BETHESDA, MD USA (UroToday.com) - Dr. Karen Knudsen opened today’s State-of-the-Art Lecture by identifying prior studies demonstrating that mutations in DNA repair processes increase as a function of disease progression. What is not known, however, is that if these mutations are a driver, or passenger, of disease progression. Dr. Knudsen’s group studied PARP1 and DNAPK, both of which have dual roles in repair and transcriptional regulation, to help answer this question.
PARP1 is a protein that ADP-ribosylates other proteins, and its activity is increased in advanced disease. It has proven to be an important target in other cancers as well: PARP1 inhibitors are particularly effective in breast cancer with DNA repair pathway mutations such as BRCA1, BRCA2, and have shown promise in models with PTEN mutations as well. PARP1 binds the androgen receptor and is important in its activity.
Dr. Knudsen presented a mouse model where mice were implanted with human castrate-resistant prostate cancer, and then enrolled into a control arm or a PARP1-inhibitor treatment arm. Those randomized to the treatment arm demonstrated either stasis of disease or tumor regression. Consistent with this, there was a down-regulation of PSA, TMPRSS2, and FKBP5 only in those animals treated with a PARP1 inhibitor. Taking this one step further in human models, in collaboration with the department of urology at Jefferson University, Dr. Knudsen’s group showed that PARP-1 inhibitors produced a decrease in expression of AR in freshly extracted prostate cancer tissue.
DNAPK, like PARP1, also has an important role in advanced prostate cancer as it is the most expressed kinase in mCRPC. In response to DNA damage, AR has increased transcriptional activity. DNAPK levels become more active, leading to dsDNA strand break repair, and ultimately tumor cell survival. Thus, by blunting DNAPK, there is a decrease in dsDNA strand break repair. Further study in knockout and inhibitor models identified DNAPK to promote expression via the Rac/Rho pathway, which promotes cell migration and invasion. Animal models demonstrated that suppression of DNAPK therefore suppresses migration and invasion. One important caveat, though, is that DNAPK is critical in the early stage of metastatic disease: subjects who started as controls and were later placed on a DNAPK inhibitor showed no change in metastatic disease.
Dr. Knudsen concluded her lecture by stating that DNA repair and resistance to DNA damage may be the most important feature of AR. Upregulation of expression and activation DNAPK has implication for pathways that promote metastases. These data nominate DNAPK as a therapeutic target. Meanwhile, PARP1 inhibitors have potential as single agent in the treatment of advanced prostate cancer, as well.
Karen E. Knudsen, PhD
Thomas Jefferson University, Philadelphia, PA USA
Nikhil Waingankar, MD* from the 2014 Winter Meeting of the Society of Urologic Oncology (SUO) "Defining Excellence in Urologic Oncology" - December 3 - 5, 2014 - Bethesda, MD USA
*Fox Chase Cancer Center, Philadelphia, PA USA