relapse and significant tumor genomic re-wiring
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Lorini L, Ardighieri L, Bozzola A, Romani C, Bignotti E, Buglione M, Guerini A, Lombardi D, Deganello A, Tomasoni M, Bonini SA, Sigala S, Farina D, Ravanelli M, Bossi P. Prognosis and management of recurrent and/or metastatic head and neck adenoid cystic carcinoma. Oral Oncol 2021; 115:105213. [PMID: 33578204 DOI: 10.1016/j.oraloncology.2021.105213] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 01/10/2021] [Accepted: 01/25/2021] [Indexed: 02/07/2023]
Abstract
Adenoid cystic carcinoma (ACC) is a rare tumor, usually arising in the salivary gland, accounting for 1% of all head and neck cancers. ACC may have a long-term poor prognosis, as about 40% of radically treated patients will recur locoregionally and up to 60% will develop distant metastasis. Factors influencing risk of recurrence have been well studied, but few data exist about prognostic factors in Recurrent/Metastatic (RM) setting. Moreover, treatment of RM ACC is often a challenge for clinicians, in the context of a rare disease, which may have an indolent clinical behavior or less frequently a quicker growth and with a paucity of available clinical trials. This review critically analyzes pathological and molecular prognostic factors in RM ACC and make an overview on actual therapeutic choices and future direction of therapy. Recognized prognostic factors in RM ACC are the presence and site of distant metastasis (lung vs other), the presence of nodal metastasis and of extranodal extension, skull base recurrence, disease free interval, lymphovascular invasion, solid histotypes and grading of disease, and the presence of mutation of NOTCH1 family, PI3K, and TP53. Due to disappointing results with chemotherapy, new approaches are under study, also on the basis of biomolecular research. Ongoing clinical trials are evaluating treatment targeting MYB and NOTCH1 alterations, immunotherapy or combination of targeted treatments and immune checkpoint inhibitors.
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Affiliation(s)
- Luigi Lorini
- Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, ASST Spedali Civili of Brescia, University of Brescia, Brescia, Italy
| | - Laura Ardighieri
- Department of Pathology, ASST Spedali Civili of Brescia, Brescia, Italy
| | - Anna Bozzola
- Department of Pathology, ASST Spedali Civili of Brescia, Brescia, Italy
| | - Chiara Romani
- Angelo Nocivelli Institute of Molecular Medicine, University of Brescia and ASST-Spedali Civili of Brescia, 25123 Brescia, Italy
| | - Eliana Bignotti
- Angelo Nocivelli Institute of Molecular Medicine, University of Brescia and ASST-Spedali Civili of Brescia, 25123 Brescia, Italy
| | - Michela Buglione
- Radiation Oncology Unit, Department of Medical and Surgical Specialties, Radiological Science and Public Health, ASST Spedali Civili of Brescia, University of Brescia, Brescia, Italy
| | - Andrea Guerini
- Radiation Oncology Unit, Department of Medical and Surgical Specialties, Radiological Science and Public Health, ASST Spedali Civili of Brescia, University of Brescia, Brescia, Italy
| | - Davide Lombardi
- Unit of Otorhinolaryngology-Head and Neck Surgery, ASST Spedali Civili of Brescia, Department of Medical and Surgical Specialties, Radiologic Sciences, and Public Health, University of Brescia, Brescia, Italy
| | - Alberto Deganello
- Unit of Otorhinolaryngology-Head and Neck Surgery, ASST Spedali Civili of Brescia, Department of Medical and Surgical Specialties, Radiologic Sciences, and Public Health, University of Brescia, Brescia, Italy
| | - Michele Tomasoni
- Unit of Otorhinolaryngology-Head and Neck Surgery, ASST Spedali Civili of Brescia, Department of Medical and Surgical Specialties, Radiologic Sciences, and Public Health, University of Brescia, Brescia, Italy
| | - Sara Anna Bonini
- Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Sandra Sigala
- Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Davide Farina
- Department of Radiology, University of Brescia, Italy
| | | | - Paolo Bossi
- Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, ASST Spedali Civili of Brescia, University of Brescia, Brescia, Italy.
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Jenke R, Reßing N, Hansen FK, Aigner A, Büch T. Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives. Cancers (Basel) 2021; 13:634. [PMID: 33562653 PMCID: PMC7915831 DOI: 10.3390/cancers13040634] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/30/2021] [Accepted: 02/02/2021] [Indexed: 12/26/2022] Open
Abstract
The increasing knowledge of molecular drivers of tumorigenesis has fueled targeted cancer therapies based on specific inhibitors. Beyond "classic" oncogene inhibitors, epigenetic therapy is an emerging field. Epigenetic alterations can occur at any time during cancer progression, altering the structure of the chromatin, the accessibility for transcription factors and thus the transcription of genes. They rely on post-translational histone modifications, particularly the acetylation of histone lysine residues, and are determined by the inverse action of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Importantly, HDACs are often aberrantly overexpressed, predominantly leading to the transcriptional repression of tumor suppressor genes. Thus, histone deacetylase inhibitors (HDACis) are powerful drugs, with some already approved for certain hematological cancers. Albeit HDACis show activity in solid tumors as well, further refinement and the development of novel drugs are needed. This review describes the capability of HDACis to influence various pathways and, based on this knowledge, gives a comprehensive overview of various preclinical and clinical studies on solid tumors. A particular focus is placed on strategies for achieving higher efficacy by combination therapies, including phosphoinositide 3-kinase (PI3K)-EGFR inhibitors and hormone- or immunotherapy. This also includes new bifunctional inhibitors as well as novel approaches for HDAC degradation via PROteolysis-TArgeting Chimeras (PROTACs).
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Affiliation(s)
- Robert Jenke
- University Cancer Center Leipzig (UCCL), University Hospital Leipzig, D-04103 Leipzig, Germany
- Clinical Pharmacology, Rudolf-Boehm-Institute for Pharmacology and Toxicology, Medical Faculty, University of Leipzig, D-04107 Leipzig, Germany;
| | - Nina Reßing
- Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, Rheinische Fried-rich-Wilhelms-Universität Bonn, D-53121 Bonn, Germany; (N.R.); (F.K.H.)
| | - Finn K. Hansen
- Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, Rheinische Fried-rich-Wilhelms-Universität Bonn, D-53121 Bonn, Germany; (N.R.); (F.K.H.)
| | - Achim Aigner
- Clinical Pharmacology, Rudolf-Boehm-Institute for Pharmacology and Toxicology, Medical Faculty, University of Leipzig, D-04107 Leipzig, Germany;
| | - Thomas Büch
- Clinical Pharmacology, Rudolf-Boehm-Institute for Pharmacology and Toxicology, Medical Faculty, University of Leipzig, D-04107 Leipzig, Germany;
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Di Villeneuve L, Souza IL, Tolentino FDS, Ferrarotto R, Schvartsman G. Salivary Gland Carcinoma: Novel Targets to Overcome Treatment Resistance in Advanced Disease. Front Oncol 2020; 10:580141. [PMID: 33194707 PMCID: PMC7649804 DOI: 10.3389/fonc.2020.580141] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Accepted: 09/09/2020] [Indexed: 12/20/2022] Open
Abstract
Salivary gland carcinomas (SGCs) account for <5% of head and neck malignant neoplasms, further subcategorized in over 20 histological subtypes. For the most part, treatment for advanced disease is guided by morphology. SGCs in general respond poorly to a wide array of standard chemotherapy, with short durability, and significant toxicity. More recently, next-generation sequencing provided significant input on the molecular characterization of each SGC subtype, not only improving diagnostic differentiation between morphologically similar tumor types but also identifying novel driver pathways that determine tumor biology and may be amenable to targeted therapy. Among the most common histological subtype is adenoid cystic carcinoma, which often harbors a chromosome translocation resulting in an MYB-NFIB oncogene, with various degrees of Myb surface expression. In a smaller subset, NOTCH1 mutations occur, conferring a more aggressive pattern and potential sensitivity to Notch inhibitors. Salivary duct carcinomas may overexpress Her-2 and androgen receptors, with promising clinical outcomes after exposure to targeted therapies approved for other indications. Secretory carcinoma, previously known as mammary analog secretory carcinoma, is distinguished by an ETV6-NTRK3 fusion that can both help differentiate it from its morphologically similar acinar cell carcinoma and make it susceptible to Trk inhibitors. In the present article, we discuss the molecular abnormalities, their impact on tumor biology, and therapeutic opportunities for the most common SGC subtypes and review published and ongoing clinical trials and future perspectives for this rare disease.
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Affiliation(s)
- Larissa Di Villeneuve
- Department of Medical Oncology, Hospital Israelita Albert Einstein, São Paulo, Brazil
| | - Ive Lima Souza
- Department of Medical Oncology, Hospital Israelita Albert Einstein, São Paulo, Brazil
| | | | - Renata Ferrarotto
- Department of Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Gustavo Schvartsman
- Department of Medical Oncology, Hospital Israelita Albert Einstein, São Paulo, Brazil
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38
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Small Ones to Fight a Big Problem-Intervention of Cancer Metastasis by Small Molecules. Cancers (Basel) 2020; 12:cancers12061454. [PMID: 32503267 PMCID: PMC7352875 DOI: 10.3390/cancers12061454] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 05/26/2020] [Accepted: 05/28/2020] [Indexed: 02/07/2023] Open
Abstract
Metastasis represents the most lethal attribute of cancer and critically limits successful therapies in many tumor entities. The clinical need is defined by the fact that all cancer patients, who have or who will develop distant metastasis, will experience shorter survival. Thus, the ultimate goal in cancer therapy is the restriction of solid cancer metastasis by novel molecularly targeted small molecule based therapies. Biomarkers identifying cancer patients at high risk for metastasis and simultaneously acting as key drivers for metastasis are extremely desired. Clinical interventions targeting these key molecules will result in high efficiency in metastasis intervention. In result of this, personalized tailored interventions for restriction and prevention of cancer progression and metastasis will improve patient survival. This review defines crucial biological steps of the metastatic cascade, such as cell dissemination, migration and invasion as well as the action of metastasis suppressors. Targeting these biological steps with tailored therapeutic strategies of intervention or even prevention of metastasis using a wide range of small molecules will be discussed.
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Morales Torres C, Wu MY, Hobor S, Wainwright EN, Martin MJ, Patel H, Grey W, Grönroos E, Howell S, Carvalho J, Snijders AP, Bustin M, Bonnet D, Smith PD, Swanton C, Howell M, Scaffidi P. Selective inhibition of cancer cell self-renewal through a Quisinostat-histone H1.0 axis. Nat Commun 2020; 11:1792. [PMID: 32286289 PMCID: PMC7156485 DOI: 10.1038/s41467-020-15615-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Accepted: 03/19/2020] [Indexed: 12/24/2022] Open
Abstract
Continuous cancer growth is driven by subsets of self-renewing malignant cells. Targeting of uncontrolled self-renewal through inhibition of stem cell-related signaling pathways has proven challenging. Here, we show that cancer cells can be selectively deprived of self-renewal ability by interfering with their epigenetic state. Re-expression of histone H1.0, a tumor-suppressive factor that inhibits cancer cell self-renewal in many cancer types, can be broadly induced by the clinically well-tolerated compound Quisinostat. Through H1.0, Quisinostat inhibits cancer cell self-renewal and halts tumor maintenance without affecting normal stem cell function. Quisinostat also hinders expansion of cells surviving targeted therapy, independently of the cancer types and the resistance mechanism, and inhibits disease relapse in mouse models of lung cancer. Our results identify H1.0 as a major mediator of Quisinostat's antitumor effect and suggest that sequential administration of targeted therapy and Quisinostat may be a broadly applicable strategy to induce a prolonged response in patients.
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Affiliation(s)
| | - Mary Y Wu
- High-Throughput Screening, Francis Crick Institute, London, NW1 1AT, UK
| | - Sebastijan Hobor
- Cancer Evolution and Genome Instability Laboratory, Francis Crick Institute, London, NW1 1AT, UK
| | | | | | - Harshil Patel
- Bioinformatics and Biostatistics, Francis Crick Institute, London, NW1 1AT, UK
| | - William Grey
- Haematopoietic Stem Cell Laboratory, Francis Crick Institute, London, NW1 1AT, UK
| | - Eva Grönroos
- Cancer Evolution and Genome Instability Laboratory, Francis Crick Institute, London, NW1 1AT, UK
| | - Steven Howell
- Proteomics, Francis Crick Institute, London, NW1 1AT, UK
| | - Joana Carvalho
- Experimental Histopathology, Francis Crick Institute, London, NW1 1AT, UK
| | | | - Michael Bustin
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20814, USA
| | - Dominique Bonnet
- Haematopoietic Stem Cell Laboratory, Francis Crick Institute, London, NW1 1AT, UK
| | - Paul D Smith
- Oncology R&D, AstraZeneca, Cambridge, CB2 0RE, UK
| | - Charles Swanton
- Cancer Evolution and Genome Instability Laboratory, Francis Crick Institute, London, NW1 1AT, UK
- Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, University College London, London, WC1E 6BT, UK
| | - Michael Howell
- High-Throughput Screening, Francis Crick Institute, London, NW1 1AT, UK
| | - Paola Scaffidi
- Cancer Epigenetics Laboratory, Francis Crick Institute, London, NW1 1AT, UK.
- UCL Cancer Institute, University College London, London, WC1E 6DD, UK.
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Prabhash K, Kapoor A, Noronha V, Chougule A, Chandrani P, Shetty O, Patil V, Joshi A, Menon N, Bal M, Vaish R, Kumar A. Molecular tumor board: Case 4 Salivary Gland Cancer: Novel therapeutic options as a result of comprehensive molecular profiling. CANCER RESEARCH, STATISTICS, AND TREATMENT 2020. [DOI: 10.4103/crst.crst_258_20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
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Rodriguez CP, Wu Q(V, Voutsinas J, Fromm JR, Jiang X, Pillarisetty VG, Lee SM, Santana-Davila R, Goulart B, Baik CS, Chow LQ, Eaton K, Martins R. A Phase II Trial of Pembrolizumab and Vorinostat in Recurrent Metastatic Head and Neck Squamous Cell Carcinomas and Salivary Gland Cancer. Clin Cancer Res 2019; 26:837-845. [DOI: 10.1158/1078-0432.ccr-19-2214] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 10/29/2019] [Accepted: 11/26/2019] [Indexed: 11/16/2022]
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Cherifi F, Rambeau A, Johnson A, Florescu C, Géry B, Babin E, Thariat J. Traitements systémiques du carcinome adénoïde kystique de la sphère ORL localement avancé ou métastatique, une revue systématique. Bull Cancer 2019; 106:923-938. [DOI: 10.1016/j.bulcan.2019.05.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 03/17/2019] [Accepted: 05/11/2019] [Indexed: 02/07/2023]
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Mettananda S, Yasara N, Fisher CA, Taylor S, Gibbons R, Higgs D. Synergistic silencing of α-globin and induction of γ-globin by histone deacetylase inhibitor, vorinostat as a potential therapy for β-thalassaemia. Sci Rep 2019; 9:11649. [PMID: 31406232 PMCID: PMC6690964 DOI: 10.1038/s41598-019-48204-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Accepted: 07/30/2019] [Indexed: 12/22/2022] Open
Abstract
β-Thalassaemia is one of the most common monogenic diseases with no effective cure in the majority of patients. Unbalanced production of α-globin in the presence of defective synthesis of β-globin is the primary mechanism for anaemia in β-thalassaemia. Clinical genetic data accumulated over three decades have clearly demonstrated that direct suppression of α-globin and induction of γ-globin are effective in reducing the globin chain imbalance in erythroid cells hence improving the clinical outcome of patients with β-thalassaemia. Here, we show that the histone deacetylase inhibitor drug, vorinostat, in addition to its beneficial effects for patients with β-thalassaemia through induction of γ-globin, has the potential to simultaneously suppress α-globin. We further show that vorinostat exhibits these synergistic beneficial effects in globin gene expression at nanomolar concentrations without perturbing erythroid expansion, viability, differentiation or the transcriptome. This new evidence will be helpful for the interpretation of existing clinical trials and future clinical studies that are directed towards finding a cure for β-thalassaemia using vorinostat.
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Affiliation(s)
- Sachith Mettananda
- Department of Paediatrics, University of Kelaniya, Thalagolla Road, Ragama, 11010, Sri Lanka. .,Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, UK.
| | - Nirmani Yasara
- Department of Paediatrics, University of Kelaniya, Thalagolla Road, Ragama, 11010, Sri Lanka
| | - Christopher A Fisher
- Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, UK
| | - Stephen Taylor
- Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
| | - Richard Gibbons
- Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, UK
| | - Doug Higgs
- Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, UK
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Abstract
The most common type of head and neck cancer, head and neck squamous cell carcinoma (HNSCC), can develop therapeutic resistance that complicates its treatment. The 5-y survival rate for HNSCC remains at ~50%, and improving these outcomes requires a better understanding of the pathogenesis of HNSCC. Studies of HNSCC using in vitro, ex vivo, and in vivo approaches provide a novel conceptual framework based on epigenetic mechanisms for developing future clinical applications. Normal oral tissues are influenced by environmental factors that induce pathological changes affecting the network of epigenetic enzymes and signaling pathways to induce HNSCC growth and metastasis. Although various epigenetic regulator families, such as DNA methyltransferases, ten-eleven translocation proteins, histone acetyltransferases, histone deacetylases, BET bromodomain proteins, protein arginine methyltransferases, histone lysine methyltransferases, and histone lysine demethylases, have a role in diverse cancers, specific members have a function in HNSCC. Recently, lysine-specific demethylases have been identified as a potential, attractive, and novel target of HNSCC. Lysine-specific demethylase 1 (LSD1) expression is inappropriately upregulated in HNSCC and an orthotopic HNSCC mouse model. LSD1 can demethylate lysine at specific histone positions to repress gene expression or stimulate transcription, indicating a dual and context-dependent role in transcriptional regulation. Our study showed that LSD1 promotes HNSCC growth and metastasis. Pharmacological attenuation of LSD1 inhibits orthotopic and patient-derived HNSCC xenograft growth-specific target genes and signaling pathways. This review provides recent evidence demonstrating the function of epigenetic regulator enzymes in HNSCC progression, including potential therapeutic applications for such enzymes in combination and immunotherapy.
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Affiliation(s)
- M.V. Bais
- Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA, USA
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Doddapaneni R, Tao W, Naranjo A, Nikpoor N, Tse DT, Pelaez D. Fibroblast growth factor receptor 1 (FGFR1) as a therapeutic target in adenoid cystic carcinoma of the lacrimal gland. Oncotarget 2019; 10:480-493. [PMID: 30728899 PMCID: PMC6355187 DOI: 10.18632/oncotarget.26558] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 12/20/2018] [Indexed: 11/25/2022] Open
Abstract
Identification of molecular targets is the first step in developing efficacious therapeutic strategies for tumors. A tumors' biological response to perturbagens yields important information on the molecular determinants for tumor growth. The aim of this study was to characterize the response of adenoid cystic carcinoma of the lacrimal gland (LGACC) to intra-arterial cytoreductive chemotherapy (IACC) in order to identify novel targets to enhance therapy. We performed high-throughput proteomic analysis on paired samples from pre-IACC diagnostic biopsies and post-IACC excised tumor samples from 6 LGACC patients. This proteomic analysis provides a comprehensive landscape of the cellular compartments contained within the excised tumors. Interestingly, we found a strong upregulation across the fibroblast growth factor (FGF) signaling pathway, with FGF receptor 1 (FGFR1) exhibiting a consistent and significant upregulation in all post-IACC samples. We thus evaluated the therapeutic efficacy of a novel FGFR1 selective inhibitor, AZD4547, in combination with cisplatin on LGACC cells in-vitro. The combination index (CI) value (<0.895) demonstrated synergistic effect of AZD4547 and cisplatin in inhibiting cell growth and viability (p<0.02), with a differential response seen in post-IACC cultures when compared to pre-IACC cultures. The combination approach showed synergy of the drugs in the migration assay. Western blot analysis indicated a significant upregulation of cleaved caspase-3 and downregulation the expression of FGFR1 (p<0.05) with the combination treatment as compared to either agent independently. Our findings demonstrate that FGFR1 inhibition potentiates the cytoreductive effects of cisplatin and suggest a potential therapeutic benefit of using AZD4547 in the management of LGACC.
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Affiliation(s)
- Ravi Doddapaneni
- Dr. Nasser Al-Rashid Orbital Vision Research Center, Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Wensi Tao
- Dr. Nasser Al-Rashid Orbital Vision Research Center, Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Andrea Naranjo
- Dr. Nasser Al-Rashid Orbital Vision Research Center, Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Neda Nikpoor
- Dr. Nasser Al-Rashid Orbital Vision Research Center, Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - David T Tse
- Dr. Nasser Al-Rashid Orbital Vision Research Center, Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Daniel Pelaez
- Dr. Nasser Al-Rashid Orbital Vision Research Center, Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Department of Biomedical Engineering, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Department of Cell Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
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Schvartsman G, Pinto NA, Bell D, Ferrarotto R. Salivary gland tumors: Molecular characterization and therapeutic advances for metastatic disease. Head Neck 2018; 41:239-247. [PMID: 30552848 DOI: 10.1002/hed.25468] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 06/11/2018] [Accepted: 07/05/2018] [Indexed: 01/03/2023] Open
Abstract
Salivary gland cancers represent a rare group of tumors composed by over 20 histological subtypes. Initially treated as one single disease, its diagnosis, prognosis, and treatment are currently being stratified based on morphology. More recently, insight has been provided on the molecular characterization of each subtype, further improving diagnostic accuracy and paving the way for personalized therapy. In this article, we provide a comprehensive review of recent breakthroughs, preliminary results of novel therapy, and future directions on the treatment of these complex malignancies.
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Affiliation(s)
- Gustavo Schvartsman
- Department of Oncology, Hospital Israelita Albert Einstein, São Paulo, Brazil
| | | | - Diana Bell
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Renata Ferrarotto
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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The MYB/miR-130a/NDRG2 axis modulates tumor proliferation and metastatic potential in salivary adenoid cystic carcinoma. Cell Death Dis 2018; 9:917. [PMID: 30206227 PMCID: PMC6134089 DOI: 10.1038/s41419-018-0966-2] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Revised: 08/09/2018] [Accepted: 08/20/2018] [Indexed: 12/13/2022]
Abstract
Increasing evidence has emerged to suggest that N-myc downstream-regulated gene 2 (NDRG2) dysregulation participates in a number of tumor biological processes. However, the role of NDRG2 and miRNA-mediated NDRG2 regulation in salivary adenoid cystic carcinoma (SACC) progression remain unknown. Here, we determined that SACC tissues exhibited decreased level of NDRG2, which was associated with poorer rates of overall survival and distant metastasis-free survival. Silencing NDRG2 promoted SACC cell proliferation and metastasis both in vitro and in vivo. MiRNAs have been reported as vital regulators of NDRG2 expression. Based on micronome sequencing of three paired samples of SACC and normal salivary gland tissue and on an online database analysis, miR-130a was identified as a candidate miRNA that potentially regulates NDRG2. We demonstrated that the expression level of NDRG2 was dramatically reduced by exogenous miR-130a. Moreover, a luciferase assay further validated that miR-130a could degrade NDRG2 mRNA by targeting sites in the NDRG2 3'UTR. A rescue experiment suggested that NDRG2 expression could reverse the miR-130a-mediated promotion of cell proliferation and invasion. The expression of miR-130a has been reported to be regulated by certain transcription factors. In the preset study, we verified that the transcription factor MYB acted as the critical driver in SACC-upregulated miR-130a expression directly and induced NDRG2 downregulation in SACC tissues. Additionally, MYB/miR-130a activated the STAT3 and AKT pathways by downregulating NDRG2. These observations suggest that the MYB/miR-130a/NDRG2 axis, which modulates proliferation and metastasis in SACC, provides promising targets for the treatment of SACC.
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Rack S, Rahman R, Carter L, McKay C, Metcalf R. Impact of tumour profiling on clinical trials in salivary gland cancer. Clin Otolaryngol 2018; 44:1-6. [PMID: 30102009 DOI: 10.1111/coa.13206] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 08/02/2018] [Indexed: 01/21/2023]
Affiliation(s)
- Samuel Rack
- The University of Manchester, Manchester, UK
| | | | - Louise Carter
- The University of Manchester, Manchester, UK.,The Christie NHS Foundation Trust, Manchester, UK
| | - Craig McKay
- The Christie NHS Foundation Trust, Manchester, UK
| | - Robert Metcalf
- The Christie NHS Foundation Trust, Manchester, UK.,The Cancer Research UK Manchester Institute, Manchester, UK
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Tan E, Mody MD, Saba NF. Systemic therapy in non-conventional cancers of the larynx. Oral Oncol 2018; 82:61-68. [DOI: 10.1016/j.oraloncology.2018.05.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2018] [Revised: 05/05/2018] [Accepted: 05/10/2018] [Indexed: 12/11/2022]
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Chahal M, Pleasance E, Grewal J, Zhao E, Ng T, Chapman E, Jones MR, Shen Y, Mungall KL, Bonakdar M, Taylor GA, Ma Y, Mungall AJ, Moore RA, Lim H, Renouf D, Yip S, Jones SJM, Marra MA, Laskin J. Personalized oncogenomic analysis of metastatic adenoid cystic carcinoma: using whole-genome sequencing to inform clinical decision-making. Cold Spring Harb Mol Case Stud 2018; 4:a002626. [PMID: 29610392 PMCID: PMC5880267 DOI: 10.1101/mcs.a002626] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Accepted: 02/13/2018] [Indexed: 12/19/2022] Open
Abstract
Metastatic adenoid cystic carcinomas (ACCs) can cause significant morbidity and mortality. Because of their slow growth and relative rarity, there is limited evidence for systemic therapy regimens. Recently, molecular profiling studies have begun to reveal the genetic landscape of these poorly understood cancers, and new treatment possibilities are beginning to emerge. The objective is to use whole-genome and transcriptome sequencing and analysis to better understand the genetic alterations underlying the pathology of metastatic and rare ACCs and determine potentially actionable therapeutic targets. We report five cases of metastatic ACC, not originating in the salivary glands, in patients enrolled in the Personalized Oncogenomics (POG) Program at the BC Cancer Agency. Genomic workup included whole-genome and transcriptome sequencing, detailed analysis of tumor alterations, and integration with existing knowledge of drug-target combinations to identify potential therapeutic targets. Analysis reveals low mutational burden in these five ACC cases, and mutation signatures that are commonly observed in multiple cancer types. Notably, the only recurrent structural aberration identified was the well-described MYB-NFIB fusion that was present in four of five cases, and one case exhibited a closely related MYBL1-NFIB fusion. Recurrent mutations were also identified in BAP1 and BCOR, with additional mutations in individual samples affecting NOTCH1 and the epigenetic regulators ARID2, SMARCA2, and SMARCB1. Copy changes were rare, and they included amplification of MYC and homozygous loss of CDKN2A in individual samples. Genomic analysis revealed therapeutic targets in all five cases and served to inform a therapeutic choice in three of the cases to date.
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Affiliation(s)
- Manik Chahal
- Department of Medicine, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada
| | - Erin Pleasance
- British Columbia Cancer Agency, Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 4E6, Canada
| | - Jasleen Grewal
- British Columbia Cancer Agency, Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 4E6, Canada
| | - Eric Zhao
- British Columbia Cancer Agency, Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 4E6, Canada
| | - Tony Ng
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada
| | - Erin Chapman
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada
| | - Martin R Jones
- British Columbia Cancer Agency, Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 4E6, Canada
| | - Yaoqing Shen
- British Columbia Cancer Agency, Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 4E6, Canada
| | - Karen L Mungall
- British Columbia Cancer Agency, Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 4E6, Canada
| | - Melika Bonakdar
- British Columbia Cancer Agency, Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 4E6, Canada
| | - Gregory A Taylor
- British Columbia Cancer Agency, Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 4E6, Canada
| | - Yussanne Ma
- British Columbia Cancer Agency, Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 4E6, Canada
| | - Andrew J Mungall
- British Columbia Cancer Agency, Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 4E6, Canada
| | - Richard A Moore
- British Columbia Cancer Agency, Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 4E6, Canada
| | - Howard Lim
- British Columbia Cancer Agency, Division of Medical Oncology, Vancouver, British Columbia V5Z 4E6, Canada
| | - Daniel Renouf
- British Columbia Cancer Agency, Division of Medical Oncology, Vancouver, British Columbia V5Z 4E6, Canada
| | - Stephen Yip
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada
| | - Steven J M Jones
- British Columbia Cancer Agency, Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 4E6, Canada
- Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada
| | - Marco A Marra
- British Columbia Cancer Agency, Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 4E6, Canada
- Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada
| | - Janessa Laskin
- British Columbia Cancer Agency, Division of Medical Oncology, Vancouver, British Columbia V5Z 4E6, Canada
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