Basic Science Research
The Department of Urology's basic science research focuses on understanding:
- How and why prostate cancer (Pca) cells respond to hormonal therapies
- What causes prostate cancer to progress to metastatic and castrate-resistant cancer
Investigators Robert J. Matusik, PhD and Renjie Jin, MD, PhD successfully isolated a DNA fragment (probasin promoter) that can be manipulated to limit gene expression to the prostate and measure androgen receptor (AR) activity. This breakthrough allows for the creation of mouse models for prostate cancer that reproduce the full spectrum of transformation seen in human prostate disease including:
- Benign hyperplasia
- Pre-neoplastic lesions
- Local invasive carcinoma
- Androgen-dependant cancer
- Progression to NEPC (neuroendocrine prostate cancer)
Testing therapies in our mouse models let us take research findings from the bench to the patient. We also research in the reverse, to confirm if genetic changes seen in human disease are sufficient to drive prostate cancer in mouse models.
Forkhead BoxA1 (FOXA1)
Our studies on how the androgen receptor regulates gene expression and tumor growth led to our identification of the Forkhead BoxA1 (FOXA1) transcription factor. FOXA1 co-regulates androgen receptor action. This finding is important because we also learned:
- FOXA1 mutations that increase androgen receptor activity define one of four subsets of genetic changes that drive prostate cancer progression.
- FOXA1 plays an opposite role in bladder cancer, where the loss of the transcription factor drives aggressive disease.
- FOXA1 mutations are found in bladder, breast, and salivary gland cancer.
Treatments that co-target the AR and FOXA1 could lead to new therapeutic approaches for prostate cancer.
Nuclear Factor I Family
The Nuclear Factory I family (NFIA, NFIB, NFIC, NFIX) also are important co-regulators of AR action. In studying the AR transcription factor complex, we found that NFIB levels increase during the progression of the adenocarcinoma to therapy-induced NEPC.
This suggests that NFIB may be a central driver to this late stage of prostate cancer, which often fails conventional therapy.
Dr. Matsuik's and Dr. Jin's lab found that the NFkB pathway turns on the expression of AR variants (AR-V) in human benign prostatic hyperplasia (hBPH) and prostate cancer (Pca). This helps explain the continued growth of the prostate in hBPH and Pca.
Blocking the NFkB pathway can restore the responsiveness of human castrate-resistant prostate cancer (CRPC) xenografts to anti-androgen therapy. This:
- Shows the NFkB pathway plays a major role in AR function during failure of androgen deprivation therapy (ADT)
- Opens a door for a therapeutic approach that inhibits AR splice variant function by down-regulating the NFkB pathway to delay or reverse progression to CRPC
Dr. Jin's lab determined long-term ADT induces neuroendocrine differentiation (NED) and increases NE peptide expression in prostate cancer cell lines. The increased level of NE secreted peptides contribute to castrate-resistant growth of prostate cancer by activating the NFkB pathway.
Dr. Jin's research discovered that NFkB signaling also:
- Promotes the development of osseous metastasis
- Contributes to the development of castrate resistance by activating the expression of AR splice variants (AR-Vs) in prostate cancer
To restore the responsiveness of the CRPC to hormonal therapy, we are developing an innovative approach that:
- Targets the cells that undergo transdifferentiation to NE cancer
- Blocks the NFkB pathway to down-regulate AR-Vs expression
3D Organoid Cultures
To study the critical pathways responsible for failure to respond to drug therapy and the continued growth of the prostate, we established 3D organoid cultures from human prostate samples:
- Patient-derived prostate cells are isolated and placed in culture with a special media on a collagen matrix.
- The mixture of cells self-organizes into spheroid structures that send out buds.
- As the buds elongate, they form branches.
- The process repeats itself, resulting in a tree-like structure that mimics the normal prostate gland.
Using this process we can create a miniature prostate in culture from a patient that failed medical therapy. These organoid cultures mirror the patient's response to therapy allowing us to test different therapies on these cultures to understand:
- What caused the unrestrained prostate cell growth?
- Why do these patients fail the medical therapy used to treat hBPH?
- Can we reverse the prostatic unrestrained growth?
Since 3D organoid culture can accurately predict a patient's response to therapy, the goal is to use this approach to allow physicians to personalize medical treatment for benign disease and cancer based upon results in 3D culture.
Prostate Cancer Bone Metastasis
Work in Dr. Jin’s lab determined that long-term ADT can reprogram prostate cancer cells to change their characteristics in ways that enable non-bone-growing prostate cancer cells to colonize and grow in the bone microenvironment.
His lab showed that antiandrogen-resistant or therapy (t) induced neuroendocrine prostate cancer cells can cause bone marrow-derived macrophages to stimulate tumor growth by polarizing M2 pro-tumorigenic macrophages. Activated M2 macrophages:
- Feed prostate cancer cells
- Contribute to cancer cell survival
- Help prostate cancer cells to grow in the bone microenvironment
With these findings, our researchers are developing a new therapeutic approach to prevent and treat prostate cancer bone metastasis by blocking the interacting loop between cancer cells and the bone microenvironment.