Radiosensitizing Pancreatic Cancer with PARP Inhibitor and Gemcitabine: An In Vivo and a Whole-Transcriptome Analysis after Proton or Photon Irradiation

Abstract

Over the past few years, studies have focused on the development of targeted radiosensitizers such as poly(ADP-ribose) polymerase inhibitors. We performed an in vivo study and a whole-transcriptome analysis to determine whether PARP inhibition enhanced gemcitabine-based chemoradiosensitization of pancreatic cancer xenografts, combined with either proton or photon irradiation. NMRI mice bearing MIA PaCa-2 xenografts were treated with olaparib and/or gemcitabine and irradiated with 10 Gy photon or proton. First, a significant growth inhibition was obtained after 10 Gy proton irradiation compared to 10 Gy photon irradiation (p = 0.046). Moreover, the combination of olaparib, gemcitabine and proton therapy significantly sensitized tumor xenografts, compared to gemcitabine (p = 0.05), olaparib (p = 0.034) or proton therapy (p < 0.0001) alone or to the association of olaparib, gemcitabine and radiotherapy (p = 0.024). Simultaneously, whole RNA sequencing profiling showed differentially expressed genes implicated in categories such as DNA repair, type I interferon signaling and cell cycle. Moreover, a large amount of lncRNA was dysregulated after proton therapy, gemcitabine and olaparib. This is the first study showing that addition of olaparib to gemcitabine-based chemoradiotherapy improved significantly local control in vivo, especially after proton therapy. RNA sequencing profiling analysis presented dynamic alteration of transcriptome after chemoradiation and identified a classifier of gemcitabine response.

Charged Particle Irradiation for Pancreatic Cancer: A Systematic Review of In Vitro Studies

“…All the included studies demonstrated the enhanced therapeutic effect of combined therapies. Similarly, Waissi and colleagues ( 51 ) confirmed that a combination of GEM, Ola, and proton irradiation can significantly improve local control of pancreatic cancer in vivo . A phase I trial ( 62 ) of PARPi in combination with GEM and photon radiotherapy in LAPC has shown that this regimen is safe and tolerable, with a median OS of 15 months.…”

“…Our results showed that, compared with photon, carbon ion irradiation induced greater G2/M arrest and longer-lasting expression of γH2AX as well as an increase in γH2AX clusters, indicating a high level of DNA damage. These clustered DNA lesions are difficult to repair and may induce different signaling pathways compared with photon irradiation, such as DNA repair, type I interferon signaling, and cell cycle pathways ( 51 , 52 ). Unrepaired or misrepaired damage can inhibit cell proliferation via checkpoints; cells may therefore stay in the G2/M phase, undergoing genomic instability or cell death by several mechanisms, including apoptosis, mitotic catastrophe, or senescence.…”

Models for Translational Proton Radiobiology—From Bench to Bedside and Back

“…While studies that evaluate combination therapies with proton irradiation are still scarce, the cell-derived xenograft model is valuable for this research question. For example, Waissi et al [234] found that application of gemcitabine-and olaparib-based chemoradiotherapy in such models displays a higher effectiveness when using proton therapy. Another preclinical study deduced that the combination of proton beam therapy with targeted radionuclide therapy can produce a type-dependent additive or synergetic effect [235].…”

Pancreatic cancer: genetics, disease progression, therapeutic resistance and treatment strategies

“…It is known to induce tumor cells S-phase arrest and thus sensitize cells to DNA damage [108] . PARPi could sensitize cells to exogenous DNA damage inducer treatment, such as irradiation in pancreatic cancer cell's [110] or gemcitabine in non-small-cell lung cancer [111] . Combination treatment of PARPi-olaparib with gemcitabine and proton therapy significantly enhanced tumor response and progression-free survival in pancreatic cancer mice model [112] .…”