Prostate Cancer Rodent Model Using Mouse Probasin Regulatory Elements
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Solution Overview
Problem
Current mouse models of prostate cancer exhibit rapid disease progression and limited relevance due to incorrect expression patterns and the prevalence of neuroendocrine carcinomas, which do not accurately represent human prostate cancer development.
Innovation Solution
A novel rodent model utilizing a transgene with the SV40 tumor antigen or Myc operably linked to 5′ and 3′ regulatory regions of a mouse probasin gene, ensuring prostate-specific expression and mimicking the slow progression of human prostate cancer, with predominant expression in the dorsolateral lobes and absence of neuroendocrine carcinomas.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If transgenic mice express SV40 tumor antigen under rat probasin promoter, then prostate cancer develops rapidly (PIN by 6-12 weeks, invasive carcinoma by 18-22 weeks), but this rapid progression does not resemble the slow development of human prostate cancer
Solution Approach 1:
The patent changes the promoter source from rat probasin to mouse probasin, which alters the expression kinetics and disease progression timeline. This parameter change in the regulatory element results in slower disease progression that better mirrors human prostate cancer development while maintaining prostate-specific expression.
2Quantity of substance
If transgene is expressed in ventral lobes of mouse prostate, then tumor develops in that region, but this does not match human prostate carcinoma which typically arises in the peripheral zone
Solution Approach 1:
The patent uses mouse probasin regulatory elements to achieve localized expression specifically in the dorsolateral lobes of the mouse prostate, which are anatomically analogous to the human peripheral zone. This localizes the tumor initiation to the correct anatomical region, improving the model's anatomical relevance to human prostate cancer.
3Quantity of substance
If mouse models show prevalence of neuroendocrine carcinomas, then this tumor type is common in the model, but this limits relevance to the small subpopulation of patients with neuroendocrine disease
Solution Approach 1:
The patent changes the oncogene from SV40 large T antigen to SV40 small t antigen, which alters the tumor type distribution. This parameter change in the oncogenic driver results in predominantly adenocarcinoma formation rather than neuroendocrine carcinoma, making the model representative of the majority of human prostate cancer cases.
Data Source
AI summary
This disclosure provides a rodent model of prostate cancer. The rodents disclosed herein comprise a transgene that provides prostate-specific expression of an oncogenic protein (e.g, an SV40 tumor antigen) under the control of 5′ and 3′ regulatory regions of a mouse probasin gene. The rodents develop progressive forms of prostate tumor that resemble the development of human prostate cancer.