Delineating the Mechanistic Basis and Therapeutic Vulnerabilities of Lethal Bladder Cancer and Variants
Abstract
Bladder cancer is the fourth most common cancer among Veterans and a leading cause of cancer mortality in the United States. Veterans are especially at risk for bladder cancer based on risk factors including male sex, advancing age, tobacco use, and chemical exposures. The most common type of bladder cancer is urothelial carcinoma, but 25% of patients exhibit variant bladder cancers which are intermixed with urothelial carcinoma (about 20,000 patients per year in the United States alone). These variant bladder cancers include squamous and sarcomatoid carcinomas which behave aggressively and are associated with poor outcomes for patients. Little is known about how these cancers arise, and their study in the laboratory has been limited by a complete lack of experimental model systems. Most do not respond to standard chemotherapies, and it is unclear if treatments that activate the immune system to fight cancer (immunotherapies) and are commonly used for patients with urothelial carcinoma are also effective in variant bladder cancers. To address these important deficits in the field, we have assembled a very collaborative team of basic, translational, and clinical investigators with complementary expertise in bladder cancer biology and therapy. In preliminary work, we have developed an innovative experimental approach to rapidly generate new tumor models of urothelial carcinoma and variant bladder cancers from normal mouse bladder cells. Many of these model systems are first-in-field. In initial studies we have found that specific transcription and translation factors may be essential for the growth of variant bladder cancer. Excitingly, through these studies we have found drugs that can target these factors, which we will test in the new models we have generated in conjunction with immunotherapy. It will also be very important for us to study our mouse findings in human bladder cancer tissues. To this end, we have operated a highly successful rapid autopsy program for patients with lethal, metastatic bladder cancer that has focused on the acquisition of variant bladder cancer biospecimens. This resource will enable the correlation of our scientific findings between mice and humans. In Aim 1, we will determine whether transcription factors associated with the identities of variant bladder cancers are necessary for their survival. We will then use the novel drug SY-5609 that disrupts the expression of master cancer genes to investigate whether they can block the growth of variant bladder cancers. In addition, we will test if SY-5609 treatment combined with immunotherapy may result in enhanced tumor control or regression in variant bladder cancer models in mice. In Aim 2, we will use genetically engineered mice with an impaired translation factor to characterize the role of protein synthesis on the initiation of variant bladder cancers and on their supportive tumor microenvironments. We will also evaluate whether blocking a key regulator of translation with the drug eFT508 improves the antitumor effects of immunotherapy. In Aim 3, we will further confirm our findings in human primary and metastatic bladder cancer specimens by analyzing human biospecimens from our rapid autopsy program and pre- and post-treatment tissues from two clinical trials. The anticipated outcome of these studies is to greatly improve our understanding of the determinants of conventional and variant bladder cancers and identify new therapeutic strategies to combat them. We expect that targeting operative master transcription or translation regulators in variant bladder cancer cells and their surrounding tumor microenvironments are likely to have antitumor activity and improve the effectiveness of immunotherapy. We anticipate that the findings from these experiments will also be confirmed in our investigation of human urothelial carcinoma and variant bladder cancer tissues. Notably, the drugs that we are testing to disrupt master t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311055
Entities
People
- Andrew C Hsieh
Organizations
- Fred Hutchinson Cancer Center
- United States Army