PET imaging of PARP using 18F-olaparib

The integrity of the genetic material, a cell's DNA, is extremely important for an organism's survival. It is therefore no wonder that all cells possess a whole range of enzymes that detect and repair DNA damage. This DNA damage can be the accidental result of UV radiation of e.g. the skin, toxins from tobacco smoke, or the process of tumour formation, but can also be the result of purposely inflicted damage, such as during radiotherapy or chemotherapy of tumours. Because DNA damage repair is such a significant factor in tumour treatment and tumour formation, it presents a promising target for developing novel drugs that would target these mechanisms, and increase tumour cell DNA damage, and as a result, tumour cell kill.
One DNA damage repair inhibitor is further advanced in clinical testing than any other: olaparib (Lynparza) blocks the activity of the enzyme PARP, which is involved in the repair of simple, single-strand, DNA damage. If olaparib stops the PARP enzyme working, especially in tumours with other DNA damage repair defects, the build-up to DNA damage in the tumour cells causes the cells to die, and the tumour to shrink. Olaparib is currently the subject of nearly one hundred clinical trials.
However, it is still difficult to predict which patients will respond to the drug, even though patients are now pre-selected by looking for DNA damage repair defects (such as mutations in a gene called BRCA). Also, it is not always known whether the drug is actively pumped out of the tumour, or will even reach its target. The latter is of the utmost importance in brain tumours, as they are often protected by a layer called the blood-brain-barrier that normally protects the brain from blood-borne toxins, and in pancreatic tumours, where a build-up of stiff scar-like tissue in the tumour prevents drug delivery.
To address these concerns, we have recently generated a radioactive version of olaparib, called 18F-olaparib. Here, we replaced the fluorine atom in the chemical structure of olaparib with a radioactive version, or isotope, fluoride-18 (18F). The radioactive emission from 18F can be measured using a dedicated medical scanner called a PET scanner. It can visualise the three-dimensional distribution of 18F in the body, with only the need of a single intravenous injection of the radiolabelled olaparib. PET imaging using 18F-olaparib will show exactly where the drug travels, whether and how much it is delivered to a tumour, and how fast it is removed. We therefore aim to develop 18F-olaparib as a novel imaging agent for PET imaging.
In addition, the levels of the target for 18F-olaparib, the PARP enzyme, increase after radiotherapy. We therefore also aim to use 18F-olaparib for visualising the biological effects of radiotherapy, to determine if the dose of irradiation will be sufficient to kill the tumour, or if changes need to be made to the therapy plan.

Given the increasing number of cancer drugs exploiting DNA damage repair defects in tumour tissue, such as PARP inhibitors, there is a clear need for patient stratification, therapy prediction and evaluation tools. Previously, our group has developed several methods for visualising DNA damage and genetic instability (a key hallmark of cancer), based on medical imaging techniques used in routine clinical practice, such as positron emission tomography (PET).
Poly ADP ribose polymerase (PARP) is critical in the repair of DNA damage and is expressed to high levels in many tumours. Currently, PARP inhibitors are being studied in >100 clinical trials as a single agent or in combination with both chemo- and radiation therapy. To date, no companion biomarkers exist that predict the pharmacokinetic/dynamic behaviour of the most studied PARP inhibitor, olaparib (Lynparza), in individual patients. Such a tool would nonetheless be exceedingly useful to select patients that may or may not respond to the treatment.
Therefore, to olaparib, we have tagged a radioactive isotope, 18F, while retaining its original chemical structure, to allow visualisation of olaparib biodistribution and PARP expression using a PET scanner. We hypothesize that PET imaging with radiolabelled olaparib can be used to determine the response to chemo- and radiotherapy of pancreatic cancers. Molecular information about the response to treatment will allow much faster decision making regarding treatment, compared to the anatomical changes such as tumour shrinkage that is used routinely. Also, 18F-olaparib may be used as an early diagnosis system, detecting the increased genomic instability that accompanies tumorigenesis. Although here we are using PDAC and glioma cells in vitro and in vivo as a model system, given applications of PARP inhibitors in many other tumour types, the approach may be expanded to other disease sites.

18F-olaparib (a) Demonstrates use of a novel reaction mechanism for accessing radiofluorination of otherwise challenging chemical motifs and its first application in a biological system; (b) for the first time, allows to study the distribution of the much-studied PARP-inhibitor olaparib in a non-invasive fashion, in vivo; (c) Provides a tool for rapid pharmacodynamic study of novel competitive PARP inhibitors; (d) Provides a tool to study the biological effects of radiation therapy and other genotoxic insults in vivo, in a non-invasive fashion.
For patients: Radiolabelled olaparib will allow direct measurement of PARP expression in patients, enabling improved patient stratification, quantification of target engagement of therapeutic inhibitors, and will allow non-invasive monitoring of treatments, including radiation therapy. Radiolabelled olaparib allows the study of pharmacokinetics, pharmacodynamics, prediction of PARP inhibitor therapy, and, most importantly, prediction of olaparib delivery, a non-trivial point in highly fibrotic PDAC tumours, or in the tumour margins of glioblastomas or in brain metastases, where blood-brain-barrier may remain intact.
For drug development (academic and large pharmaceutical companies): this compound would allow non-invasive assessment of target engagement of novel, improved PARP inhibitors.
For the healthcare system: 18F-olaparib will allow triage of patients that will not benefit from olaparib or other PARP inhibitor treatments, and avoid unnecessary, yet expensive, treatment. It will also allow rapid decision-making for non-effective therapies, avoiding unnecessary side-effects and treatment delays.
Although we are using in vitro and in vivo models of mostly PDAC and brain tumours in this project, PARP inhibition using olaparib is approved and being investigated for non-small cell lung, colorectal, head-and-neck small cell, ovarian and breast cancer, and would be equally valuable in those disease settings.