Protein Found in Prostate Cancer May Promote Cancer Growth and Progression
October 19, 2012 -- The protein PARP1 is known to play a crucial role in DNA repair (i.e., facilitating the recovery of a normal cell from DNA damage by repairing breaks in DNA strands). PARP1 is overexpressed in many cancers, such as breast, ovarian and colorectal cancers. This abnormal expression of the protein increases with the stage of the disease, higher expression being associated with poor prognosis. Therefore, PARP1 is a good target for cancer therapeutics and many experimental PARP1 inhibitors have shown promising results in clinical trials.
In a PCF-funded study, published in the journal Cancer Discovery, Dr. Karen Knudsen at Thomas Jefferson University and colleagues have identified a second role for PARP1, in addition to its role in DNA repair. Their results show that the activity of PARP1 is enhanced in advanced prostate cancer and it is recruited to sites of androgen receptor (AR) function. The androgen receptor mediates the activity of male hormones, androgens and drives prostate cancer growth and progression. Unfortunately, despite androgen ablation, the primary treatment for prostate cancer, the disease returns in most patients. Studies have shown that this recurrence of now ‘treatment-resistant’ prostate cancer is promoted by the erroneous activity of AR. Since there is no durable cure for this stage of disease, there is an urgent need to develop strategies to sustainably suppress AR function and/or sensitize prostate cancer cells to chemotherapy.
Dr. Knudsen and colleagues show that PARP1 is required for AR activity in both the hormone-dependent and treatment-refractory stages of the disease. Inhibiting PARP1 results in a sharp decline in the expression of genes that are activated by AR (such as PSA, TMPRSS2, FKBP5, etc.) Therefore, these studies have identified an important second function of PARP1 in prostate cancer cells in addition to its role in DNA damage response, that of a potent modulator of AR function.
These findings validate PARP1 as a good therapeutic target in prostate cancer as its inhibition will have dual effects on cancer cells; one, its inhibition will impair DNA repair in the tumor and two, it will suppress AR signaling, halting cancer progression and activating pro-survival and pro-proliferative programs in prostate cancer. Administering PARP inhibitors in combination with other AR-directed therapies will potentially inhibit prostate tumor proliferation in both early and late stage prostate disease.
Dr. Knudsen and team tested this hypothesis using experimental PARP inhibitors, olaparib and veliparib, both of which strongly suppressed prostate cancer tumor growth in vivo. Preclinical studies conducted by this team showed that PARP1 inhibition significantly suppressed tumor doubling.
In summary, these PCF-funded studies identify novel functions of PARP-1 in promoting prostate cancer progression, and suggest that the dual functions of PARP-1 can be targeted in human disease to suppress tumor growth and progression to castration-resistance.
These studies are another example of PCF-funded team science that has led to major advances in our understanding of this complex disease. A collaborative effort, other members on this PCF-funded team are , Felix Feng MD, (University of Michigan), Ganesh Raj, MD(UT Southwestern Medical Center), Adam Dicker, MD, PhD (Thomas Jefferson University), Wayne Tilley, PhD (The University of Adelaide) and Arul Chinnaiyan, MD (University of Michigan).