Presentation Authors: Matthew Sullivan, Sayani Bhattacharjee, Rebecca Wynn, Nagalakshmi Nadiminty*, Toledo, OH
Introduction: Bladder cancer (BLCA) is the sixth most common cancer in the US and the ninth most common worldwide. BLCA management has not changed significantly in the last 3 decades, with platinum-based chemotherapy (MVAC) being the systemic therapy of choice since 1985. MVAC can reduce recurrence after tumor resection, but only 50% of patients are either eligible or respond, and it is associated with several life threatening toxicities. Breakthrough immunotherapy with checkpoint inhibitors produces partial or complete responses in only 20-30% of patients with metastatic BLCA. Hence, the need for more therapeutic options is paramount. Cells deficient in homologous recombination (HR) via loss of BRCA proteins and in SSB repair via inactivation of PARP are subject to synthetic lethality when treated with PARP inhibitors (PARPi). BLCA exhibit somatic loss of function mutations in several HR genes, which can amplify the effects of DNA damage caused by ionizing radiation or platinum drugs. Hence, we tested the sensitivity of BLCA cells to commercially available PARPi either singly or in combination with cisplatin.
Methods: BLCA cell lines and xenografts in SCID mice were treated with different concentrations of PARPi (niraparib, olaparib, veliparib, rucaparib, or talazoparib) as single agents or in combination with cisplatin. Cell survival, apoptosis, and clonogenic ability were measured in vitro. Tumor growth of xenografts was measured in vivo. The levels of proliferation and apoptosis in the xenograft tumors were assessed using immunohistochemistry. Expression of PARP enzymes in the BLCA cells and xenograft tumors was examined using Western blotting.
Results: BLCA cells responded differently to each PARPi. Niraparib and talazoparib were the most effective at reducing cell survival of BLCA cells compared with normal urothelial cells. Veliparib was not effective in reducing cell survival even at high concentrations. Combinations of PARPi with cisplatin exhibited strongly additive effects on cell survival and apoptosis in vitro. In vivo, niraparib, rucaparib, and talazoparib were the most effective at reducing tumor growth of BLCA xenografts. The combination of olaparib with cisplatin exhibited strongly additive effects in reducing tumor growth.
Conclusions: We provide preliminary evidence that PARPi can be effective therapeutic options against BLCA cells. Given that the anti-tumor activity of PARPi is via the inhibition of PARP catalytic activity and/or PARP trapping, our results suggest that the higher PARP trapping activity of niraparib, olaparib, rucaparib, and talazoparib plays the major role in their activity against BLCA cells compared with veliparib, which is a primarily catalytic inhibitor.
Source of Funding: NIH/NCI R21CA202404NIH/NCI R03CA198696