Developing a KMT2D/MLL2-Deleted Preclinical Mouse Model of Bladder Urothelial Cancer
Abstract
Background: The topic area for this proposal is "Genetic cancer research." The Military Relevance Focus Area is "Gaps in cancer prevention, diagnosis, early detection, or treatment that may affect the general population but have a particularly profound impact on military health." The most lethal form of bladder cancer is muscle-invasive urothelial (transitional cell) carcinoma, with a 5-year survival rate of about 50%. New therapies for bladder cancer are greatly needed. We believe that the most promising new treatments for bladder cancer will be tailored towards the specific mutations in an individual s tumor, as those mutations may lead to specific vulnerabilities to drugs that kill tumor cells but spare normal dividing cells. Mutation-specific targeted therapy has been successful in many cancers, but bladder cancer patients currently have no such options. A recent comprehensive examination of the mutations in bladder cancer patients has revealed an unexpected gene, MLL2, to be among the most frequently mutated genes in bladder cancer. Scientific Objective and Rationale: Building upon a recent discovery that the MLL2 gene is among the most frequently mutated genes in human bladder cancer, we aim to develop a mouse model with mutations in Mll2 with a major objective to use the model to test preclinical therapies. A lack of animal models that recapitulate the genetic alterations found in human bladder cancer has limited the emergence of new therapies for bladder cancer. We aim to overcome this current limitation. We also propose a new way to treat bladder tumors that harbor MLL2 mutation. MLL2 loss causes a mark on DNA (an "epigenetic mark") to be lost, and this mark determines what genes are turned on or off. We propose to use a drug (an LSD1 inhibitor) that we propose will turn that epigenetic mark on DNA back on, and, potentially reverse the effects on MLL2 mutation to cause MLL2 mutant cells to die and/or stop dividing. Research Applicability: If our hypothesis is correct, this could be rapidly translated towards improved therapy for bladder cancer patients that harbor MLL2 mutation (about 27% of bladder urothelial cancer patients). It is also possible that the therapy could work in some bladder cancers without MLL2 mutation. The mouse models we generate will also be ideal tools to test whether this or other therapeutic approaches can lead to bladder tumor elimination. Over the course of the 2-year grant, we will develop a new mouse model of bladder cancer and generate early data on the potential for LSD1 inhibition as a therapeutic strategy for MLL2-deleted bladder cancer cells. Subsequent use of the mouse model to test this idea in vivo could rapidly lead to clinical trials in humans if successful in the rigorous mouse model. Thus, clinical applicability could occur in the 3- to 5-year range, and could potentially occur rather quickly, as there is already a well-tolerated LSD1 inhibitor that is Food and Drug Administration-approved for the treatment of depression that could be repurposed to treat bladder cancer patients. The utility of the novel mouse models extend well beyond testing LSD1 inhibitors as the models can be used to test any new therapeutic approach. Military Relevance: Smoking is the most critical risk factor for bladder cancer. Use of tobacco products occurs at higher rates in active military than the general population and is particularly high in deployed military. Active and former military are therefore disproportionally at risk for tobacco-linked cancers such as bladder cancer and are particularly affected by the lack of targeted therapies for this tumor type. The mouse models we generate could be used to test many novel therapeutic approaches for bladder cancer. Thus, the proposed work holds great potential for improving survival in military and their family members who develop bladder cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510402
Entities
People
- David MacPherson
Organizations
- Fred Hutchinson Cancer Center
- United States Army