Co-targeting the Cell Cycle and Androgen Signaling Axis via CDK4/6 Inhibition and Androgen Deprivation: A Novel Paradigm for treating Metastatic Hormone-sensitive Prostate cancer
About Co-targeting the Cell Cycle and Androgen Signaling Axis via CDK4/6 Inhibition and Androgen Deprivation: A Novel Paradigm for treating Metastatic Hormone-sensitive Prostate cancer
Once prostate cancer metastasizes, or spreads, beyond the prostate gland, the vast majority of patients will ultimately succumb to this disease. Prostate cancer (PCa) spread is fueled by male hormones, or androgens, and the androgen receptor (AR) protein. For over 70 years, androgen deprivation therapy (ADT) has served as first-line treatment of men with metastatic PCa. Most men diagnosed with metastatic PCa have tumors that respond to ADT and their disease is said to be “hormone sensitive.” However, most men with hormone-sensitive PCa will eventually develop resistance to ADT. At that point, their disease is said to be treatment-resistant and mostly insensitive to hormone therapy. Prognosis at this stage is grim. Drs. Hussain, Feng and Knudsen will undertake an ambitious first-in-field investigation to determine if men with hormone-sensitive, metastatic PCa who are given a novel combination of drugs can delay the onset of resistance to ADT, and thus delay progression to end-stage disease.
The researchers will conduct a randomized, multi-center Phase II clinical trial in which men with metastatic hormone-sensitive PCa, whose tumors express a genetic alteration of the RB gene that can be targeted, will be randomly assigned to receive either ADT alone or ADT in combination with an experimental oral drug known as PD-0332991. The experimental compound inhibits CDK4/6, two kinase proteins that play a key role in cell growth cycles. Inhibiting CDK4/6 kinases may block cancer cell growth and can re-boot the activity of the retinoblastoma (RB) tumor suppressor gene. The tumor suppressor activity of the RB gene is often weakened in tumors, and to date, CDK4/6 inhibitors have shown significant anti-tumor effects against breast cancer. Preliminary data from these Challenge Award researchers shows that loss of RB tumor suppressor activity is found in 60% of men with far-advanced treatment-resistant PCa; however 80 to 90% of men with hormone-sensitive PCa (HSPC) continue to have some RB tumor suppressor activity. This Challenge Award team has also found that alterations in RB tumor suppressor activity have a direct impact on the function of the androgen receptor and can lead to AR malfunction which leads to end-stage, treatment-resistant disease.
In the clinical trial, patients will undergo biopsies of a metastatic site to determine their level of RB activity. This will greatly aid in future determinations of which patients with metastatic HSPC would likely benefit from this combination therapy. The team, using the metastatic biopsy samples from the Phase II clinical trial, will use genomic sequencing to determine other biomarkers that may make men good candidates for combination therapy of ADT and CDK4/6 inhibitors.
What this means for patients: Currently there is no cure for patients with metastatic treatment-resistant prostate cancer. This trio of researchers will combine a novel drug being developed by Pfizer—the candidate drug boosts the activity of a vital tumor suppressor gene and interrupts cancer cell growth cycles—with traditional androgen deprivation therapy in an attempt to prevent or delay cancer progression to end-stage disease. The novel investigational drug was recently shown to be safe and effective against a common form of advanced breast cancer. In the clinical trial, men whose tumors have functioning (RB) tumor suppressor gene activity—such men are the most likely responders and thus the best candidates for this new drug—will be given either the combination of drugs or ADT alone. This work is a study in precision medicine and may not only lead to the rapid development of a novel drug against PCa, it may well enable doctors to determine at the outset of therapy which men will be the strongest responders to this combination therapy.
Maha Hussain, MD (University of Michigan)
Felix Feng, MD (University of Michigan), Karen Knudsen, PhD (Thomas Jefferson University).