Imaging-Guided Therapy Simultaneously Targeting HER2 and EpCAM with Trastuzumab and EpCAM-Directed Toxin Provides Additive Effect in Ovarian Cancer Model

Published on Aug 4, 2021in Cancers6.639
· DOI :10.3390/CANCERS13163939
Tianqi Xu3
Estimated H-index: 3
(Uppsala University),
Anzhelika Vorobyeva11
Estimated H-index: 11
(Uppsala University)
+ 8 AuthorsVladimir Tolmachev62
Estimated H-index: 62
(Uppsala University)
Source
Abstract
Efficient treatment of disseminated ovarian cancer (OC) is challenging due to its heterogeneity and chemoresistance. Overexpression of human epidermal growth factor receptor 2 (HER2) and epithelial cell adhesion molecule (EpCAM) in approx. 30% and 70% of ovarian cancers, respectively, allows for co-targeted treatment. The clinical efficacy of the monoclonal antibody trastuzumab in patients with HER2-positive breast, gastric and gastroesophageal cancers makes it readily available as the HER2-targeting component. As the EpCAM-targeting component, we investigated the designed ankyrin repeat protein (DARPin) Ec1 fused to a truncated variant of Pseudomonas exotoxin A with reduced immunogenicity and low general toxicity (LoPE). Ec1-LoPE was radiolabeled, evaluated in ovarian cancer cells in vitro and its biodistribution and tumor-targeting properties were studied in vivo. The therapeutic efficacy of Ec1-LoPE alone and in combination with trastuzumab was studied in mice bearing EpCAM- and HER2-expressing SKOV3 xenografts. SPECT/CT imaging enabled visualization of EpCAM and HER2 expression in the tumors. Co-treatment using Ec1-LoPE and trastuzumab was more effective at reducing tumor growth and prolonged the median survival of mice compared with mice in the control and monotherapy groups. Repeated administration of Ec1-LoPE was well tolerated without signs of hepatic or kidney toxicity. Co-treatment with trastuzumab and Ec1-LoPE might be a potential therapeutic strategy for HER2- and EpCAM-positive OC.
References88
Newest
#1Sergey M. Deyev (Tomsk Polytechnic University)H-Index: 29
#2Tianqi Xu (Uppsala University)H-Index: 3
Last. Torbjörn Gräslund (KTH: Royal Institute of Technology)H-Index: 21
view all 13 authors...
The epithelial cell adhesion molecule (EpCAM) is intensively overexpressed in 40–60% of prostate cancer (PCa) cases and can be used as a target for the delivery of drugs and toxins. The designed ankyrin repeat protein (DARPin) Ec1 has a high affinity to EpCAM (68 pM) and a small size (18 kDa). Radiolabeled Ec1 might be used as a companion diagnostic for the selection of PCa patients for therapy. The study aimed to investigate the influence of radiolabel position (N- or C-terminal) and compositio...
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#1Ami Patel (University of Texas MD Anderson Cancer Center)H-Index: 3
#2Puja Iyer (University of Texas MD Anderson Cancer Center)H-Index: 1
Last. Nicole D. Fleming (University of Texas MD Anderson Cancer Center)H-Index: 17
view all 6 authors...
Epithelial ovarian cancer remains a leading cause of death amongst all gynecologic cancers despite advances in surgical and medical therapy. Historically, patients with ovarian cancer underwent primary tumor reductive surgery followed by postoperative chemotherapy; however, neoadjuvant chemotherapy followed by interval tumor reductive surgery has gradually become an alternative approach for patients with advanced-stage ovarian cancer for whom primary tumor reductive surgery is not feasible. Deci...
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#1Tianqi XuH-Index: 3
#2Haozhong DingH-Index: 5
Last. Torbjörn GräslundH-Index: 21
view all 7 authors...
The human epidermal growth factor receptor 2 (HER2) is frequently overexpressed in a variety of cancers and therapies targeting HER2 are routinely used in the clinic. Recently, small engineered scaffold proteins, such as affibody molecules, have shown promise as carriers of cytotoxic drugs, and these drug conjugates may become complements or alternatives to the current HER2-targeting therapies. Here, we investigated if a monovalent HER2-binding affibody molecule, ZHER2:2891, fused with a plasma ...
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HER2-targeting agents have dramatically changed the therapeutic landscape of HER2+ advanced breast cancer (ABC). Within a short time frame, the rapid introduction of new therapeutics has led to the approval of pertuzumab combined with trastuzumab and a taxane in first-line, and trastuzumab emtansine (T-DM1) in second-line. Thereby, evidence of T-DM1 efficacy following trastuzumab/pertuzumab combination is limited, with data from some retrospective reports suggesting lower activity. The purpose o...
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#1François Fagotto (University of Montpellier)H-Index: 32
#2Azam Aslemarz (McGill University)H-Index: 1
Abstract EpCAM has long been known as a cell surface protein highly expressed in carcinomas. It has since become one of the key cancer biomarkers. Despite its high fame, its actual role in cancer development is still controversial. Beyond a flurry of correlative studies, which point either to a positive or a negative link with tumour progression, there has been surprisingly few studies on the actual cellular mechanisms of EpCAM and on their functional consequences. Clearly, EpCAM plays multiple ...
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#1E. I. ShramovaH-Index: 8
#2G. M. ProshkinaH-Index: 13
Last. Sergey M. DeyevH-Index: 29
view all 10 authors...
We report here a combined anti-cancer therapy directed toward HER2 and EpCAM, common tumor-associated antigens of breast cancer cells. The combined therapeutic effect is achieved owing to two highly toxic proteins-a low immunogenic variant of Pseudomonas aeruginosa exotoxin A and ribonuclease Barnase from Bacillus amyloliquefaciens. The delivery of toxins to cancer cells was carried out by targeting designed ankyrin repeat proteins (DARPins). We have shown that both target agents efficiently acc...
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#1Anzhelika Vorobyeva (Uppsala University)H-Index: 11
#2Ekaterina Bezverkhniaia (Tomsk Polytechnic University)H-Index: 1
Last. Vladimir Tolmachev (Uppsala University)H-Index: 62
view all 10 authors...
Efficient treatment of disseminated triple-negative breast cancer (TNBC) remains an unmet clinical need. The epithelial cell adhesion molecule (EpCAM) is often overexpressed on the surface of TNBC cells, which makes EpCAM a potential therapeutic target. Radionuclide molecular imaging of EpCAM expression might permit selection of patients for EpCAM-targeting therapies. In this study, we evaluated a scaffold protein, designed ankyrin repeat protein (DARPin) Ec1, for imaging of EpCAM in TNBC. DARPi...
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#1Anzhelika Vorobyeva (Uppsala University)H-Index: 11
#2Elena Konovalova (RAS: Russian Academy of Sciences)H-Index: 5
Last. Sergey Deyev (Tomsk Polytechnic University)H-Index: 2
view all 10 authors...
Epithelial cell adhesion molecule (EpCAM) is overexpressed in 55%–75% of ovarian carcinomas (OC). EpCAM might be used as a target for a treatment of disseminated OC. Designed ankyrin repeats protein (DARPin) Ec1 is a small (18 kDa) protein, which binds to EpCAM with subnanomolar affinity. We tested a hypothesis that Ec1 labeled with a non-residualizing label might serve as a companion imaging diagnostic for stratification of patients for EpCAM-targeting therapy. Ec1 was labeled with 125I using N...
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#1Kristina Goutsouliak (BCM: Baylor College of Medicine)H-Index: 1
#2Jamunarani Veeraraghavan (BCM: Baylor College of Medicine)H-Index: 18
Last. Rachel SchiffH-Index: 74
view all 7 authors...
Advances in HER2-targeted therapies have improved the survival of patients with HER2-positive breast cancer. The standard-of-care treatment for localized disease has been chemotherapy and 1 year of adjuvant HER2-targeted therapy, typically with the anti-HER2 antibody trastuzumab. Despite the effectiveness of this treatment, disease relapse occurs in a subset of patients; thus, focus has been placed on escalating treatment by either combining different HER2-targeted agents or extending the durati...
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Cited By1
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#1G. M. Proshkina (RAS: Russian Academy of Sciences)H-Index: 13
#2E. I. Shramova (RAS: Russian Academy of Sciences)H-Index: 8
Last. Alexander Kotlyar (TAU: Tel Aviv University)H-Index: 31
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Near-infrared phototherapy has great therapeutic potential for cancer treatment. However, for efficient application, in vivo photothermal agents should demonstrate excellent stability in blood and targeted delivery to pathological tissue. Here, we demonstrated that stable bovine serum albumin-coated gold mini nanorods conjugated to a HER2-specific designed ankyrin repeat protein, DARPin_9-29, selectively accumulate in HER2-positive xenograft tumors in mice and lead to a strong reduction in the t...
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#1Edward MausolfH-Index: 11
#2Erik JohnstoneH-Index: 2
Last. C. GaryH-Index: 3
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Presented are the results of 99mTc and 101Tc production via neutron irradiation of natural isotopic molybdenum (Mo) with epithermal/resonance neutrons. Neutrons were produced using a deuterium-deuterium (D-D) neutron generator with an output of 2 × 1010 n/s. The separation of Tc from an irradiated source of bulk, low-specific activity (LSA) Mo on activated carbon (AC) was demonstrated. The yields of 99mTc and 101Tc, together with their potential use in medical single-photon emission computed tom...
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