Therapeutic Targeting of B7-H3 to Reverse Prostate Cancer Treatment Resistance
Abstract
Rationale and Objective: Prostate cancer is the most common cancer that occurs in men and is the second most common cause of cancer death. Though there are several drugs that are active in prostate cancer, a fundamental problem with this disease is that it is not curable once it has spread outside of the prostate. This is because after a certain period of time under drug treatment, prostate cancer cells acquire the ability to resist the drug and thus grow freely once again. Additionally, in order to spread outside of the prostate, prostate cancer cells have to also evade the immune system, which is normally programmed to seek out and destroy cancer cells. One molecule, called B7-H3, might be responsible for helping prostate cancer cells become resistant to treatment and avoid the immune system. B7-H3 is normally found on many cells of the immune system and works to turn off unwanted immune reactions. Several lines of evidence suggest that B7-H3 has an important role in prostate cancer. First, B7-H3 is not found in normal prostate tissue but is found in 99% of prostate cancers. Second, some prostate cancers make more B7-H3 than others. Prostate cancers that make lots of B7-H3 tend to be high-grade and high-stage (i.e., more aggressive). Third, men whose prostate cancers have high B7-H3 levels are twice as likely to develop metastases than those men whose prostate cancers have low levels (i.e., more aggressive). Fourth, prostate tumors with high B7-H3 are more likely to be resistant to second-line radiation therapy if prostate cancer returns after radical prostate surgery (i.e., treatment resistance). Fifth, prostate cancers with high B7-H3 production have lower levels of immune cell activation (i.e., immune suppression). Sixth, prostate cancer metastases have high levels of B7-H3 (i.e., more aggressive). Seventh, B7-H3 levels increase after treatment of metastatic prostate cancer with first-line pharmaceutical castration (i.e., treatment resistance). Lastly, B7-H3 can be found on the surface of prostate cancer cells but can also be found in the blood in a form that is still biologically active. This suggests that B7-H3 may not only be active within the tumor but also could be active systemically within the prostate cancer patient. Taken together, the above facts make B7-H3 a strong candidate for causing treatment resistance, immune evasion, and worse outcomes in prostate cancer. The objective of this research proposal is to prove that B7-H3 is associated with treatment resistance, immune evasion, and worse outcomes in prostate cancer. We also want to determine if blocking B7-H3 is an effective method of restoring prostate cancer sensitivity to common treatments like androgen deprivation, chemotherapy, and immunotherapy. To achieve our objective, we will pursue several lines of investigation (aims). (1) We will examine B7-H3 production in human prostate cancer specimens and determine if B7-H3 is associated with cancer severity, response to treatment, or survival outcomes. (2) We will measure B7-H3 levels in the blood and determine if it is associated with cancer severity, response to treatment, or survival outcomes. (3) Using three mouse models of prostate cancer, we will examine new methods of interfering with B7-H3 and determine if we can increase treatment sensitivity and improve outcomes. Why this research matters and how this research will be applied: Our research project will shed light on the central issue of how prostate cancer manages to evade the immune system and become resistant to treatment and, consequently, is most relevant to men with advanced prostate cancer. The outcome of this research is pertinent to all men with prostate cancer who develop resistance to currently used treatments and the cancer spreads freely outside the prostate. If this research is successful, several important deliverables will result. First, measuring blood B7-H3 would be a new test for prostate cancer
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610505
Entities
People
- Smita K Nair
Organizations
- Duke University
- United States Army