ABSTRACT
Ovarian clear cell carcinoma (OCCC) is a subtype of ovarian cancer and is highly malignant with high chemoresistance. CACNA1H is pivotal in tumor development. However, the role of CACNA1H in the acquisition process of chemotherapeutic resistance in OCCC cells is rarely reported. Therefore, this study aimed to explore the role of CACNA1H in chemotherapy resistance of OCCC cells and its related mechanism. Based on bioinformatics analysis, we found that CACNA1H was downregulated in chemoresistant OCCC patients compared to chemosensitive OCCC patients. Comparing DDP-resistant and sensitive OCCC cell lines, the resistant strain showed lower CACNA1H mRNA expression. CACNA1H expression was associated with calcium signaling pathways in chemoresistant OCCC patients. CACNA1H mRNA expression was significantly downregulated in OCCC cells compared to normal ovarian epithelial cells. When CACNA1H was overexpressed, intracellular Ca2+ concentration and protein levels of p-CaMKII and p-Akt were significantly upregulated, while protein levels of LC3-II/LC3-I and Beclin1 were downregulated, indicating a repression of autophagy. The rescue experiment revealed that CACNA1H overexpression in drug-resistant OCCC cells reduced autophagy-induced DDP resistance via CaMKII/Akt signaling. Overall, CACNA1H increased intracellular Ca2+ concentration and activated CaMKII/Akt signaling pathway in OCCC, thereby repressing autophagy to maintain the sensitivity of OCCC cells to DDP.
Subject(s)
Adenocarcinoma, Clear Cell , Autophagy , Drug Resistance, Neoplasm , Gene Expression Regulation, Neoplastic , Ovarian Neoplasms , Female , Humans , Adenocarcinoma, Clear Cell/genetics , Adenocarcinoma, Clear Cell/drug therapy , Adenocarcinoma, Clear Cell/pathology , Adenocarcinoma, Clear Cell/metabolism , Autophagy/genetics , Autophagy/drug effects , Calcium/metabolism , Calcium Signaling/genetics , Calcium Signaling/drug effects , Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Cell Line, Tumor , Gene Expression Regulation, Neoplastic/drug effects , Ovarian Neoplasms/genetics , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-akt/geneticsABSTRACT
Ovarian clear cell carcinoma (OCCC) is often considered a relatively platinum-resistant malignancy. The aim of this study was to explore the influence of progesterone receptor (PR) expression levels on platinum sensitivity and survival outcomes in people with OCCC. A retrospective analysis was conducted with 80 people with OCCC who underwent surgery followed by adjuvant chemotherapy. PR expression was assessed via immunohistochemical (IHC) staining and quantified using the H score. The platinum sensitivity and survival outcomes of patients with weak and strong PR expression were compared. Additionally, cisplatin viability and migration experiments were conducted with OCCC cell lines (ES-2 and TOV-21G) with varying PR isoform expressions. Among the 80 patients, 62 were classified as having platinum-sensitive disease, while 18 had platinum-resistant disease. The mean total PR H- score of platinum-sensitive tumors was significantly higher than that of platinum-resistant tumors (p = 0.002). Although no significant differences in progression-free and overall survival were observed between patients with high and low PR expression, those with high PR expression tended to have longer survival. While PR protein was only weakly detectable in ES-2 and TOV-21G cells, a transfection of the PR-A or PR-B gene resulted in a strong expression of PR-A or PR-B, which led to significantly reduced proliferation and migration in ES-2 and TOV-21G cells. Furthermore, overexpression of PR-A or PR-B enhanced cisplatin cytotoxicity in these cell lines. In conclusion, strong PR expression was associated with improved platinum sensitivity and survival outcomes, consistent with our experimental findings. The potential of PR as a tumor sensitizer to cisplatin in OCCC warrants further investigation.
Subject(s)
Adenocarcinoma, Clear Cell , Cisplatin , Drug Resistance, Neoplasm , Ovarian Neoplasms , Receptors, Progesterone , Humans , Female , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Receptors, Progesterone/metabolism , Receptors, Progesterone/genetics , Middle Aged , Adenocarcinoma, Clear Cell/metabolism , Adenocarcinoma, Clear Cell/drug therapy , Adenocarcinoma, Clear Cell/pathology , Adenocarcinoma, Clear Cell/genetics , Drug Resistance, Neoplasm/genetics , Cisplatin/pharmacology , Cisplatin/therapeutic use , Cell Line, Tumor , Aged , Adult , Retrospective Studies , Cell Movement/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Platinum/pharmacology , Platinum/therapeutic use , Gene Expression Regulation, Neoplastic/drug effectsABSTRACT
Case report of a HER2-expressed ovarian clear cell carcinoma with exceptional response to trastuzumab deruxtecan.
Subject(s)
Neoplasm Recurrence, Local , Ovarian Neoplasms , Receptor, ErbB-2 , Trastuzumab , Humans , Female , Trastuzumab/therapeutic use , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Receptor, ErbB-2/genetics , Neoplasm Recurrence, Local/drug therapy , Adenocarcinoma, Clear Cell/drug therapy , Adenocarcinoma, Clear Cell/pathology , Adenocarcinoma, Clear Cell/genetics , Antineoplastic Agents, Immunological/therapeutic use , Camptothecin/analogs & derivatives , Camptothecin/therapeutic use , Middle Aged , Immunoconjugates/therapeutic useABSTRACT
BACKGROUND: Ovarian clear cell carcinoma (OCCC), well known for its chemoresistance to platinum-based chemotherapy, exhibited a good response in clinical trials of anti-PD-1/PD-L1 inhibitors. By assessing PD-L1 expression, we sought to determine the potential therapeutic benefit of PD-1/PD-L1 inhibitors in OCCC. METHODS AND RESULTS: The retrospective study included 152 individuals with OCCC between 2019 and 2022 at Peking Union Medical College Hospital. Paired tumors of primary versus recurrent lesions (17 pairs from 15 patients) or primary versus metastatic lesions (11 pairs from 9 patients) were also included. The 22C3 pharmDx assay and whole sections were used for PD-L1 immunohistochemical staining. Pathologists with experience in premarket clinical trials evaluated PD-L1 expression based on various diagnostic criteria (TPS 1%, CPS 1, or CPS 10). The number and percentage of positive PD-L1 cases were 34 (22.4%, TPS ≥ 1%) and 59 (38.8%, CPS ≥ 1), respectively. Thirty-three (21.7%) of the cases had high PD-L1 expression (CPS ≥ 10). Half of the platinum-resistant patients (11/22) were PD-L1 positive (CPS ≥ 1). In addition, positive PD-L1 expression (CPS ≥ 1) was related to clinicopathological characteristics that represented a worse prognosis, such as advanced stages, lymph node metastasis, and distant metastasis (p = 0.032, p < 0.001 and p = 0.003, separately). PD-L1 was expressed equally or more in the recurrent lesion compared with its matched primary lesion. CONCLUSIONS: In conclusion, anti-PD-1/PD-L1 inhibitors are a promising therapeutic choice for OCCC. For evaluation of PD-L1 expression, CPS is more recommended than TPS. Evaluation of recurrent lesion was still suitable and predictive when the primary tumor tissue was not available. Distant metastatic lesions can serve as alternative samples for PD-L1 evaluation, while usage of lymphatic metastatic lesions is not recommended.
Subject(s)
Adenocarcinoma, Clear Cell , B7-H1 Antigen , Biomarkers, Tumor , Ovarian Neoplasms , Humans , Female , B7-H1 Antigen/analysis , B7-H1 Antigen/metabolism , Retrospective Studies , Middle Aged , Ovarian Neoplasms/pathology , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/drug therapy , Adult , Aged , Biomarkers, Tumor/analysis , Biomarkers, Tumor/metabolism , Adenocarcinoma, Clear Cell/metabolism , Adenocarcinoma, Clear Cell/pathology , Adenocarcinoma, Clear Cell/drug therapy , Immunohistochemistry , Drug Resistance, Neoplasm , Neoplasm Recurrence, Local/metabolism , Neoplasm Recurrence, Local/pathology , Aged, 80 and overABSTRACT
Our patient initially presented with 6 months of left jaw pain and gingival bleeding, leading to the discovery of a radiolucent left maxillary mass on dental evaluation. A biopsy confirmed clear cell odontogenic carcinoma, and the patient was treated with definitive surgery and radiation for localised disease. Unfortunately, the patient was found to have pulmonary metastases 3 months after initial management and was subsequently treated with a combination of cytotoxic chemotherapy and immunotherapy with a partial response. To our knowledge, this is the first case demonstrating the successful use of chemoimmunotherapy in metastatic clear cell odontogenic carcinoma.
Subject(s)
Odontogenic Tumors , Female , Humans , Male , Adenocarcinoma, Clear Cell/secondary , Adenocarcinoma, Clear Cell/therapy , Adenocarcinoma, Clear Cell/pathology , Adenocarcinoma, Clear Cell/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Immunotherapy/methods , Lung Neoplasms/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/therapy , Maxillary Neoplasms/drug therapy , Maxillary Neoplasms/pathology , Maxillary Neoplasms/diagnostic imaging , Odontogenic Tumors/pathology , Odontogenic Tumors/drug therapy , Odontogenic Tumors/diagnostic imaging , AgedABSTRACT
Ovarian clear cell carcinoma (OCCC) is a gynecological cancer with a dismal prognosis; however, the mechanism underlying OCCC chemoresistance is not well understood. To explore the intracellular networks associated with the chemoresistance, we analyze surgical specimens by performing integrative analyses that combine single-cell analyses and spatial transcriptomics. We find that a chemoresistant OCCC subpopulation with elevated HIF activity localizes mainly in areas populated by cancer-associated fibroblasts (CAFs) with a myofibroblastic phenotype, which is corroborated by quantitative immunostaining. CAF-enhanced chemoresistance and HIF-1α induction are recapitulated in co-culture assays, which show that cancer-derived platelet-derived growth factor (PDGF) contributes to the chemoresistance and HIF-1α induction via PDGF receptor signaling in CAFs. Ripretinib is identified as an effective receptor tyrosine kinase inhibitor against CAF survival. In the co-culture system and xenograft tumors, ripretinib prevents CAF survival and suppresses OCCC proliferation in the presence of carboplatin, indicating that combination of conventional chemotherapy and CAF-targeted agents is effective against OCCC.
Subject(s)
Cancer-Associated Fibroblasts , Hypoxia-Inducible Factor 1, alpha Subunit , Ovarian Neoplasms , Platelet-Derived Growth Factor , Signal Transduction , Female , Humans , Cancer-Associated Fibroblasts/metabolism , Cancer-Associated Fibroblasts/pathology , Cancer-Associated Fibroblasts/drug effects , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Ovarian Neoplasms/pathology , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Platelet-Derived Growth Factor/metabolism , Signal Transduction/drug effects , Animals , Mice , Cell Line, Tumor , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Disease Progression , Coculture Techniques , Cell Proliferation/drug effects , Mice, Nude , Adenocarcinoma, Clear Cell/metabolism , Adenocarcinoma, Clear Cell/pathology , Adenocarcinoma, Clear Cell/drug therapy , Adenocarcinoma, Clear Cell/genetics , Feedback, Physiological/drug effects , Xenograft Model Antitumor AssaysABSTRACT
INTRODUCTION: Early reports of PD-1 inhibition in ovarian clear cell carcinomas (OCCC) demonstrate promising response. We evaluated the combination of pembrolizumab and IDO-1 inhibitor epacadostat in patients with recurrent OCCC. METHODS: This single arm, two-stage, phase 2 trial included those with measurable disease and 1-3 prior regimens. Patients received intravenous pembrolizumab 200 mg every 3 weeks and oral epacadostat 100 mg twice a day. Primary endpoint was overall response rate (ORR), secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS). The study was powered to detect an absolute 25% increase in response (15% to 40%). RESULTS: Between September 28, 2018 and April 10, 2019, 14 patients enrolled at first stage. Rate of accrual was 2.3 patients per month. Median age was 65 years (44-89), 10 (71.4%) had ≥2 prior regimens. ORR was 21% (95% CI 5-51%) within 7 months of study entry with 3 partial responses, and 4 had stable disease (disease control rate 50%). Median PFS was 4.8 months (95% CI: 1.9-9.6), OS 18.9 months (95% CI: 1.9-NR). Most common grade ≥ 3 adverse events were electrolyte abnormalities and gastrointestinal pain, nausea, vomiting, bowel obstruction. In July 2019, the study reached the pre-specified criteria to re-open to second stage; however, the study closed prematurely in February 2021 due to insufficient drug supply. CONCLUSIONS: Pembrolizumab and epacadostat demonstrated an ORR of 21% in this small cohort of recurrent OCCC. The rapid rate of accrual highlights the enthusiasm and need for therapeutic studies in patients with OCCC.
Subject(s)
Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols , Neoplasm Recurrence, Local , Ovarian Neoplasms , Sulfonamides , Humans , Female , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Middle Aged , Aged , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Ovarian Neoplasms/mortality , Adult , Aged, 80 and over , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathology , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Sulfonamides/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Adenocarcinoma, Clear Cell/drug therapy , Adenocarcinoma, Clear Cell/pathology , Adenocarcinoma, Clear Cell/mortality , Progression-Free Survival , OximesABSTRACT
Purpose Treatment of recurrent ovarian carcinoma is a challenge, particularly for the clear cell (CCC) subtype. However, there is a preclinical rationale that these patients could achieve a benefit from antiangiogenic therapy. To assess this hypothesis, we used the growth modulation index (GMI), which represents an intrapatient comparison of two successive progression-free survival (PFS). Methods We conducted a retrospective real-world study performed on 34 patients with recurrent ovarian cancer, treated with bevacizumab-containing regimens from January 2009 to December 2017. The primary endpoint was GMI. An established cut-off > 1.33 was defined as a sign of drug activity. Results 73.5% of patients had high-grade serous ovarian carcinoma (HGSOC), and 17.7% had CCC; 70.6% of patients received carboplatin/gemcitabine/bevacizumab, and 29.4% received weekly paclitaxel/bevacizumab. According to histological subtype, the overall response rate and median PFS were 52% and 14 months for HGSOC and 83.3% and 20 months for CCC, respectively. The overall population median GMI was 0.99; it was 0.95 and 2.36 for HGSOC and CCC, respectively. CCC subtype was significantly correlated with GMI > 1.33 (odds ratio 41.67; 95% confidence interval 3.6486.94; p = .03). Conclusion Adding bevacizumab to chemotherapy in recurrent CCC is associated with a remarkable benefit in this cohort. The efficacy of antiangiogenic drugs in CCC warrants further prospective evaluation (AU)
Subject(s)
Humans , Female , Adult , Middle Aged , Aged , Adenocarcinoma, Clear Cell/drug therapy , Ovarian Neoplasms/drug therapy , Bevacizumab/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Angiogenesis Inhibitors/therapeutic use , Neoplasm Recurrence, Local , Treatment OutcomeABSTRACT
No disponible
Subject(s)
Humans , Male , Middle Aged , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Renal Dialysis , Kidney Transplantation/adverse effects , Adenocarcinoma, Clear Cell/drug therapy , Immunosuppression Therapy/methods , Primary Graft Dysfunction , Treatment OutcomeABSTRACT
Clear cell carcinoma (CCC) of the ovary is known to show poorer sensitivity to chemotherapeutic agents and to be associated with a worse prognosis than the more common serous adenocarcinoma or endometrioid adenocarcinoma. To improve the survival of patients with ovarian CCC, the deeper understanding of the mechanism of CCC carcinogenesis as well as the efforts to develop novel treatment strategies in the setting of both front-line treatment and salvage treatment for recurrent disease are needed. In this presentation, we first summarize the mechanism responsible for carcinogenesis. Then, we highlight the promising therapeutic targets in ovarian CCC and provide information on the novel agents which inhibit these molecular targets. Moreover, we discuss on the cytotoxic anti-cancer agents that can be best combined with targeted agents in the treatment of ovarian CCC.
Subject(s)
Female , Humans , Adenocarcinoma, Clear Cell/drug therapy , Antineoplastic Agents/therapeutic use , Forecasting , Neoplasm Recurrence, Local/prevention & control , Ovarian Neoplasms/drug therapyABSTRACT
PURPOSE: To investigate chemosensitivity with an adenosine triphosphate-based chemotherapy response assay in patients with epithelial ovarian or peritoneal cancer according to tumor histology, grade, and disease status. MATERIALS AND METHODS: One hundred specimens were collected during primary or secondary debulking from 67 patients with primary ovarian cancer, 24 patients with recurrent ovarian cancer, 5 patients with primary peritoneal cancer, and 4 patients with recurrent peritoneal cancer; samples were collected between August 2006 and June 2009. Tumor cells were isolated and cultured for 48 hours in media containing chemotherapy. The chemosensitivity index (CI) was calculated as 300 minus the sum of the cell death rate at 0.2x, 1x, and 5x drug concentrations, and the CI values were compared. RESULTS: CI values were obtained from 93 of 100 patients. The most active agents against primary disease were ifosfamide and paclitaxel. For primary serous adenocarcinoma, paclitaxel and irinotecan were the most active, followed by ifosfamide. For clear cell carcinoma, ifosfamide was the most active, followed by paclitaxel and irinotecan. Although not statistically significant, the CIs of cisplatin, carboplatin, paclitaxel, and docetaxel decreased as tumor grade increased. In 14 cases of recurrent disease, paclitaxel was the most active, followed by ifosfamide and cisplatin. CONCLUSION: Ifosfamide and paclitaxel were the most active drugs for primary and recurrent disease. Therefore, we recommend further clinical studies to confirm the efficacy of paclitaxel, ifosfamide, and cisplatin combination chemotherapy for recurrent and primary ovarian cancer.
Subject(s)
Adult , Aged , Female , Humans , Middle Aged , Adenocarcinoma, Clear Cell/drug therapy , Adenosine Triphosphate/metabolism , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Camptothecin/administration & dosage , Carboplatin/therapeutic use , Cisplatin/administration & dosage , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor/methods , Ifosfamide/administration & dosage , Neoplasm Recurrence, Local/drug therapy , Neoplasms, Glandular and Epithelial/drug therapy , Ovarian Neoplasms/drug therapy , Paclitaxel/therapeutic use , Peritoneal Neoplasms/drug therapy , Predictive Value of Tests , Sensitivity and Specificity , Taxoids/administration & dosageABSTRACT
BACKGROUND: Renal cell carcinoma (RCC) represents approximately 3% of malignant tumors in adults and occurs in a M:F ratio of 1.5:1.0. Although in most cases it occurs in persons 50 to 70 years of age, there are also reports in children. Clear cell carcinoma is the most frequent histological type, and 30% of renal carcinomas have metastasized at the time of diagnosis. The objective of the present study is to report colon metastasis of clear cell carcinoma that required surgery and chemotherapy. CLINICAL CASE: We report the case of a 60-year-old male with a history of metastatic RCC. His treatment consisted of cytoreductive radical nephrectomy and interferon because of pulmonary disease. He was followed-up for 8 years. Nevertheless, he presented with hematochezia and underwent colonoscopy where a splenic flexure tumor was demonstrated. Biopsy reported a clear cell tumor. We performed a left hemicolectomy. Pathology report was clear cell carcinoma with involvement of the colon from the mucosa to serosa. The patient again received interferon. Currently, there is no evidence of tumor activity and the patient is being followed-up. CONCLUSIONS: RCC metastases are most frequent in lung, liver, and bone and less frequent in brain, skin, and soft tissue. Metachromic metastases are identified in the first to second year after nephrectomy in most cases. Survival of patients who present metastasis <1 year after nephrectomy is 33 months vs. patients who present metastasis after 1 year from nephrectomy (55 months). Metastatic clear cell carcinoma requires surgery and immunotherapy. Surgery is the first step for disease control and metastatecomies are indicated in localized disease or when one organ is affected and surgically accessible.
Subject(s)
Humans , Male , Middle Aged , Adenocarcinoma, Clear Cell/secondary , Carcinoma, Renal Cell/secondary , Kidney Neoplasms/pathology , Colonic Neoplasms/secondary , Adenocarcinoma, Clear Cell/drug therapy , Adenocarcinoma, Clear Cell/surgery , Antineoplastic Agents/therapeutic use , Combined Modality Therapy , Carcinoma, Renal Cell/complications , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/surgery , Colectomy/methods , Follow-Up Studies , Gastrointestinal Hemorrhage/etiology , Immunotherapy , Interferon-alpha/therapeutic use , Nephrectomy/methods , Lung Neoplasms/secondary , Kidney Neoplasms/drug therapy , Kidney Neoplasms/surgery , Colonic Neoplasms/complications , Colonic Neoplasms/drug therapy , Colonic Neoplasms/surgery , Remission InductionABSTRACT
Presentamos el caso clínico de una mujer de 60 años con gran tumoración abdominal que, una vez intervenida, fue diagnosticada de una asociación de un adenocarcinoma de ovario de células claras y un adenocarcinoma de endometrio. Recibió quimioterapia con platino, seis ciclos, por enfermedad residual. Presentó una trombosis venosa profunda, y se comprobaron metástasis peritoneales. Falleció a los 9 meses por progresión de la enfermedad. Revisamos los adenocarcinomas de ovario de células claras a la luz de la bibliografía más reciente (AU)