Discovery of a First-in-Class MPP8 Antagonist to Reverse Lineage Plasticity in Bladder Cancer

Bladder cancer is a common and deadly disease. In the United States, bladder cancer is the sixth most commonly diagnosed malignancy; however, bladder cancer is the fourth most common cancer diagnosed in the VA Health System, making it even more common than melanoma. In addition to modifiable risk factors like tobacco use, exposure to pesticides like Agent Blue, and Agent Orange exposure among Vietnam War Veterans, as well as exposure to contaminated drinking water at Camp LeJeune, North Carolina have been linked with increased risk of bladder cancer. In bladder cancer, a phenomenon called 'lineage plasticity' or 'epithelial to mesenchymal transition' (EMT) can occur where cells lose their original identity and assume the identity of a different kind of cell. Then they are able to escape the bladder and metastasize to different parts of the body, which makes the disease extremely challenging to treat at this point. EMT has been associated with increased risk of invasion into the muscle (i.e., progression to 'muscle invasive bladder cancer'), resistance to a standard chemotherapy called cisplatin, and worsened survival among metastatic bladder cancer patients.

Chromatin is a complex of DNA and proteins found in all of our cells. Modifications to the DNA that do not result in changes to the actual DNA code are called epigenetics, and these modifications dictate how genes are expressed. Recently, scientists have begun to more fully appreciate how epigenetic changes, or 'epigenetic dysregulation,' can influence human diseases. Despite the fact that epigenetic dysregulation is a common feature of most pediatric and adult cancers, understanding of chromatin regulation is still in its infancy. Chemical biology and developmental therapeutics are poised to help advance scientific knowledge and assess therapeutic opportunities in this field. The oncology scientific community's interest in chromatin regulation and epigenetics have intersected with drug development, and numerous compounds for several classes of epigenetic regulatory proteins have resulted in clinical translation over the past decade. In fact, some have even been Food and Drug Administration-approved in hematologic malignancies, while others having progressed past first-in-human clinical trials in solid tumors.

Altered chromatin and epigenetics are common in advanced bladder cancer, and epigenetic changes to chromatin have been associated with EMT. In bladder cancer, a protective gene called CDH1 can be silenced, which leads to EMT, resistance to cisplatin, and increased risk of metastasis. However, mechanisms of CDH1 silencing and EMT are still not well understood, which has made developing new treatments challenging. MPP8 is an epigenetic protein that has been linked to EMT in many types of cancer and has been implicated in CDH1 silencing. Therefore, the goal of this Fiscal Year 2020 (FY20) Peer Reviewed Cancer Research Program (PRCRP) Career Development Award is to develop a potent and selective MPP8 antagonist compound (1) to validate MPP8 as a novel epigenomic protein that regulates EMT in bladder cancer and (2) to as a potential therapeutic strategy in bladder cancer.

In this research proposal, our team addresses one of FY20 PRCRP Topic Area: 'Bladder Cancer,' and one of the FY20 PRCRP Military Health Focus Areas: 'Mission Readiness.' We have assembled a multi-disciplinary research team with complementary expertise in basic and translational research experience in bladder cancer, medicinal chemistry, chemical biology, molecular biology, pharmacology, and developmental therapeutics. We envision that our powerful technology will be developed into a viable therapeutic strategy for patients with bladder cancer. We believe that if we can develop a therapy that binds to the MPP8 protein and modifies how protective tumor suppressor genes are expressed, we can prevent EMT so that the bladder cancer remains sensitive to chemotherapy and does not metastasize to other parts of the body. Our team has many years of experience working together clinically and on research studies, and has produced compelling preliminary data that demonstrate that our first-generation MPP8 antagonist compound is potent and selective within cell systems that represent bladder cancer. Our complementary expertise, the duration of our collaborations, and our preliminary experimental data have substantially de-risked this project.

Our first-in-class MPP8 antagonist is technically advanced and state-of-the art, and has the distinct potential to be clinically impactful, because it represents an exciting new treatment strategy for patients with bladder cancer. We envision that our innovative technology will serve as a critical target validation tool and also has the potential to be developed into a novel cancer therapy aimed at combating EMT-related treatment resistance in bladder cancer. We foresee a viable path toward the clinic, where our MPP8 antagonist could lead to substantial improvements in overall survival, and could be beneficial for all patients with advanced bladder cancer, including Service Members, family members of Service Members, Veterans, and the American public alike.