PARP again

I have already written about PARP inhibitors here so this will be a follow up for some. A paper in the November 25th Blood tells of the pre-clinical basis of these new agents which are now in a clinical trial. The paper is from Tanya Stankovic from Birmingham and is a collaboration between several labs including my old lab.
The PARP inhibitor olaparib induces significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo
Victoria J. Weston, Ceri E. Oldreive, Anna Skowronska, David G. Oscier, Guy Pratt, Martin J. S. Dyer, Graeme Smith, Judy E. Powell, Zbigniew Rudzki, Pamela Kearns, Paul A. H. Moss, A. Malcolm R. Taylor, and Tatjana Stankovic. Blood. 2010; 116(22):4578-87.

This is of interest to those who are 11q23 deleted. The Ataxia Telangiectasia Mutated (ATM) gene is frequently inactivated by either deletion or mutation in lymphoid malignancies such as CLL, T-PLL, and mantle cell lymphoma (MCL) and is associated with defective apoptosis in response to alkylating agents and purine analogues.

ATM mutant cells exhibit impaired DNA double strand break repair. Poly (ADP-ribose) polymerase (PARP) inhibition that imposes the requirement for DNA double strand break repair should selectively sensitize ATM-deficient tumor cells to killing. They have investigated sensitivity to the PARP inhibitor, olaparib, in the test tube of 5 ATM mutant lymphoblastoid cell lines (LCL), an ATM mutant MCL cell line, an ATM knockdown PGA CLL cell line, and 9 ATM-deficient primary CLLs induced to cycle and observed differential killing compared with ATM wildtype counterparts.

Pharmacologic inhibition of ATM and ATM knockdown confirmed the effect was ATM dependent and mediated through mitotic catastrophe independently of apoptosis.

A non-obese diabetic/severe combined immunodeficient (NOD/SCID) murine xenograft model of an ATM mutant MCL cell line demonstrated significantly reduced tumor load and an increased survival of animals after olaparib treatment in vivo.

Addition of olaparib sensitized ATM null tumor cells to DNA-damaging agents.

They suggested that olaparib would be an appropriate agent for treating refractory ATM mutant lymphoid tumors.

Olaparib, here, targets only proliferating cells with ATM dysfunction, consistent with a cytotoxic mechanism involving the conversion of single-stranded DNA breaks into double stranded breaks during DNA replication that cannot be repaired efficiently in cells with a homologous repair (HR) defect. PARP inhibition did not lead to the same degree of cytotoxicity of ATM deficient tumor cells as BRCA mutant cells because the major role of ATM is in sensing the damage that is subsequently repaired by HR repair in which Rad51, BRCA2 and BRCA1 proteins play a major role. The response of ATM mutant lymphoid tumor cells to PARP inhibition is, therefore, comparable to, although not the same as, the scenario previously described for BRCA1/2 mutant breast carcinoma cells which has resulted in Phase I and ongoing Phase II clinical trials with orally administrated olaparib, providing evidence that this agent is well tolerated and exhibits clinical potency. Thus, the clear differential sensitivity of ATM mutant lymphoid cells to submicromolar concentrations of olaparib and the necessity to improve treatment for chemoresistant ATM mutant lymphoid tumors makes olaparib a compelling candidate for trials in these malignancies. Indeed, progressive tumors with especially active proliferation centers may provide the ideal
cellular scenario for targeting by olaparib with the aim of at least delaying disease progression.

It is possible that loss of a single ATM allele by 11q deletion does not affect ATM function and it is therefore conceivable that only 11q-deleted tumors that exhibit mutation in the remaining ATM allele and consequently lose ATM function will
respond differentially to treatment with olaparib. While olaparib monotherapy is an attractive proposition for treating these tumors, there is also the possibility of combining olaparib with chemotherapy agents.

Clinical trials of olaparib in CLL, T-PLL and MCL have begun in the UK.