Is a PARP1 targeted imaging agent a predictive marker for radiotherapy success and how does it perform in comparison to 18F-FDG imaging?
Final Report Abstract
During my research fellowship at MSK, under the mentoring of Dr. Thomas Reiner and Dr. Wolfgang Weber, I worked on several projects revolving around Molecular Imaging of the DNA repair enzyme PARP1 using optical and nuclear probes. During the first year, my work was focused on developing clinically relevant applications for the fluorescently labeled PARP inhibitor (PARPi) PARPi-FL, which is based on Olaparib, a PARPi that is FDA approved for treatment of ovarian cancer. PARP1 is overexpressed in many tumor types, and non-invasive imaging of PARP1 expression could aid in tumor detection, patient selection for PARP1 targeted therapies and assessment of treatment response. PARPi-FL is a cell penetrating optical reporter that has a high affinity to PARP1 and specifically accumulates in nuclei of PARP1 expressing cells. I could show that we were able to image changes in PARP1 expression after radiation therapy using PARPi-FL in an oral squamous cell carcinoma (OSCC) mouse model, which could be important in evaluating the response of tumor cells to such treatments. In a second project, I showed that PARP1 is overexpressed in human tissue and mouse models of OSCC and that we can use PARPi-FL to detect tumor lesions with high sensitivity and specificity using several clinically relevant imaging systems. Furthermore, I showed that a topical application approach is also feasible, which enables a highly translatable approach for early detection of oral cancer lesions and intraoperative guidance during surgery. I will be involved in conducting the clinical study, especially in acquiring and analyzing the PARPi-FL imaging data. Successful translation of this approach could enable a specific, noninvasive, cost-effective and fast OSCC screening method, which is currently not available. In a third project, we employed Molecular Imaging of PARP1 in a type of childhood brain cancer (diffuse intrinsic pontine glioma, DIPG) that is incurable and has a median survival of less than one year. Here, we used a genetically engineered mouse model of the disease and conducted whole body PET/CT imaging using a 18F labeled version of our PARP1 imaging probe, [18F]PARPi, and confirmed the results on the cellular level using PARPi- FL. We could show overexpression of PARP1 in human biopsy samples. We were able to image DIPG development and progression and show specific uptake into PARP1 expressing tumor cells using [18F]PARPi and PARPi-FL. I was awarded with a Young Investigator Award from the Society of Nuclear Medicine and Molecular Imaging in 2015. When I applied for the fellowship, PARP1 was already an important factor of the initially outlined project. The research question, however, was focused on addressing if a strong activation of PARP1 after radiation therapy could deplete NAD pools and hence make tumors invisible for FDG imaging. As described above, I was able to show the correlation between radiation therapy and increased PARP1 expression. To show the correlation between PARP1 activation, NAD depletion and FDG uptake, has turned out very challenging, and will continue in the future. In parallel, it turned out that PARPi-FL and [18F]PARPi are very potent compounds in outlining tumors, since almost all investigated tumor entities showed high PARP1 expression levels as opposed to normal tissues. The very promising results of the oral cancer imaging study encouraged us to follow this path and accelerate the translational efforts of this approach, which has been very successful so far. The ability to work with human tissues and be involved in a clinical study was a great learning opportunity, which I want to expand on in my future career.
Publications
- (2017) Biomarker-Based PET Imaging of Diffuse Intrinsic Pontine Glioma in Mouse Models. Cancer research 77 (8) 2112–2123
Kossatz, Susanne; Carney, Brandon; Schweitzer, Melanie; Carlucci, Giuseppe; Miloushev, Vesselin Z.; Maachani, Uday B.; Rajappa, Prajwal; Keshari, Kayvan R.; Pisapia, David; Weber, Wolfgang A.; Souweidane, Mark M.; Reiner, Thomas
(See online at https://doi.org/10.1158/0008-5472.CAN-16-2850) - Dual Modality Optical/PET Imaging of PARP1 in Glioblastoma. 2015, Molecular Imaging and Biology 17.6 (2015): 848-855
Carlucci G, Carney B, Brand C, Kossatz S, Irwin C, Carlin SD, Keliher EJ, Weber W, Reiner T
(See online at https://doi.org/10.1007/s11307-015-0858-0) - Radioiodinated PARP1 tracers for glioblastoma imaging. 2015, EJNMMI research, 5(1), 1-14
Salinas B, Irwin CP, Kossatz S, Bolaender A, Chiosis G, Pillarsetty N, Weber WA, Reiner T
(See online at https://doi.org/10.1186/s13550-015-0123-1) - Detection and delineation of oral cancer with a PARP1 targeted optical imaging agent. 2016, Scientific Reports 6: 21371
Kossatz S, Brand C, Gutiontov S, Liu JTC, Lee N, Gonen M, Weber AW
(See online at https://doi.org/10.1038/srep21371) - Non-invasive PET Imaging of PARP1 Expression in Glioblastoma Models. 2015, Molecular Imaging and Biology 18.3 (2016): 386-392
Carney B, Carlucci G, Salinas B, Di Gialleonardo V, Kossatz S, Vansteene A, Longo V, Bolaender A, Keshari KR, Weber WA, Reiner T
(See online at https://doi.org/10.1007/s11307-015-0904-y) - Optical Imaging of PARP1 in response to radiation in Oral Squamous Cell Carcinoma. 2016, PloS one 11.1: e0147752
Kossatz S, Weber AW, Reiner T
(See online at https://doi.org/10.1371/journal.pone.0147752)
