George Li

Introduction:  Osteosarcoma is the most common primary bone malignancy in pediatric patients that often aggressively metastasizes if improperly managed. ¹ Current early phase clinical trials are focused on modification of current antineoplastic agents, but have only managed to demonstrate that they are tolerable with questionable efficacy. ² Poly-ADP-Ribose-Polymerase (PARP) is a family of enzymes that play a role in DNA single-strand break (DSSB) repair. ⁶ Inhibiting PARP 1/2, has been shown to be selectively lethal in certain cancer cells such as BRCA1/2 mutant ovarian cancer, but most notably Ewing Sarcoma—a subtype of osteosarcoma. ^{4, 5} RB1 is a tumor suppressor gene that acts to halt the cell cycle in the setting of DNA damage to prevent further propagation.  Osteosarcoma cells lacking RB1 demonstrated greater cell death when exposed to PARP inhibitors (PARPi) both in vitro and in vivo. ³  Methods: In vitro validation to measure if PARPi induced cell death was first performed across various osteosarcoma cell lines that were either RB1- or RB1+, as well as a BRCA2 mutant cancer that was RB1+. Small-hairpin RNA (shRNA) was then used to silence the expression of RB1 in osteosarcoma cells that normally express RB1 to see if vulnerability to PARPi could be induced. The different osteosarcoma lines that were RB1+/- were then exposed to cisplatin to see if there was any change in sensitivity. In vivo, mice with RB1+ or RB1- human tumors xenografts were treated five times per week for 3 weeks with either 0.33 mg/kg of talazoparib (a PARPi), or DMSO—the vehicle for dissolving talazoparib. ³  Results:  In vitro, RB1- osteosarcoma cell cultures showed significant sensitivity to PARPi comparable to BRCA2 mutant cancers. When exposed to shRNA to silence the expression of RB1, sensitivity to PARPi was shown to be inducible in RB1+ osteosarcoma. While RB1- osteosarcoma is more vulnerable to PARPi, it does not demonstrate increased sensitivity to cisplatin when compared to RB1+ osteosarcoma. In the mice with human tumor xenografts, the RB1- mice treated with talazoparib had a tumor volume that was 25% smaller when compared to the RB1- mice treated with the vehicle, DMSO or the RB1+ treated with talazoparib or DMSO. ³   Conclusions:  PARPi shows promise as an effective treatment for osteosarcoma that does not express RB1. Given that PARPi are currently used clinically to treat certain cancer types, the results here highlight the imminent opportunity for clinical translation of the results.

1. Ritter J, Bielack SS. Osteosarcoma. Ann Oncol. 2010;21 Suppl 7:vii320-vii325. doi:10.1093/annonc/mdq276
2. Wen XZ, Pan QZ, Xu BS, et al. Phase I study of pegylated liposomal doxorubicin and cisplatin in patients with advanced osteosarcoma. Cancer Chemother Pharmacol. 2022;89(2):209-215. doi:1007/s00280-021-04371-6
3. Zoumpoulidou G, Alvarez-Mendoza C, Mancusi C, et al. Therapeutic vulnerability to PARP1,2 inhibition in RB1-mutant osteosarcoma. Nat Commun. 2021;12(1):7064. Published 2021 Dec 3. doi:10.1038/s41467-021-27291-8
4. Arnaldez FI, Helman LJ. New strategies in ewing sarcoma: lost in translation?. Clin Cancer Res. 2014;20(12):3050-3056. doi:10.1158/1078-0432.CCR-13-0633
5. Curtin NJ, Szabo C. Poly(ADP-ribose) polymerase inhibition: past, present and future. Nat Rev Drug Discov. 2020;19(10):711-736. doi:10.1038/s41573-020-0076-6
6. D’Andrea AD. Mechanisms of PARP inhibitor sensitivity and resistance. DNA Repair (Amst). 2018;71:172-176. doi:10.1016/j.dnarep.2018.08.021