This article reviews the status of PARP inhibitors for prostate cancer treatment and focuses on recent developments in drug approvals.
How PARP Inhibitors help in Prostate Cancer Treatment?
Prostate cancer is a heterogeneous disease, often driven by specific genomic alterations. The defects in DNA repair/DNA-damage response pathways are critical to the risky malignant transformation of prostate cancer. The enzymes PARP, BRCA 1/2, and ATM play important roles in the malignant transformation of prostate cells and drug developers are taking advantage of this concept for devising prostate cancer cure. In this concept, where one gene is inactivated by mutation, the other is inactivated by a drug. This approach of PARP inhibitors is successfully used in tumors having DNA damage defects and therefore can be used for prostate treatment.
Two PARP Inhibitors for the Cure of Prostate Cancer
Recently, the FDA approved two PARP inhibitors for prostate cancer treatment—Rucaparib and Olaparib. These drugs were found to delay cancer progression in men with metastatic prostate cancer.
Rucaparib was the first of the two approved PARP inhibitors and is indicated for the cure of adult patients with metastatic prostate cancer having a BRCA mutation. The approval for rucaparib for prostate cancer treatment was supported by a multicenter, single-arm trial known as “TRITON2”. Shortly after the Rucaparib approval, the FDA announced the approval of Olaparib based on data from the PROfound clinical trial.
Ongoing PARP Inhibitor Clinical Trials for Prostate Cancer
Some of the ongoing PARP inhibitor clinical trials include:
PROpel [Olaparib]: This is a Phase III trial for testing Olaparib as a 1st-line medicine in genetically unselected metastatic prostate cancer treatment in combination with Abiraterone.
TALAPRO- 1 [Talazoparib]: This is an open-label, Phase II trial evaluating Talazoparib in metastatic prostate treatment of cancer with DNA damage defects after 1–2 chemotherapy regimens.
TRITON3 [Rucaparib]: This is an open-label Phase III trial comparing Rucaparib with a physician’s choice of therapy for metastatic prostate cancer treatment associated with an HRR gene defect.
MAGNITUDE [Niraparib]: This is a Phase III trial evaluating Niraparib in combination with Abiraterone and Prednisone in adults for metastatic prostate cancer treatment.
More Information on Using PARP inhibitors for Cancer
Most of human prostate cancer pathogenesis tend to form spheres and adaptation of cancer cells or cancer stem cells to non-adherent culture conditions may be a crucial factor in this regard. In prostate cancer pathogenesis, the holoclone-forming cells, which are adherent and highly clonogenic, have been associated with stem cell phenotypes, suggesting their inclination towards being tumor-initiating cells with stem cell-like features of strong self-renewal and pro-angiogenic capability. Accordingly, in these prostate cancer sphere models, the expression of putative cancer stem cell markers such as ALDH1A1, CD44, CD133, showed a strong correlation with progression and metastasis.
Researchers are working towards using PARP inhibitors to inhibit cancer metastasis in these prostate cancer sphere models and moreover, reconstruction of tumorspheres using bioscaffold mesenchymal stem cells are also being sought to understand the mechanism of cancer resistance. In addition to being targeted for prostate cancer treatment, PARP1 is also reported to repress NKG2DLs expression and mediate immune evasion of leukemic stem cells (LSCs) in the case of acute myeloid leukemia. Therefore, PARP1 inhibition could restore NKG2DL expression and promote their immune-mediated clearance. Thus, the multifactorial functions of PARP1 in immunomodulation and immune escape of cancer adult stem cells may pave the way for novel therapeutic strategies in the clinic.
PARP inhibitors are exciting and novel precision therapeutics for prostate cancer treatment and more research is underway to establish further efficiency of PARP inhibitors. If your lab is working on prostate cancer treatment research and you are looking for cancer cell lines or disease-specific primary cell culture, contact us at firstname.lastname@example.org with your inquiries.