PSMA PET Imaging and Therapy in Adenoid Cystic Carcinoma and Other Salivary Gland Cancers: A Systematic Review.
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ABSTRACT:
SUBMITTER: Tan BF
PROVIDER: S-EPMC9330626 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
| S-EPMC8493384 | biostudies-literature
Project description:Rationale: Treatment options for recurrent and/or metastatic (R/M) adenoid cystic carcinoma (ACC) and salivary duct carcinoma (SDC), major subtypes of salivary gland cancer, are limited. Both tumors often show overexpression of prostate-specific membrane antigen (PSMA). In prostate cancer, PSMA-ligands labeled with 68Ga or 177Lu are used for imaging and therapy, respectively. Primary aim of this study in R/M ACC and SDC patients was to systematically investigate 68Ga-PSMA-uptake by PET/CT imaging to determine if PSMA radionuclide therapy could be a treatment option. Methods: In a prospective phase II study, PET/CT imaging was performed 1 h post injection of 68Ga-PSMA-HBED-CC in 15 ACC patients and 10 SDC patients. Maximum standardized uptake values (SUV) were determined in tumor lesions. Immunohistochemical PSMA expression was scored in primary tumors and metastatic tissue. Standard imaging (MRI or CT) was performed for comparison. Results: In ACC patients, SUVmax ranged from 1.1 to 30.2 with a tumor/liver-ratio >1 in 13 out of 14 evaluable patients (93%). In SDC patients, SUVmax ranged from 0.3 to 25.9 with a tumor/liver-ratio >1 in 4 out of 10 patients (40%). We found a large intra-patient inter-metastatic variation in uptake of 68Ga-PSMA, and immunohistochemistry did not predict ligand uptake in ACC and SDC. Finally, PSMA-PET detected additional bone metastases compared to CT in 2 ACC patients with unexplained pain. Conclusion: In 93% of ACC patients and 40% of SDC patients we detected relevant PSMA-ligand uptake, which warrants to study PSMA radionuclide therapy in these patients. Additionally, our data provide arguments for patient selection and treatment timing. Finally, PSMA-PET imaging has added diagnostic value compared to CT in selected patients.
| S-EPMC7019174 | biostudies-literature
Project description:Adenoid cystic carcinomas (ACC) of the salivary glands are challenging to understand, treat, and cure. To better understand the genetic alterations underlying the pathogenesis of these tumors, we performed comprehensive genome analyses of 25 fresh-frozen tumors, including whole-genome sequencing and expression and pathway analyses. In addition to the well-described MYB-NFIB fusion that was found in 11 tumors (44%), we observed five different rearrangements involving the NFIB transcription factor gene in seven tumors (28%). Taken together, NFIB translocations occurred in 15 of 25 samples (60%, 95% CI, 41%-77%). In addition, mRNA expression analysis of 17 tumors revealed overexpression of NFIB in ACC tumors compared with normal tissues (P = 0.002). There was no difference in NFIB mRNA expression in tumors with NFIB fusions compared with those without. We also report somatic mutations of genes involved in the axonal guidance and Rho family signaling pathways. Finally, we confirm previously described alterations in genes related to chromatin regulation and Notch signaling. Our findings suggest a separate role for NFIB in ACC oncogenesis and highlight important signaling pathways for future functional characterization and potential therapeutic targeting.
| S-EPMC4818686 | biostudies-literature
Project description:OBJECTIVES:The patterns of care for salivary gland adenoid cystic carcinomas (ACC) are unknown. We sought to assess predictors of receiving postoperative radiation and/or chemotherapy for patients with nonmetastatic, definitively resected ACC, as well as report unexpected nodal disease. METHODS:The National Cancer Data Base was queried for definitively resected nonmetastatic ACC from 2004 to 2014. Logistic regression, Kaplan-Meier, and Cox proportional-hazard models were utilized. Propensity-score matched analysis was employed to reduce confounding variables. RESULTS:A total of 3,136 patients met entry criteria: 2,252 (71.8%) received postoperative radiation, with 223 (7.4%) also receiving concurrent chemotherapy. Median follow-up was 4.87 years. In clinically lymph node negative (cN0) patients, 7.4% had pathologically positive lymph nodes (pN)?+?after elective neck dissection. Patients who lived closer to their treatment facility and had positive margins were more likely to receive postoperative radiation. Black patients and uninsured patients were less likely to receive radiation. Older age, male sex, advancing stage, and positive surgical margins were associated with worse overall survival (OS). With limited follow-up, receipt of radiation or chemotherapy was not associated with OS. CONCLUSION:Postoperative radiation was frequently given for resected ACC, with a minority receiving chemotherapy. Black patients and uninsured patients were less likely to receive radiation. Postoperative radiation and/or chemotherapy had no association with OS but were given in greater frequency in more advanced disease, and our series is limited by short follow-up. The disparity findings for this rare disease need to be addressed in future studies. LEVEL OF EVIDENCE:2c Laryngoscope, 129:377-386, 2019.
| S-EPMC6344280 | biostudies-literature
Project description:Salivary gland adenoid cystic carcinoma (ACC) is a rare malignancy that is poorly understood. To look for relevant oncogene candidates under the control of promoter methylation, an integrated, genome-wide screen was conducted.Global demethylation of normal salivary gland cell strains using 5-aza-2'-deoxycytidine (5-aza-dC) and trichostatin A (TSA), followed by expression array analysis was conducted. ACC-specific expression profiling was generated using expression microarray analysis of primary ACC and normal samples. Next, the two profiles were integrated to identify a subset of genes for further validation of promoter demethylation in ACC versus normal. Finally, promising candidates were further validated for mRNA, protein, and promoter methylation levels in larger ACC cohorts. Functional validation was then conducted in cancer cell lines.We found 159 genes that were significantly re-expressed after 5-aza-dC/TSA treatment and overexpressed in ACC. After initial validation, eight candidates showed hypomethylation in ACC: AQP1, CECR1, C1QR1, CTAG2, P53AIP1, TDRD12, BEX1, and DYNLT3. Aquaporin 1 (AQP1) showed the most significant hypomethylation and was further validated. AQP1 hypomethylation in ACC was confirmed with two independent cohorts. Of note, there was significant overexpression of AQP1 in both mRNA and protein in the paraffin-embedded ACC cohort. Furthermore, AQP1 was upregulated in 5-aza-dC/TSA-treated SACC83. Finally, AQP1 promoted cell proliferation and colony formation in SACC83.Our integrated, genome-wide screening method proved to be an effective strategy for detecting novel oncogenes in ACC. AQP1 is a promising oncogene candidate for ACC and is transcriptionally regulated by promoter hypomethylation.
| S-EPMC3131484 | biostudies-literature
Project description:In this study, we accessed the expression and correlation of p-STAT3 with Survivin, Cyclin D1, CD147, Slug and Ki67 by immunohistochemical staining of human tissue microarray which contains 72 adenoid cystic carcinoma (AdCC), 12 pleomorphic adenoma (PMA) and 18 normal salivary gland (NSG) using digital pathological scanner and scoring system. We found that the expression of p-STAT3, Survivin, Slug, Cyclin D1 and CD147 was significantly increased in AdCC as compared with PMA and (or) NSG (p<0.05). While, the level of p-STAT3 and expression of Cyclin D1 and CD147 was not associated with pathological type of human AdCC (p>0.05). Correlation analysis of these proteins revealed that p-STAT3 up-regulates the expression of Survivin, Slug, Cyclin D1 and CD147 (p<0.05). Moreover, the activation of STAT3 was associated with proliferation marker Ki-67 (p<0.05). Selective inhibition of STAT3 by a small molecule S3I-201 significantly reduced human SACC-83 and SACC-LM cells proliferation, migration and invasion with the corresponding decrease in expression of Survivin, Slug, Cyclin D1 and CD147. These findings indicate that high phosphorylation level of STAT3 in AdCC is related to Survivin, Slug, Cyclin D1 and CD147. We suggest that the inhibition of STAT3 may be a novel strategy for neoadjuvant chemotherapeutic treatment of AdCC.
| S-EPMC4497441 | biostudies-literature
Project description:Adenoid cystic carcinoma (ACC) is a tumor of the exocrine glands that originates primarily from the minor and major salivary glands, nasopharynx, and lacrimal glands. ACC grows slowly but is locally aggressive and prone to recurrence. It is uncommon for ACCs to develop in the pituitary gland as a primary tumor. We present a case of primary pituitary ACC extending to the sphenoid sinus resembling an invasive adenoma in a 71-year-old woman with a history of nasal epistaxis. We reviewed other reported cases of pituitary ACCs with retrospective validation of whether the tumor was primary or not. The intrasellar tumor exhibited MYB rearrangement with enlargement and destruction of the sella turcica and dural tears toward the sphenoid sinus, which would be consistent for a tumor originating from the pituitary gland. Including our case, only four intrasellar and one suprasellar ACC have been confirmed as primary tumors. All intrasellar ACCs had the characteristic of some form of invasion of neighboring structures with evidence of hyperprolactinemia. ACC could develop in the pituitary gland as a form of salivary gland-like tumor derived from the ectopic salivary gland rests. ACCs rarely arise from the pituitary gland; however, the accurate determination of primary occurrence is difficult because of the invasive nature of these tumors, and the anatomical relationship with the sphenoid sinus and the cavernous sinus. Excessive bleeding from the tumor or unexpected internal carotid artery injury should be avoided during surgery for primary and secondary pituitary ACC.
| S-EPMC8633198 | biostudies-literature
Project description:BackgroundThis pilot study was designed to evaluate the diagnostic value of 68 Ga-PSMA-617 and 18F-FDG PET/CT in adenoid cystic carcinoma (ACC) and to assess the safety and therapeutic response to PSMA radioligand therapy (RLT) in ACC patients.MethodsThirty patients pathologically diagnosed with ACC were recruited into the cohort. Each patient underwent 68 Ga-PSMA-617 and 18F-FDG PET/CT within 1 week. The number and SUVmax of PET-positive lesions were recorded and compared. Four patients accepted RLT using 177Lu-EB-PSMA-617, in a dosage of approximately 1.85 GBq (50 mCi) per cycle for up to 3 cycles.ResultsCompared with 18F-FDG, 68 Ga-PSMA-617 revealed more PET-positive extrapulmonary tumors (157 vs. 141, P = 0.016) and higher SUVmax (8.8 ± 3.6 vs. 6.4 ± 4.2, P = 0.027). However, 68 Ga-PSMA-617 revealed less PET-positive pulmonary lesions (202 vs. 301, P < 0.001) and lower SUVmax of tumors (3.1 ± 3.0 vs. 4.2 ± 3.9, P < 0.001) than 18F-FDG. The combination of 68 Ga-PSMA-617 and 18F-FDG can detect 469 PET-positive lesions, which was superior to each alone (469 vs. 359 vs. 442, P < 0.001). Two patients achieved remarkable response after PSMA RLT, while the other two patients showed reduced tumor uptake of recurrent foci, lung and liver metastases, whereas increased SUVmax of bone metastases.Conclusions68 Ga-PSMA-617 PET/CT is a valuable imaging modality for the detection of ACC and combining with 18F-FDG PET/CT will achieve a higher detection efficiency. PSMA RLT may be a promising treatment for ACC and is worth of further investigation.Trial registrationDiagnosis of Adenoid Cystic Carcinoma on 68 Ga-PSMA-617 PET-CT and Therapy With 177Lu-EB-PSMA-617 (NCT04801264, Registered 16 March 2021, retrospectively registered). URL of registry: https://clinicaltrials.gov/ct2/show/NCT04801264 .
| S-EPMC9390098 | biostudies-literature
Project description:The CD117 (KIT) protein is overexpressed in many human neoplasms including adenoid cystic carcinoma of salivary glands. To evaluate the function of c-kit-activating mutations in adenoid cystic carcinoma of the salivary gland, we studied 14 cases (13 primary, 1 cervical lymph node metastasis) from our institution. KIT protein expression was evaluated by immunohistochemistry using formalin-fixed paraffin-embedded tissue. Mutational analyses of c-kit extracellular (exon 9), juxtamembrane (exon 11) and tyrosine kinase domains (exons 13 and 17) were performed by polymerase chain reaction, clonal selection and DNA sequencing. All 14 cases demonstrated strong KIT expression by immunohistochemistry. Molecular analysis was successful in 8 of 14 cases, and c-kit missense point mutations were detected in seven of eight cases (88%) including seven in exon 11, two in exon 9, two in exon 13 and two in exon 17. Eight silent point mutations were detected in five cases. Two cases contained missense mutations in more than one exon. Different mutations were found in the primary tumor and the cervical lymph node metastasis of one patient. Point mutations in domains similar to those described in gastrointestinal stromal tumors were detected, including Pro551Leu and Lys558Glu (5' end of exon 11), Leu576Phe (3' end of exon 11), Val643Ala (exon 13) and Asn822Ser (exon 17). Additional novel point mutations in exons 9, 11, 13 and 17 were also identified. This study is the first to report c-kit gene mutations in primary adenoid cystic carcinoma of the salivary gland. Identification of such potential gain-of-function mutations in exon 11, and less frequently in exons 9, 13 and 17, suggests that KIT may be involved in the pathogenesis of adenoid cystic carcinoma of salivary glands. Our study raises a prospect of correlation of c-kit mutation and a potential treatment of adenoid cystic carcinoma with tyrosine kinase inhibitor (imatinib).
| S-EPMC3746033 | biostudies-literature
Project description:Angiogenesis is a complex biological process, which is involved in tumorigenesis and progression. However, the molecular mechanism of underlying angiogenesis remains largely unknown. In this study, we accessed the expression of proteins related angiogenesis by immunohistochemical staining of human tissue microarray which contains 72 adenoid cystic carcinoma (AdCC), 12 pleomorphic adenoma (PMA) and 18 normal salivary gland (NSG) using digital pathological scanner and scoring system. We found that the expression of p-S6(S235/236) (a downstream molecule of mTOR), p-Stat3(T705), PAI, EGFR, and HIF-1α was significantly increased in AdCC as compared with PMA and (or) NSG (p < 0.05). While, the expression of these proteins was not associated with pathological type of human AdCC (p > 0.05). Correlation analysis of these proteins revealed that p-S6(S235/236) up-regulates the expression of EGFR/p-Stat3(T705) (p < 0.05) and HIF-1α/PAI (p < 0.05). Moreover, the activation of p-S6(S235/236), EGFR/p-Stat3(T705) and HIF-1α/PAI associated with angiogenesis (CD34) and proliferation (Ki-67). In vitro, Rapamycin suppressed the expression of p-S6(S235/236), EGFR, p-Stat3(T705), HIF-1α and PAI. Further more, target inhibition of mTOR by rapamycin effectively reduced tumor growth of SACC-83 cells line nude mice xenograft and decreased the expression of p-S6(S235/236), EGFR/p-Stat3(T705) and HIF-1α/PAI. Taken together, these data revealed that mTOR signaling pathway regulates tumor angiogenesis by EGFR/p-Stat3(T705) and HIF-1α/PAI. Inhibition of mTOR by rapamycin could effectively reduced tumor growth. It is likely that mTOR inhibitors may be a potential candidate for treatment of AdCC.
| S-EPMC4266710 | biostudies-literature