scholarly journals Evaluating the Therapeutic Efficacy of Mono- and Bivalent Affibody-Based Fusion Proteins Targeting HER3 in a Pancreatic Cancer Xenograft Model

Pharmaceutics ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 551
Author(s):  
Charles Dahlsson Leitao ◽  
Sara S. Rinne ◽  
Mohamed Altai ◽  
Olga Vorontsova ◽  
Finn Dunås ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Growth ◽  
Therapeutic Efficacy ◽  
Xenograft Model ◽  
Receptor Occupancy ◽  
Ct Imaging ◽  
Vehicle Group ◽  
Tumor Growth Inhibition ◽  
Affibody Molecules ◽  
Pet Ct

Human epidermal growth factor receptor 3 (HER3) has been increasingly scrutinized as a potential drug target since the elucidation of its role in mediating tumor growth and acquired therapy resistance. Affibody molecules are so-called scaffold proteins with favorable biophysical properties, such as a small size for improved tissue penetration and extravasation, thermal and chemical stability, and a high tolerance to modifications. Additionally, affibody molecules are efficiently produced in prokaryotic hosts or by chemical peptide synthesis. We have previously evaluated the biodistribution profiles of five mono- and bivalent anti-HER3 affibody molecules (designated as 3) fused to an albumin-binding domain (designated as A), 3A, 33A, 3A3, A33, and A3, that inhibit ligand-dependent phosphorylation. In the present study, we examined the therapeutic efficacy of the three most promising variants, 3A, 33A, and 3A3, in a direct comparison with the HER3-targeting monoclonal antibody seribantumab (MM-121) in a preclinical BxPC-3 pancreatic cancer model. Xenografted mice were treated with either an affibody construct or MM-121 and the tumor growth was compared to a vehicle group. Receptor occupancy was estimated by positron emission tomography/computed tomography (PET/CT) imaging using a HER3-targeting affibody imaging agent [68Ga]Ga-(HE)3-Z08698-NODAGA. The affibody molecules could inhibit ligand-dependent phosphorylation and cell proliferation in vitro and demonstrated tumor growth inhibition in vivo comparable to that of MM-121. PET/CT imaging showed full receptor occupancy for all tested drug candidates. Treatment with 3A and 3A3 affibody constructs was more efficient than with 33A and similar to the anti-HER3 antibody seribantumab, showing that the molecular design of affibody-based therapeutics targeting HER3 in terms of the relative position of functional domains and valency has an impact on therapeutic effect.

MRI apparent diffusion coefficient in a murine orthotopic glioblastoma model as a clinically translatable early readout of efficacy for AMG 595, an antibody drug conjugate targeting EGFRvIII.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 11095-11095
Author(s):  
Brittany Yerby ◽  
Juan Estrada ◽  
Matthew D. Silva ◽  
Kevin J. Hamblett ◽  
Suzanne K. Coberly ◽  
...  
Keyword(s):  
Diffusion Coefficient ◽  
Apparent Diffusion Coefficient ◽  
Tumor Growth ◽  
Therapeutic Efficacy ◽  
Tumor Volume ◽  
Treated Group ◽  
Vehicle Group ◽  
Tumor Growth Inhibition ◽  
Apparent Diffusion Coefficients ◽  
Apparent Diffusion

11095 Background: Epidermal growth factor receptor variant III (EGFRvIII) is a constitutively active mutant of EGFR present in thirty to fifty percent of glioblastoma (GBM) patients. AMG 595, currently in Phase I trials, is composed of a fully human anti-EGFRvIII-specific antibody conjugated to the maytansinoid DM1 via a non-cleavable linker. The MRI apparent diffusion coefficient (MRI ADC) has been shown to correlate with tissue cellularity, and changes in MRI ADC can be an early indicator of therapeutic efficacy. The aim of this work is to evaluate MRI ADC as a clinically translatable early readout of tissue changes due to AMG 595 treatment in a murine orthotopic GBM model. Methods: D317 human GBM cells were intracranially injected into in female CB17 SCID mice at Day 0. Mice were randomized at Day 7, using tumor volumes calculated by MRI, and were treated with vehicle, 6.5, 11, or 22 mg/kg AMG 595 i.v. twice per week, or temozolomide 10 mg/kg p.o. daily five days per week (N=8/group). MRI was repeated at days 14 and 21. Tumor volumes were manually traced on multi-slice T2-weighted RARE images covering the entire tumor volume. The mean MRI apparent diffusion coefficients for each tumor in the vehicle and 22 mg/kg AMG 595-treated groups were calculated from diffusion-weighted spin echo images (b = 100-1200 s/mm2). Results: A dose-dependent effect of AMG 595 on tumor volume was observed at Day 21; growth was inhibited in both the temozolomide and AMG 595-treated groups (22 and 11 mg/kg) relative to vehicle (p<0.0001). At Day 14, this significant treatment effect on tumor volume was not yet detectable. However, mean MRI ADC values were already significantly higher in the AMG 595 (22 mg/kg) treated group than in the vehicle group (23% higher at Day 14, p<0.01 vs vehicle; 32% higher at Day 21, p<0.0001 vs vehicle). The increase in MRI ADC in the AMG 595-treated group preceded observable tumor growth inhibition in the AMG 595-treated animals. Conclusions: Increases in tumor MRI ADC in response to AMG 595 treatment precede measurable inhibition of tumor growth, supporting the use of MRI ADC as a clinically relevant early biomarker for therapeutic efficacy.

scholarly journals Doxorubicin Embedded into Nanofibrillated Bacterial Cellulose (NFBC) Produces a Promising Therapeutic Outcome for Peritoneally Metastatic Gastric Cancer in Mice Models via Intraperitoneal Direct Injection

Nanomaterials ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1697
Author(s):  
Hidenori Ando ◽  
Takashi Mochizuki ◽  
Amr S. Abu Lila ◽  
Shunsuke Akagi ◽  
Kenji Tajima ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Drug Delivery ◽  
Tumor Growth ◽  
Bacterial Cellulose ◽  
Anticancer Agents ◽  
Intraperitoneal Administration ◽  
In Vitro Release ◽  
Xenograft Model ◽  
Tumor Growth Inhibition

Natural materials such as bacterial cellulose are gaining interest for their use as drug-delivery vehicles. Herein, the utility of nanofibrillated bacterial cellulose (NFBC), which is produced by culturing a cellulose-producing bacterium (Gluconacetobacter intermedius NEDO-01) in a medium supplemented with carboxymethylcellulose (CMC) that is referred to as CM-NFBC, is described. Recently, we demonstrated that intraperitoneal administration of paclitaxel (PTX)-containing CM-NFBC efficiently suppressed tumor growth in a peritoneally disseminated cancer xenograft model. In this study, to confirm the applicability of NFBC in cancer therapy, a chemotherapeutic agent, doxorubicin (DXR), embedded into CM-NFBC, was examined for its efficiency to treat a peritoneally disseminated gastric cancer via intraperitoneal administration. DXR was efficiently embedded into CM-NFBC (DXR/CM-NFBC). In an in vitro release experiment, 79.5% of DXR was released linearly into the peritoneal wash fluid over a period of 24 h. In the peritoneally disseminated gastric cancer xenograft model, intraperitoneal administration of DXR/CM-NFBC induced superior tumor growth inhibition (TGI = 85.5%) by day 35 post-tumor inoculation, compared to free DXR (TGI = 62.4%). In addition, compared with free DXR, the severe side effects that cause body weight loss were lessened via treatment with DXR/CM-NFBC. These results support the feasibility of CM-NFBC as a drug-delivery vehicle for various anticancer agents. This approach may lead to improved therapeutic outcomes for the treatment of intraperitoneally disseminated cancers.

68Ga-FAPI PET/CT Imaging of Multiple Muscle Metastases of Pancreatic Cancer

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Weidong Gong ◽  
Xiao Yang ◽  
Junhao Wu ◽  
Lei Ou ◽  
Chunyin Zhang
Keyword(s):  
Pancreatic Cancer ◽  
Ct Imaging ◽  
Pet Ct

Comparative benefits of nab-paclitaxel over gemcitabine or polysorbate-based docetaxel in experimental pancreatic cancer.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 192-192
Author(s):  
Niranjan Awasthi ◽  
Katherine T Ostapoff ◽  
Changhua Zhang ◽  
Margaret A. Schwarz ◽  
Roderich Schwarz
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Growth ◽  
Single Agent ◽  
Nuclear Antigen ◽  
In Vivo Model ◽  
Tumor Growth Inhibition ◽  
Multiple Tumor ◽  
Animal Survival ◽  
Experimental Pancreatic Cancer

192 Background: Gemcitabine (Gem), a standard cytotoxic therapy for pancreatic cancer, has shown limited clinical benefits. Nanoparticle albumin-bound (nab) paclitaxel (NPT), an approved treatment for breast cancer, has shown efficacy as mono- and combination therapy in multiple tumor types including pancreatic, lung and ovarian cancer. We evaluated the NPT treatment benefits compared with Gem or solvent-based taxane docetaxel (DT) in experimental pancreatic cancer. Methods: In vitro cell proliferation and protein expression were measured by WST-1 assay and immunoblotting. Tumor growth and animal survival studies were performed in murine xenografts. Intratumoral proliferative activity was measured using Ki67 nuclear antigen staining. Results: For AsPC-1, BxPC-3, MIA PaCa-2 and Panc-1 cells in vitro, Gem IC50 levels were 23.9 mM, 506 nM, 332 nM and 14.5 nM; DT IC50 levels were 30 nM, 4.6 nM, 37.5 nM and 27 nM; and NPT IC50 levels were 7.6 mM, 208 nM, 519 nM and 526 nM. NPT addition decreased Gem IC50 to 1.7 mM, 189 nM, 123 nM and 913 nM; DT addition decreased Gem IC50 to 436 nM, 470 nM, 124 nM and 0.2 nM in AsPC-1, BxPC-3, MIA PaCa-2 and Panc-1 cells, respectively. NPT and DT treatment increased stathmin phosphorylation and decreased tubulin expression in vitro. In a heterotopic in vivo model, net tumor growth inhibition after Gem, DT and NPT was 67, 31 and 72 percent, while intratumoral proliferative index inhibition was 41, 53 and 68 percent, respectively. In an intraperitoneal model, median animal survival was significantly longer in the NPT treatment group (41 days, p<0.002 vs. control and Gem) compared to Gem (32 days, p=0.005 vs. control), DT (32 days, p=0.005 vs. control) and controls (20 days). Animal survival in NPT-Gem and DT-Gem sequential treatment groups was 43 and 40 days, and thus not superior to NPT alone. Conclusions: Nab-paclitaxel has significantly superior antitumor activity as a single agent in experimental pancreatic cancer compared with gemcitabine or docetaxel. These findings provide a strong rationale for considering nab-paclitaxel as first-line monotherapy in patients with pancreatic cancer.

scholarly journals The Use of Steroid Sulfatase Inhibitors as a Novel Therapeutic Strategy Against Hormone-Dependent Endometrial Cancer

Endocrinology ◽  
2008 ◽  
Vol 149 (8) ◽  
pp. 4035-4042 ◽  
Author(s):  
Paul A. Foster ◽  
L. W. Lawrence Woo ◽  
Barry V. L. Potter ◽  
Michael J. Reed ◽  
Atul Purohit
Keyword(s):  
Endometrial Cancer ◽  
Tumor Growth ◽  
Female Genital Tract ◽  
Xenograft Model ◽  
Tumor Growth Inhibition ◽  
Steroid Sulfatase ◽  
Ovariectomized Mice ◽  
Estrogen Production ◽  
Novel Therapeutic

The past few years have seen an increase in the reported incidence of endometrial carcinoma, one of the most frequently diagnosed malignancies of the female genital tract. Estrogen production is vital for the mitogenesis of endometrial tumors. Inhibition of steroid sulfatase (STS), an enzyme responsible for the synthesis of steroids with estrogenic properties, may represent a novel therapeutic target for this type of cancer. This study investigates the effects of STX64 (also known as 667Coumate and BN83495) and STX213, two potent STS inhibitors, on hormone-dependent endometrial cancer cell growth in vivo. When tested in intact mice with endometrial cancer xenografts, STX64 had limited effect on tumor growth. In contrast, the microtubule disruptor STX140 reduced tumor growth by 55%. In a hormone-dependent endometrial xenograft model in ovariectomized mice, both STX64 and STX213 given orally, daily at 1 mg/kg significantly inhibited tumor growth by 48 and 67%, respectively. However, when given orally at 1 mg/kg once weekly, only STX213 still inhibited tumor proliferation. At a higher dose of STX64 (10 mg/kg, orally, daily), a greater tumor growth inhibition of 59% was observed. Liver and tumor STS activity was completely inhibited in all daily treatment groups. Plasma estradiol (E2) levels were also significantly decreased. A significant correlation was observed between plasma E2 concentrations and STS activity, indicating the importance of circulating E2 on tumor growth. This novel study demonstrates for the first time that STS inhibitors are potent inhibitors of endometrial cancer growth in nude mice.

Biodegradable nanoparticles as siRNA carriers for in vivo gene silencing and pancreatic cancer therapy

2017 ◽  
Vol 5 (18) ◽  
pp. 3327-3337 ◽  
Author(s):  
Guimiao Lin ◽  
Chih-Kuang Chen ◽  
Feng Yin ◽  
Chengbin Yang ◽  
Jinglin Tian ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Therapy ◽  
Tumor Growth ◽  
Gene Silencing ◽  
Xenograft Model ◽  
Biodegradable Nanoparticles ◽  
Pancreatic Cancer Therapy

Biodegradable charged polyester-based vectors (BCPVs) were utilized for efficiently delivering mutatedK-Ras-targeting siRNA and successfully inhibiting tumor growth in a pancreatic xenograft modelin vivo.

6591 The role of PET/CT imaging in patients with suspected recurrence of pancreatic cancer

2009 ◽  
Vol 7 (2) ◽  
pp. 387
Author(s):  
R. Epelbaum ◽  
R. Bar-Shalom ◽  
Z. Keidar ◽  
D. Gaitini ◽  
O. Israel
Keyword(s):  
Pancreatic Cancer ◽  
Ct Imaging ◽  
Pet Ct ◽  
Suspected Recurrence
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