scholarly journals Positron Emission Tomographic Imaging of Tumor Cell Death Using Zirconium-89-Labeled APOMAB® Following Cisplatin Chemotherapy in Lung and Ovarian Cancer Xenograft Models

2021 ◽  
Author(s):  
Vasilios Liapis ◽  
William Tieu ◽  
Nicole L. Wittwer ◽  
Tessa Gargett ◽  
Andreas Evdokiou ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Predictive Marker ◽  
Tumor Treatment ◽  
Tumor Cell Death ◽  
Noninvasive Methods ◽  
Normal Tissues ◽  
Positron Emission ◽  
Xenograft Models ◽  
Treatment Responses

Abstract Purpose Early detection of tumor treatment responses represents an unmet clinical need with no approved noninvasive methods. DAB4, or its chimeric derivative, chDAB4 (APOMAB®) is an antibody that targets the Lupus associated antigen (La/SSB). La/SSB is over-expressed in malignancy and selectively targeted by chDAB4 in cancer cells dying from DNA-damaging treatment. Therefore, chDAB4 is a unique diagnostic tool that detects dead cancer cells and thus could distinguish between treatment responsive and nonresponsive patients. Procedures In clinically relevant tumor models, mice bearing subcutaneous xenografts of human ovarian or lung cancer cell lines or intraperitoneal ovarian cancer xenografts were untreated or given chemotherapy followed 24h later by chDAB4 radiolabeled with [89Zr]ZrIV. Tumor responses were monitored using bioluminescence imaging and caliper measurements. [89Zr]Zr-chDAB4 uptake in tumor and normal tissues was measured using an Albira SI Positron-Emission Tomography (PET) imager and its biodistribution was measured using a Hidex gamma-counter. Results Tumor uptake of [89Zr]Zr-chDAB4 was detected in untreated mice, and uptake significantly increased in both human lung and ovarian tumors after chemotherapy, but not in normal tissues. Conclusion Given that tumors, rather than normal tissues, were targeted after chemotherapy, these results support the clinical development of chDAB4 as a radiodiagnostic imaging agent and as a potential predictive marker of treatment response.

scholarly journals Positron Emission Tomographic imaging of tumor cell death using Zirconium-89-labeled APOMAB® Following Cisplatin Chemotherapy in Lung and Ovarian Cancer Xenograft Models

2020 ◽  
Author(s):  
Vasilios Liapis ◽  
William Tieu ◽  
Nicole Wittwer ◽  
Tessa Gargett ◽  
Andreas Evdokiou ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Whole Body ◽  
Ovarian Cancer Cells ◽  
Chemotherapy Response ◽  
Tumor Cell Death ◽  
Effector Functions ◽  
Normal Tissues ◽  
Positron Emission

Abstract Purpose. There are no currently approved non-invasive methods for detecting tumor treatment responses within the first few days of treatment. The monoclonal antibody, DAB4, or its chimeric derivative, chDAB4 (APOMAB®), targets the Lupus-associated or Sjögren Syndrome-B antigen (La/SSB). La/SSB is over-expressed in malignancy and is selectively targeted by chDAB4 in cancer cells dying after DNA-damaging treatment. Therefore, chDAB4 is a unique diagnostic tool that specifically detects dead cancer cells and could be used to distinguish between chemotherapy responsive and non-responsive patients. In this study, we performed preclinical validation studies using whole-body Positron-Emission Tomography (PET) to examine tumor and normal tissue uptake of 89Zr-labeled chDAB4 in lung or ovarian tumor-bearing mice, which were left untreated or given cisplatin chemotherapy.Methods. The binding of chDAB4 and its conjugates to dead cisplatin-treated human lung and ovarian cancer cells was assessed in vitro as well as its Fc-dependent effector functions. Mice bearing xenografts of H460 lung cancer or A2780 ovarian cancer cells were untreated or given cisplatin chemotherapy followed 24 hours later by 89Zr-labeled chDAB4. Post-cisplatin tumor responses were monitored using bioluminescence imaging and caliper measurements and 89Zr-labeled chDAB4 tumor uptake was measured using an Albira SI PET imager and PMOD analysis software. On completion of experiments, organs were dissected and biodistribution of 89Zr-labeled chDAB4 was measured using a Hidex gamma-counter.Results. The chDAB4 antibody bound only to dead A2780 and H460 cells, and its binding increased with cisplatin treatment in vitro. The chDAB4 antibody did not exhibit Fc-dependent effector functions. Chemotherapy significantly increased uptake of 89Zr-labeled chDAB4 in tumors but not in normal tissues for each tumor model. The greatest differences in average uptake of 89Zr-labeled chDAB4 in subcutaneous tumors were observed 3 days post-cisplatin chemotherapy compared to untreated mice, and before tumor shrinkage was evident.Conclusion. After administration of cisplatin chemotherapy, tumor xenograft uptake of 89Zr-labeled chDAB4 was detected in vivo by PET imaging. Given that the chDAB4 mAb lacked effector activity and that malignant rather than normal tissues were targeted after chemotherapy, these results support clinical development of chDAB4 as both a predictive marker of chemotherapy response and a theranostic imaging agent, which may guide subsequent delivery of chDAB4-directed antibody drug or radio-conjugate anticancer therapies.

scholarly journals Positron Emission Tomographic imaging of tumor cell death using Zirconium-89-labeled APOMAB® following cisplatin chemotherapy in lung and ovarian cancer xenograft models

2020 ◽  
Author(s):  
Vasilios Liapis ◽  
William Tieu ◽  
Nicole Wittwer ◽  
Tessa Gargett ◽  
Andreas Evdokiou ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Whole Body ◽  
Ovarian Cancer Cells ◽  
Chemotherapy Response ◽  
Tumor Cell Death ◽  
Effector Functions ◽  
Normal Tissues ◽  
Positron Emission

Abstract Purpose. There are no currently approved non-invasive methods for detecting tumor treatment responses within the first few days of treatment. The monoclonal antibody, DAB4, or its chimeric derivative, chDAB4 (APOMAB®), targets the Lupus-associated or Sjögren Syndrome-B antigen (La/SSB). La/SSB is over-expressed in malignancy and is selectively targeted by chDAB4 in cancer cells that have died after DNA-damaging treatment. Therefore, chDAB4 could be used to distinguish between chemotherapy responsive and non-responsive patients. In this study, we performed preclinical validation studies using whole-body Positron-Emission Tomography (PET) to examine tumor and normal tissue uptake of 89Zr-labeled chDAB4 in lung or ovarian tumor-bearing mice, which were left untreated or given cisplatin chemotherapy.Methods. The binding of chDAB4 and its conjugates to dead cisplatin-treated human lung and ovarian cancer cells was assessed in vitro as well as its Fc-dependent effector functions. Mice bearing xenografts of H460 lung cancer or A2780 ovarian cancer cells were untreated or given cisplatin chemotherapy followed 24 hours later by 89Zr-labeled chDAB4. Post-cisplatin tumor responses were monitored using bioluminescence imaging and caliper measurements and 89Zr-labeled chDAB4 tumor uptake was measured using an Albira SI PET imager and PMOD analysis software. On completion of experiments, organs were dissected and biodistribution of 89Zr-labeled chDAB4 was measured using a Hidex gamma-counter.Results. The chDAB4 antibody bound only to dead A2780 and H460 cells, and its binding increased with cisplatin treatment in vitro. The chDAB4 antibody did not exhibit Fc-dependent effector functions. Chemotherapy significantly increased uptake of 89Zr-labeled chDAB4 in tumors but not in normal tissues for each tumor model. The greatest differences in average uptake of 89Zr-labeled chDAB4 in subcutaneous tumors were observed 3 days post-cisplatin chemotherapy compared to untreated mice, and before tumor shrinkage was evident.Conclusion. After administration of cisplatin chemotherapy, tumor xenograft uptake of 89Zr-labeled chDAB4 was detected in vivo by PET imaging. Given that the chDAB4 mAb lacked effector activity and that malignant rather than normal tissues were targeted after chemotherapy, these results support clinical development of chDAB4 as both a predictive marker of chemotherapy response and a theranostic imaging agent, which may guide subsequent delivery of chDAB4-directed antibody drug or radio-conjugate anticancer therapies.

scholarly journals CircPLEKHM3 acts as a tumor suppressor through regulation of the miR-9/BRCA1/DNAJB6/KLF4/AKT1 axis in ovarian cancer

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Lei Zhang ◽  
Qing Zhou ◽  
Qiongzi Qiu ◽  
Ling Hou ◽  
Mengting Wu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Suppressor ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Cancer Biology ◽  
Ovarian Cancer Cells ◽  
Ovarian Carcinomas ◽  
Mesenchymal Transition ◽  
Normal Tissues ◽  
Endogenous Expression

Abstract Background Emerging evidence has shown that circular RNAs (circRNAs) play essential roles in cancer biology and are potential biomarkers and targets for cancer therapy. However, the expression and function of circRNAs in ovarian carcinogenesis and its progression remain elusive. Methods RNA sequencing was performed to reveal circRNA expression profiles in ovarian cancerous and normal tissues. Single-molecule RNA in-situ hybridization was used to quantify circPLEKHM3 expression in tumor tissues. Cell-based in-vitro and in-vivo assays were subsequently conducted to support the clinical findings. Results CircPLEKHM3 was identified as one of the most significantly down-regulated circRNAs in ovarian cancer tissues compared with normal tissues. Its expression was further decreased in peritoneal metastatic ovarian carcinomas compared to primary ovarian carcinomas. Patients with lower circPLEKHM3 tend to have a worse prognosis. Functionally, circPLEKHM3 overexpression inhibited cell growth, migration and epithelial–mesenchymal transition, whereas its knockdown exerted an opposite role. Further analyses showed that circPLEKHM3 sponged miR-9 to regulate the endogenous expression of BRCA1, DNAJB6 and KLF4, and consequently inactivate AKT1 signaling. In addition, AKT inhibitor MK-2206 could block the tumor-promoting effect of circPLEKHM3 depletion, and potentiate Taxol-induced growth inhibition of ovarian cancer cells. Conclusions Our findings demonstrated that circPLEKHM3 functions as a tumor suppressor in ovarian cancer cells by targeting the miR-9/BRCA1/DNAJB6/KLF4/AKT1 axis and may be used as a prognostic indicator and therapeutic target in ovarian cancer patients. The new strategy for treating ovarian cancer by a combination therapy of Taxol with MK-2206 is worth further investigation, especially in ovarian cancer patients with loss of circPLEKHM3 expression.

scholarly journals Poly(adenosine diphosphate ribose) polymerase inhibitors induce autophagy‐mediated drug resistance in ovarian cancer cells, xenografts, and patient‐derived xenograft models

Cancer ◽  
2019 ◽  
Vol 126 (4) ◽  
pp. 894-907 ◽  
Author(s):  
Janice M. Santiago‐O’Farrill ◽  
S. John Weroha ◽  
Xiaonan Hou ◽  
Ann L. Oberg ◽  
Ethan P. Heinzen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Adenosine Diphosphate ◽  
Ovarian Cancer Cells ◽  
Patient Derived Xenograft ◽  
Polymerase Inhibitors ◽  
Xenograft Models

BRCA1 as a predictive marker of survival in sporadic ovarian cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5512-5512
Author(s):  
C. R. James ◽  
J. E. Quinn ◽  
P. B. Mullan ◽  
P. G. Johnston ◽  
D. P. Harkin
Keyword(s):  
Ovarian Cancer ◽  
Mrna Expression ◽  
Cancer Cells ◽  
Predictive Marker ◽  
Ovarian Cancer Cells ◽  
Brca1 Expression ◽  
Response To Chemotherapy ◽  
Ovarian Tumours ◽  
Brca1 Mrna

5512 Background: First line treatment of ovarian cancer (OC) involves both Platinum and Taxane based chemotherapy and reduced BRCA1 mRNA and protein expression levels are observed in up to 70% of sporadic ovarian tumours. We, therefore, investigated whether BRCA1 may represent a biomarker of response to chemotherapy in sporadic ovarian cancer. Methods: As in vitro models of sporadic ovarian cancer, we used both antisense and siRNA to abrogate BRCA1 expression in BG-1 and OVCAR5 ovarian cancer cells, respectively. Apoptotic responses to DNA damaging agents and antimicrotubule agents were measured using dose inhibition assays and Annexin V flow cytometry. Quantitiative real time PCR analysis (qRTPCR) was employed to measure BRCA1 mRNA expression in 54 surgically resected ovarian tumours. Univariate analysis provided an evaluation of the effect of BRCA1 mRNA expression and response to platinum or platinum/Taxane containing chemotherapy. Results: We provide in vitro evidence that BRCA1 differentially modulates chemosensitivity in sporadic ovarian cancer. Specifically, we demonstrate that antisense and siRNA inhibition of BRCA1 expression in both BG1 and OVCAR5 ovarian cancer cells, respectively, results in increased sensitivity to both cisplatin and carboplatin and decreased apoptotic response to both paclitaxel and docetaxel. Subsequently, by retrospective clinical analysis of 54 fresh frozen sporadic ovarian tumours we demonstrate that patients with low levels of BRCA1 have a significantly improved overall survival when treated with a platinum based chemotherapy regimen in comparison to patients with high levels of BRCA1 (30.4 months vs 21 months, p=0.047, HR 0.5). In addition, overall median survival for high BRCA1 expressing patients was found to double upon the addition of a taxane containing regimen (46.82 months vs 21 months, p=0.068, HR 0.44). Conclusions: We demonstrate both in vitro and in vivo evidence to support a role for BRCA1 as a predictive marker of response to chemotherapy in sporadic ovarian cancer. We believe that this study is significant given the high incidence of reduced BRCA1 mRNA and protein levels observed in sporadic ovarian cancer and may therefore have implications for the future management of this disease. No significant financial relationships to disclose.

scholarly journals S100A10 in Cancer Progression and Chemotherapy Resistance: A Novel Therapeutic Target against Ovarian Cancer

2018 ◽  
Author(s):  
Tannith Noye ◽  
Noor Lokman ◽  
Martin Oehler ◽  
Carmela Ricciardelli
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Chemotherapy Resistance ◽  
Annexin A2 ◽  
Ovarian Cancer Cells ◽  
Functional Studies ◽  
Normal Tissues ◽  
Risk Of Death ◽  
Increased Risk

S100A10, which is also known as p11 is located in the plasma membrane and forms a heterotetramer with annexin A2. The heterotetramer, comprising of 2 subunits of annexin A2 and S100A10, activates the plasminogen activation pathway which is involved in cellular repair of normal tissues. Increased expression of annexin A2 and S100A10 in cancer cells leads to increased levels of plasmin which promote degradation of the extracellular matrix, increased angiogenesis and invasion of the surrounding organs. Although many studies have investigated the functional role of annexin A2 in cancer cells including ovarian cancer, S100A10 has been less studied. We recently demonstrated that high stromal annexin A2 and high cytoplasmic S100A10 expression is associated with a 3.4 fold increased risk of progression and 7.9 fold risk of death in ovarian cancer patients. Other studies have linked S100A10 with multidrug resistance in ovarian cancer, however, no functional studies to date have been performed in ovarian cancer cells. This article reviews the current understanding on S100A10 function in cancer with a particular focus on ovarian cancer.

scholarly journals DIRAS3-Derived Peptide Inhibits Autophagy in Ovarian Cancer Cells by Binding to Beclin1

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 557 ◽  
Author(s):  
Margie N. Sutton ◽  
Gilbert Y. Huang ◽  
Xiaowen Liang ◽  
Rajesh Sharma ◽  
Albert S. Reger ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Critical Role ◽  
Suppressor Gene ◽  
Clinical Samples ◽  
Ovarian Cancer Cells ◽  
Cancer Cell Proliferation ◽  
Acute Starvation ◽  
Xenograft Models ◽  
Resistance To Chemotherapy

Autophagy can protect cancer cells from acute starvation and enhance resistance to chemotherapy. Previously, we reported that autophagy plays a critical role in the survival of dormant, drug resistant ovarian cancer cells using human xenograft models and correlated the up-regulation of autophagy and DIRAS3 expression in clinical samples obtained during “second look” operations. DIRAS3 is an imprinted tumor suppressor gene that encodes a 26 kD GTPase with homology to RAS that inhibits cancer cell proliferation and motility. Re-expression of DIRAS3 in ovarian cancer xenografts also induces dormancy and autophagy. DIRAS3 can bind to Beclin1 forming the Autophagy Initiation Complex that triggers autophagosome formation. Both the N-terminus of DIRAS3 (residues 15–33) and the switch II region of DIRAS3 (residues 93–107) interact directly with BECN1. We have identified an autophagy-inhibiting peptide based on the switch II region of DIRAS3 linked to Tat peptide that is taken up by ovarian cancer cells, binds Beclin1 and inhibits starvation-induced DIRAS3-mediated autophagy.

Sign in / Sign up

Export Citation Format

Share Document