Boosting Complement Activity Suppresses Development of Castration Resistance
Abstract
The complement system is an important part of immune response to invading pathogens. It also plays a critical role in cancer progression. The final step of complement activation is the formation of a membrane attack complex (MAC). The MAC can cause cancer cell lysis and thereby is considered detrimental to cancer cells. C7 is an essential protein to anchor and insert MAC into cell membrane. A precisely regulated C7 expression level is extremely critical for the anti-tumor activity of MAC because insufficient C7 will result in the formation of alternative complexes that induce protumor signaling instead. In our preliminary study, we showed that C7 is specifically expressed by the stromal cells in the human prostate. Androgen deprivation or disrupting the androgen receptor (AR) in prostate stromal cells downregulates the expression of C7. We hypothesize that AR directly regulates C7 and that anti-androgen therapy like enzalutamide downregulates C7 and impairs the anti-tumor function of the complement system, which in turn contributes to development of castration-resistant prostate cancer. In Aim 1, we will investigate how AR regulates C7. In Aim 2, we will confirm that androgen deprivation reduces C7 expression in human prostate cancer specimens. In Aim 3, we will determine whether ablating C7 delays the emergence of castration-resistant prostate cancer in a mouse model for prostate cancer. In Aim 4, we will use a novel human prostate tumor slice culture to determine whether augmenting complement activity potentiates the response of prostate tumor cells to enzalutamide. Our theory that decreased C7 expression by enzalutamide contributes to development of castration-resistant prostate cancer will have a significant translational impact. If proven correct, the knowledge obtained from this study will inspire a novel therapeutic strategy: boosting the complement activity to enhance the therapeutic efficacy of anti-androgen therapy. Therefore, the proposed studies address two of the FY19 Overarching Challenges: “Develop treatments that improve outcomes for men with lethal prostate cancer,” and “Define the biology of lethal prostate cancer to reduce death.”
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010218
Entities
People
- Li Xin
Organizations
- United States Army
- University of Washington