3D Light-Sheet Microscopy: Identification and Molecular Characterization of Prostate Carcinoma with De Novo Resistant to Total Androgen Ablative Therapy
Abstract
Prostate cancer has a range of severities: some patients will never experience any symptoms from their disease, while at the other end of the spectrum, other patients will experience a rapid decline and death. In the middle of this range are patients with what is called “high-risk localized disease.” These patients with high-risk localized disease have a chance at cure with effective treatment, but are at high risk for death from prostate cancer. An increasingly common treatment for high-risk localized disease is neoadjuvant androgen ablative therapy (AAT). This treatment involves drug(s) taken before surgery that block the androgen pathway, starving the tumor of growth factors. The intention of neoadjuvant AAT is to shrink the tumor so that surgery is curative, i.e., the entire tumor is taken out at the time of surgery. However, only a minority of patients have a good response to neoadjuvant AAT, while the majority are still at risk for disease progression and cure. It is unknown why some patients respond well to neoadjuvant AAT while others do not. Further understanding of the biology of neoadjuvant AAT is needed to tailor the right treatment to the right patient and to develop new, more effective treatments. One reason for the lack of understanding of the biology of neoadjuvant AAT is the technology that is used to analyze residual post-treatment prostate cancer tissue. Much of technology used for these studies was developed in the 19th century. For instance, cancer tissue is fixed or preserved in formalin, then infused with paraffin wax to make a tissue block. A very thin section is cut from the tissue block, placed on a glass slide, stained with chemical dyes, and then viewed under a traditional light microscope. Although this technology is used in the clinical practice of pathology to diagnose prostate cancer, it is not well-suited for research studies on post-treatment prostate cancer tissue. The process damages DNA and RNA, which negatively impacts molecular analysis. In addition, the glass slides offer only a 2D view of tissue that exists in 3D, which is particularly problematic in post-treatment prostate cancer tissue, where the tumor cells are often hard to find because of their sparsity. To better understand the biology of neoadjuvant AAT, we will apply a novel technique developed in Dr. Liu’s laboratory over the past 3 years: open-top light-sheet microscopy (OTLS) with 3D microdissection. OTLS with 3D microdissection will enable us to view the tissue in 3D, find the rare tumor cells, isolate the tumor cells using 3D microdissection, and then perform molecular analysis on the microdissected tissue, which has well-preserved DNA and RNA. We aim to show that this innovative technology will lead to important insights into why some patients have a dramatic clinical response to neoadjuvant AAT while others do not. If these studies are successful, we will translate these findings into more personalized neoadjuvant AAT for patients with high-risk localized disease. These studies will allow me to gain the skills and expertise needed to be a grant-funded physician scientist in prostate pathology research while maintaining my clinical pathology practice. My career goal is to develop new technology that improves our ability to study prostate pathology and to use that technology to make discoveries that lead to more personalized therapy for prostate cancer patients. I have a mentorship team composed of leaders in biomedical optics (Dr. Jonathan Liu), prostate pathology (Dr. Lawrence True), and prostate cancer genetics (Dr. Colin Pritchard). All three mentors have made ground-breaking discoveries in their respective fields and have a track record of success in mentoring junior faculty. I have a medical oncology collaborator (Dr. Michael Schweizer) who will provide tissue samples from his clinical trial of neoadjuvant AAT in addition to provide insights into how our findings can lead to more personali
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910589
Entities
People
- Nicholas Reder
Organizations
- United States Army
- University of Washington