Sensitization of Castration-Resistant Prostate Cancer to Chemotherapy via BRCA-1- and BRCA-2-Induced DNA Replication Stress
Abstract
Background: Despite significant advances in treatment options, more than 26,000 men die of prostate cancer in the United States annually. In order to eradicate death and suffering from prostate cancer, we need to develop more effective treatments that will overcome the capacity of prostate cancers to evade current therapies. Prostate cancer cells take advantage of numerous, complex, and mutually redundant pathways to survive and grow. As a result, blocking only one of them is insufficient to achieve a cancer cure. Therefore, it is plausible that combinations of effective therapies will be needed so that we can block multiple oncogenic pathways simultaneously. In recent years, we have learned a lot about how prostate cancer cells manage to survive our current therapies. The O’Malley laboratory at Baylor College of Medicine was the first to discover and study the steroid receptor coactivators (called “p160 SRCs”). Prostate cancer cells, especially those that have developed resistance to conventional treatment, produce high amounts of these proteins and utilize them to promote their growth. Importantly, these p160 SRCs are critical for the activity of a large number of cancer-driving pathways. Fortunately, normal tissues tolerate the loss of SRCs generally well, and we have found that mice born without the p160 SRCs are viable and overall healthy. Thus, there is a therapeutic window that would make the p160 SRCs ideal therapeutic targets. We also have discovered that a protein called GATA2 is another “master switch” for prostate cancer cells and is driving the production of several proteins that are necessary for cancer growth, such as the androgen receptor, c-Myc, FOXM1, CENPF, and EZH2. Thus, we have identified the p160 SRCs and GATA2 as major drivers of cancer growth and resistance and, thus, novel therapeutic targets in prostate cancer. Our group has studied the blockade of the p160 SRCs and GATA2 in prostate cancer cells in the laboratory, and we found that one major effect is the loss of proteins that are normally needed to repair DNA. This is particularly important because cancer cells that cannot repair their DNA efficiently are very sensitive to drugs called PARP inhibitors and to other drugs such as carboplatin. So far, PARP inhibitors and carboplatin have shown potent clinical activity against cancers where the DNA repair capacity is compromised due to mutations in genes such BRCA1 and BRCA2. In prostate cancer, unfortunately, this clinical scenario is limited to a small group of patients. We are now introducing an innovative concept: We have demonstrated that it is possible to make drugs that can turn off these “master switches,” p160 SRCs and GATA2, and that this depletes the levels of BRCA1, BRCA2, and other proteins that are normally needed to repair DNA. Thus, we are functionally mimicking the situation where BRCA1 and BRCA2 are inactivated due to a mutation, making the cancer cell sensitive to the PARP inhibitors and other drugs (e.g., carboplatin). Thus, we are proposing that the combination with inhibitors of p160 SRCs and GATA2 will make the PARP inhibitors and carboplatin effective for all prostate cancer patients. Ultimate Applicability of the Research: We have synthesized novel, “first-in-class” inhibitors of the p160 SRCs and GATA2. Our preliminary results demonstrate that our novel p160 SRC inhibitors are active against prostate cancer cells and well-tolerated by mice. Our proposal aims to prove that these novel drugs can enhance and broaden the activity of therapies such as PARP inhibitors and carboplatin, which currently benefit only a small group of patients, thus expanding this benefit to all prostate cancer patients. Such a successful outcome would provide a new treatment paradigm for men with advanced and metastatic prostate cancers that no longer respond to current therapies. In summary, this is a very exciting “first-in-field” approach that will lead to future
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810288
Entities
People
- Nicholas Mitsiades
Organizations
- Baylor College of Medicine
- United States Army