Martin Day

Introduction. Prostate cancer makes up over 1 in 5 new diagnoses in men.¹ Androgen deprivation therapy is the centerpiece of treatment for prostate cancer; however, if the cancer does not respond to treatment, it may develop into an inoperable form known as metastatic castration-resistant prostate cancer (mCRPC).² PARP serves as a catalyst to alter and repair single-strand breaks (SSBs) by recruiting DNA repair factors. Poly-(ADP-ribose) polymerase (PARP) inhibitors target cells deficient in homologous recombination DNA repair mechanisms resulting from gene mutations such as BRCA, a tumor suppressor gene centered around HR.³ Olaparib, niraparib, talazoparib, and rucaparib successfully underwent clinical trials in HR DNA repair-deficient mCRPC, and were approved for monotherapy in May 2020 for patients with HRR deficiency.⁵ Combination therapies of PARP inhibitors with other forms of treatment are currently being investigated, with radiotherapy showing promising potential as an adjuvant alongside PARPi. Methods. Complementary DNA microarray, quantitative reverse transcription PCR and Western blotting of homologous recombination genes in response to enzalatumide, olaparib, and a combination of those two. Immunohistochemical analysis via immunofluorescence staining, Western blotting, and qPCR-based HR assay assessed the formation of γH2AX and RAD51, indicators of DNA damage, repair, and treatment sensitivity.² A functional assay detecting repair switch to alternative PARP-1 dependent end joining pathway revealed PCa tumors are susceptible to PARPi-mediated radiosenstitization via ex-vivo models.⁴ Olaparib was synthesized into nanoparticle form. Three PTEN-deficient cell lines were measured in response to combination therapy of radiation and NanoOlaparib.⁶ Mice were subcutaneously implanted with FKO1 cells, which was treated with radiation.⁶  Results.  Olaparib decreases HR expression in LNCaP cell lines, while combination therapy decreased expression of both LNCaP and VCaP cell lines.³ Enzalutamide and PARPi olaparib synergistically induce DNA damage–related cell death, inhibit PCa cell clonal growth, and suppress xenograft tumor growth.³ Approximately a third of PCa punch biopsies displayed a repair switch to PARP1-EJ, highlighted by an increased number of residual γH2AX/53BP1 foci solely after PARPi-radiotherapy combination treatment.⁴ NanoOlaparib enhances γ-H2AX expression in a radiation-dose dependent manner, suggesting less toxic effects while breaking dsDNA than in cells receiving PARPi without irradiation. Conclusions.  Combination of PARPi alongside radiotherapy demonstrates promising results in tumors that display a PARP-EJ switch. Nanoformulation of PARPi in combination with radiation is more efficacious in delivery its drug to its appropriate target. Further investigation of potential resistance to combined therapy of PARPi-radiotherapy should be addressed, alongside minimizing toxicity, and increasing efficacy.

1. Siegel, R.L., Miller, K.D. and Jemal, A. (2020), Cancer statistics, 2020. CA A Cancer J Clin, 70: 7-30. https://doi.org/10.3322/caac.21590.
2. Gui B, Gui F, Takai T, et al. Selective targeting of PARP-2 inhibits androgen receptor signaling and prostate cancer growth through disruption of FOXA1 function. Proc Natl Acad Sci U S A. 2019;116(29):14573-14582. doi:10.1073/pnas.1908547116.
3. Li L, Karanika S, Yang G, et al. Androgen receptor inhibitor-induced “BRCAness” and PARP inhibition are synthetically lethal for castration-resistant prostate cancer. Sci Signal. 2017;10(480):eaam7479. Published 2017 May 23. doi:10.1126/scisignal.aam7479.
4. Köcher S, Beyer B, Lange T, et al. A functional ex vivo assay to detect PARP1-EJ repair and radiosensitization by PARP-inhibitor in prostate cancer. Int J Cancer. 2019;144(7):1685-1696. doi:10.1002/ijc.32018.
5. de Bono J, Mateo J, Fizazi K, et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020;382(22):2091-2102. doi:10.1056/NEJMoa1911440.
6. van de Ven AL, Tangutoori S, Baldwin P, et al. Nanoformulation of Olaparib Amplifies PARP Inhibition and Sensitizes PTEN/TP53-Deficient Prostate Cancer to Radiation. Mol Cancer Ther. 2017;16(7):1279-1289. doi:10.1158/1535-7163.MCT-16-0740