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Drug-Resistant Models for Pancreatic Cancer
Pancreatic cancer presents a formidable challenge due to its aggressive nature and inherent resistance to traditional therapies. The drug resistance model development in pancreatic cancer is paramount in unraveling the mechanisms underpinning resistance and devising novel strategies to combat it. At Alfa Cytology, we leverage our profound expertise and state-of-the-art technology to craft a robust and reproducible drug-resistant model as a valuable tool for delving into tumor genesis, progression, and therapy response.
Overview of Drug-Resistant Models
A key challenge in the therapy development of pancreatic cancer is chemotherapy resistance, which often leads to therapy failure and disease progression. Tumor cells can acquire chemoresistance through many mechanisms, such as the following table. These mechanisms are intertwined to form a complex network that promotes tumor cell survival and proliferation in response to therapeutic agents.
- Changes in drug targets
- Activation of survival pathways
- Increased drug efflux
- Presence of cancer stem cells
To study drug resistance in pancreatic cancer, various experimental models have been developed to simulate the pancreatic cancer situation and explore the mechanisms of drug resistance. These models include cell line-derived xenografts, patient-derived xenografts, and genetically engineered mouse models. Each model has unique advantages and limitations, providing valuable insights into the biology of pancreatic cancer resistance. In addition, these models can be customized to be specific resistance models used to evaluate the effect of therapy development.
Fig. 1 Drug resistance pathways in pancreatic cancer. (Long J., et al., 2011)
Our Services
Alfa Cytology recognizes the pivotal role of developing drug resistance models in pancreatic cancer to decipher resistance mechanisms and unearth efficacious therapeutic avenues. By amalgamating experimental models with cutting-edge technologies, we are steadfast in unearthing molecular insights into drug resistance in pancreatic cancer and formulating personalized therapies to surmount this challenge.
Workflow of Drug Resistance Model Development
Through a comprehensive sequence of steps, we tailor a mouse model of pancreatic cancer that mirrors the body's drug resistance, shedding light on the intricacies of drug resistance in this context. This model serves as a springboard for the identification of novel therapeutic targets and the formulation of effective strategies to combat drug resistance in pancreatic cancer.
Selection of Drug-resistant Pancreatic Cancer Cells
The first step in creating a drug-resistant pancreatic cancer mouse model is the selection of appropriate implantable pancreatic cancer cells. These cells can be derived from established pancreatic cancer cell lines or patient-derived cells.
Drug Sensitivity Testing
The sensitivity of pancreatic cancer cells to therapy or drug is evaluated in vitro before implantation. This helps to determine drug concentrations and therapy regimens to be used in mouse models.
Injection of Cancer Cells
To obtain a mouse model of drug-resistant pancreatic cancer, pancreatic cancer cells are injected subcutaneously or orthotopically (directly into the pancreas) into immunocompromised mice.
Initiation of Therapy
After the tumor reaches a certain size, drug therapy is initiated to simulate the clinical scenario of treating drug-resistant pancreatic cancer. Drug regimens are typically designed based on in vitro susceptibility testing.
Monitoring Therapy Response
The tumor's response is monitored to assess the development of resistance. Tumor growth, volume, and molecular changes were evaluated to determine the effectiveness of therapy and the emergence of resistance mechanisms.
Characterization of Resistance Mechanisms
Analysis of molecular and cellular changes underlying drug resistance. This may involve genomic, transcriptomic, and proteomic analysis to identify key pathways associated with resistance.
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Professional team of scientists and more than ten years of experience in pancreatic cancer
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Case Study - PARP Inhibitor-Induced Resistance Model
- Model Introduction
BMN-673 (Talazoparib) is a highly potent dual PARP inhibitor that traps PARP enzymes on DNA and blocks DNA single-strand break repair, leading to synthetic lethality in BRCA1/2-deficient cells. The BMN-673-Induced Drug Resistance Model is a preclinical tool for studying acquired PARP inhibitor resistance in BRCA2-mutant pancreatic cancer. Using the Capan-1 cell line, chronic in vitro BMN-673 exposure generates a stably resistant subline, which is validated in NSG mouse xenografts.
- Model Information
- Model: PARP Inhibitor-Induced Resistance Model
- Cell Line: Capan-1 (BRCA2-mutant)
- Inducing Agent: BMN-673, a potent PARP dual inhibitor
- Weight: 18-22 g
- Key Application: Study of acquired resistance mechanisms to PARP inhibitors; Screening for combination therapies to overcome resistance.
- Cancer Type: Adenocarcinoma, Pancreatic Ductal Adenocarcinoma (PDAC)
- Resistant Subline: Capan-1/BMN673
- Animals: NSG Immunodeficient Mice
- Age: 6-8 Weeks
- Model Construction
- In Vitro Induction of Resistant Cells: The resistant cell line, named Capan-1/BMN-673, was established through long-term, stepwise exposure of human pancreatic Capan-1 cells (BRCA2-mutant) to increasing concentrations of the PARP inhibitor BMN-673 over 12 weeks. The resulting stable resistant clone demonstrated a >10-fold increase in IC50 compared to the parental sensitive cells.
- In Vivo Resistant Model Establishment: The Capan-1/BMN673-R cells were subcutaneously inoculated into NSG immunodeficient mice to establish the resistant xenograft model.
Fig. 2 Workflow of PARP inhibitor BMN-673-induced drug resistance model establishment. (Source: Alfa Cytology)
- Model Data
In a parent-sensitive Capan-1 in vivo subcutaneous tumor model, 0.1 mg/kg BMN-673 (QD administration) significantly inhibited tumor proliferation, while in a drug-resistant model, the inhibitory effect of 0.3 mg/kg BMN-673 (QD administration) on tumor proliferation was reduced, suggesting that tumor drug resistance has been formed.
Fig. 3 A mouse model of acquired resistance in human pancreatic cancer cell lines induced by the PARP inhibitor BMN-673. Data are presented as mean ± standard error (SEM). (Source: Alfa Cytology)
If you are interested in our drug resistance model development services, please contact us for more details. You can contact our staff directly and receive professional, reliable, and fast feedback.
Reference
- Long J, et al. Overcoming drug resistance in pancreatic cancer. Expert Opin Ther Targets. 2011;15(7):817-828. doi:10.1517/14728222.2011.566216
