PARP-Targeted Auger Therapy in p53 Mutant Colon Cancer Xenograft Mouse Models

Abstract

Despite Auger electrons being highly appealing due to their short-range and high linear energy transfer to surrounding tissues, the progress in the field has been limited due to the challenge in delivering a therapeutic dose within the close proximity of cancer cell’s DNA. Here, we demonstrate that the PARP inhibitor 123I-MAPi is a viable agent for the systemic administration and treatment of p53 mutant cancers. Significantly, minimal off-site toxicity was observed in mice administered with up to 74 MBq of 127I-PARPi. Taken together, these results lay the foundation for future clinical evaluation and broader preclinical investigations. By harnessing the scaffold of the PARP inhibitor Olaparib, we were able to deliver therapeutic levels of Auger radiation to the site of human colorectal cancer xenograft tumors after systemic administration. In-depth toxicity studies analyzed blood chemistry levels and markers associated with specific organ toxicity. Finally, p53+/+ and p53–/– human colorectal cancer cell lines were evaluated for the ability of 123I-MAPi to induce tumor growth delay. Toxicity studies demonstrate that both 123I-MAPi and its stable isotopologue, 127I-PARPi, have no significant off-site toxicity when administered systemically. Analysis following 123I-MAPi treatment confirmed its ability to induce DNA damage at the site of xenograft tumors when administered systemically. Finally, we demonstrate that 123I-MAPi generates a therapeutic response in p53–/–, but not p53+/+, subcutaneous xenograft tumors in mouse models. Taken together, these results represent the first example of a PARP Auger theranostic agent capable of delivering a therapeutic dose to xenograft human colorectal cancer tumors upon systemic administration without causing significant toxicity to surrounding mouse organs. Moreover, it suggests that a PARP Auger theranostic can act as a targeted therapeutic for cancers with mutated p53 pathways. This landmark goal paves the way for clinical evaluation of 123I-MAPi for pan cancer therapeutics.

PARP targeted Auger emitter therapy with [125I]PARPi-01 for triple-negative breast cancer

“…The in vivo study with [ 123 I]MAPi showed promising therapeutic efficacy and survival advantage upon intra-tumoural delivery in glioblastoma models. A recent study with systemic [ 123 I]MAPi administration presented its high therapeutic efficacy in preclinical model of colorectal cancer with p53 deficiency [ 14 ].

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DNA Repair Enzyme Poly(ADP-Ribose) Polymerase 1/2 (PARP1/2)-Targeted Nuclear Imaging and Radiotherapy

“…Although biodistribution data showed that large fractions of [ 123 I]MAPi pass through the hepatobiliary system and uptake in several organs was higher than in tumors, only minimal systemic toxicity was observed in a toxicity study after GMP guidelines. It is hypothesized that during excretion, metabolism confines the agent to the perinuclear region of the cell and therefore puts it outside the range of an Auger-emitter to achieve significant damage upon cellular DNA [99]. Recently, another therapeutic study of an Auger-emitting PARPi, [ 125 I]PARPi-01 (isotopologue of [ 131 I]I2-PARPi from [57]), was published (Morgenroth Lab) [102].…”

“…While intratumoral injection might be considered for glioblastoma treatment clinically, for other tumor entities, it is not an option. Therefore, the therapeutic potential of [ 123 I]MAPi after systemic injection was evaluated in a colorectal cancer model comparing p53 +/+ to p53 −/− models [ 99 ]. In tumors, PARP1 expression is elevated in the nucleus, increasing the likelihood for the Auger-emitting isotope to induce DNA damage.…”

“…( B ) Therapeutic efficacy of 5 × 74 MBq [ 123 I]MAPi i.v. in subcutaneous p53-deficient HCT116 colorectal cancers compared to [ 127 I]MAPi and vehicle [ 99 ]. Stars represent days of treatment.…”

“…Copyright 2018, SNMMI. ( B ) Reprinted with permission [ 99 ]. Copyright 2021, American Chemical Society.…”