Quantifying Drug-Induced Bone Marrow Toxicity Using a Novel Haematopoiesis Systems Pharmacology Model.

Haematological toxicity associated with cancer therapeutics is monitored by changes in blood cell count, and their primary effect is on proliferative progenitors in the bone marrow. Using observations in rat bone marrow and blood, we characterize a mathematical model that comprises cell proliferation and differentiation of the full haematopoietic phylogeny, with interacting feedback loops between lineages in homeostasis as well as following carboplatin exposure. We accurately predicted the temporal dynamics of several mature cell types related to carboplatin-induced bone marrow toxicity and identified novel insights into haematopoiesis. Our model confirms a significant degree of plasticity within bone marrow cells, with the number and type of both early progenitors and circulating cells affecting cell balance, via feedback mechanisms, through fate decisions of the multipotent progenitors. We also demonstrated cross-species translation of our predictions to patients, applying the same core model structure and considering differences in drug-dependent and physiology-dependent parameters

The PARP inhibitor AZD2461 provides insights into the role of PARP3 inhibition for both synthetic lethality and tolerability with chemotherapy in preclinical models

The PARP inhibitor AZD2461 was developed as a next-generation agent following olaparib, the first PARP inhibitor approved for cancer therapy. In BRCA1-deficient mouse models, olaparib resistance predominantly involves overexpression of P-glycoprotein,so AZD2461 was developed as a poor substrate for drug transporters. Here we demonstrate the efficacy of this compound against olaparib-resistant tumors that overexpress P-glycoprotein. In addition, AZD2461 was better tolerated in combination with chemotherapy than olaparib in mice, which suggests that AZD2461 could have significant advantages over olaparib in the clinic. However, this superior toxicity profile did not extend to rats. Investigations of this difference revealed a differential PARP3 inhibitory activity for each compound and a higher level of PARP3 expression in bone marrow cells from mice as compared with rats and humans. Our findings have implications for the use of mouse models to assess bone marrow toxicity for DNA-damaging agents and inhibitors of the DNA damage response. Finally, structural modeling of the PARP3-active site with different PARP inhibitors also highlights the potential to develop compounds with different PARP family member specificity profiles for optimal antitumor activity and tolerability

Radiosensitization with an inhibitor of poly(ADP-ribose) glycohydrolase: A comparison with the PARP1/2/3 inhibitor olaparib

Upon DNA binding the poly(ADP-ribose) polymerase family of enzymes (PARPs) add multiple ADP-ribose subunits to themselves and other acceptor proteins. Inhibitors of PARPs have become an exciting and real prospect for monotherapy and as sensitizers to ionising radiation (IR). The action of PARPs are reversed by poly(ADP-ribose) glycohydrolase (PARG). Until recently studies of PARG have been limited by the lack of an inhibitor. Here, a first in class, specific, and cell permeable PARG inhibitor, PDD00017273, is shown to radiosensitize. Further, PDD00017273 is compared with the PARP1/2/3 inhibitor olaparib. Both olaparib and PDD00017273 altered the repair of IR-induced DNA damage, resulting in delayed resolution of RAD51 foci compared with control cells. However, only PARG inhibition induced a rapid increase in IR-induced activation of PRKDC (DNA-PK) and perturbed mitotic progression. This suggests that PARG has additional functions in the cell compared with inhibition of PARP1/2/3, likely via reversal of tankyrase activity and/or that inhibiting the removal of poly(ADP-ribose) (PAR) has a different consequence to inhibiting PAR addition. Overall, our data are consistent with previous genetic findings, reveal new insights into the function of PAR metabolism following IR and demonstrate for the first time the therapeutic potential of PARG inhibitors as radiosensitizing agents