Identification of Novel Prostate Cancer Stem Cell Genes as Therapeutic Targets
Abstract
Background and Rationale: Due to limited treatment opportunities for men with prostate cancer that has spread to other parts of the body (also known as metastasis), this disease remains the leading cause of cancer deaths in men in the Western world. We hypothesize that this is partly due to a rare population of cancer stem-like cells that are resistant to conventional and available therapies. While standard therapies can kill the bulk of the cancer cells, the cancer stem cells survive and, due to their stem-like properties, are able to form new tumors that continue to grow and spread. In short, the cancer stem-like cells are an Achilles’ heel in prostate cancer that leads to therapy resistance. As such, the discovery of unique cancer stem cell genes that can be used to develop drugs that stop the survival and activity of stem cells could be an important step forward toward more effective treatment of advanced prostate cancer. Proposal: Our laboratory recently developed a new method that can label and isolate cancer stem-like cells from prostate cancer tissue collected in the operating room. Using this technique, we were able to capture these cells and find several unique genes that may be important for the stem cell’s activity. In the present studies, we propose three Aims. In Aim 1, we will expand the discovery of unique genes found in prostate cancer stem cells both in local prostate cancer (from the prostate gland) and in metastatic prostate cancer collected during spine stabilization in men with advanced cancer. We will sequence the genes in the cancer stem cells and identify the top genes found in both local and metastatic stem cells or ones that appear only in the cancer stem cells. In Aim 2, we will block these genes in cancer stem-like cells and determine whether this inhibition can limit their ability to divide or behave like stem cells. We will also test their effectiveness in mini-organoids grown from prostate cancer cells. In Aim 3, we will evaluate the top three genes for their ability to block tumor growth and metastasis in animal models. We will block these genes in human prostate cancer cells and transfer these cells to mice where they will grow as tumor grafts. We have several models for both local cancer and metastatic cancers, including castrate-resistant prostate cancer. The ability to block or reduce tumor growth and prevent metastasis will be evaluated. We expect to deliver 2-3 druggable gene targets that can be used to control cancer stem cell actions and help limit tumor growth. Clinical Applicability and Impact: The overall objective of the proposed study is to identify unique druggable genes enriched in prostate cancer stem cells, with the goal of discovering new targets for effective prostate cancer therapy. We hope that these “leads” will inform future drug discovery of novel small molecules that can kill cancer stem cells. These would be used in the future in combination therapy with conventional drugs (enzalutamide, docetaxel, immunotherapy) so that both the cancer stem cells and the rest of the cancer cells are eliminated together.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910253
Entities
People
- Gail Prins
Organizations
- United States Army
- University of Illinois at Chicago