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Molecular imaging and targeted therapy of the aggressive phenotype: development of uPAR theranostics for cancer patients

Periodic Reporting for period 3 - uPET (Molecular imaging and targeted therapy of the aggressive phenotype: development of uPAR theranostics for cancer patients)

Reporting period: 2018-10-01 to 2020-03-31

For practice of personalized medicine in cancer, non-invasive tools for diagnosing at the molecular level are needed. Molecular imaging methods are capable of this while at the same time circumventing sampling error as the whole tumor burden is evaluated. We recently developed and performed the first-ever clinical PET scan of uPAR, a proteolytic system known to be strongly associated with metastatic potential in most cancer forms. We believe this new concept of uPAR-PET is a major breakthrough and has the potential to become one of the most used PET tracers as it fulfills unmet needs in prostate and breast cancer. Based on this, together with additional proof-of-concept data we obtained on targeted uPAR for optical imaging and radionuclide therapy, we now plan to develop and take into patients these new technologies for improved outcome.

The aim of the project is to develop, evaluate and translate into patients, new and highly innovative molecular imaging methods with PET, 13C-hyperpolarized magnetic resonance spectroscopic imaging (MRSI) and optical imaging demonstrating the aggressiveness and metastatic potential of cancers. Also, β or α emitting therapy will be developed and used together with imaging as theranostic pairs. The overall objective is to develop methods that can be used for better cancer imaging and tailoring of therapy.

Specific aims are to develop and translate into human use:
1: A PET uPAR imaging ligand platform for visualization of the aggressive phenotype and risk-stratification to be used in tailoring therapy, e.g. in prostate cancer to decide whether prostatectomy is necessary.
2: uPAR-PET combined with simultaneous 13C-hyperpolarized pyruvate MRSI (Warburg effect). This will increase prognostic power, refine tumor phenotyping and thereby allow for better tailoring of therapy an early prediction of treatment response.
3: An uPAR optical imaging technology for guiding removal of cancer tissue during surgery. This will help delineate cancer tissue for removal while leaving healthy tissue behind. We expect better outcome with removal of less tissue.
4: Selective radionuclide therapies targeting uPAR positive, invasive cancer cells using β or α emitters. Dose planning will be performed using uPAR-PET imaging. This image therapy pairing is also known as theranostics.

We expect cancer patients to benefit from our new methods within the 5 year time-frame of the project.
Major achievements

WP1: Development of uPAR-PET imaging for imaging of the aggressive cancer phenotype: We have successfully concluded a clinical Phase I study with 68Ga-NOTA-AE105 in 10 cancer patients (Skovgaard 2017, PMID 27609788). Preclinically, we have worked further on increasing the tumor uptake (SUV) and the contrast (tumor-to-background ratio) by introducing a linker/spacer between the binding peptide and the radionuclide. It was possible to increase the uptake by a factor 2-3. This work has been undertaken in collaboration with Stanford University and was published recently (Loft 2017, PMID 28316028).

WP2: Development of combined uPAR-PET and hyperpolarised MRSI (“hyperPET/MR”): We have continued the work and published further on the topic (Hansen 2016, PMID 27102632).

WP3: Development of optical imaging of uPAR delineation of cancer during surgery: We have performed in-depth studies of ICG-glu-glu-AE105 in cancer models and have provided solid proof-of-concept data.
The data were published in a landmark paper for uPAR optical imaging (Christensen 2017, PMID 28039488).

WP4: Development of uPAR targeting radionuclide therapy for invasive cancer phenotype. Planning of clinical translation is ongoing but no studies have been performed yet.
Novel concepts of using uPAR targeting for PET imaging, radionuclide therapy and optical imaging. We expect the technologies to be translated into human testing during the project.