Purpose and aims

This research project aims to identify prostate cancer associated key targets and to evaluate them as potential novel targets for both diagnosis and therapy of advanced prostate cancer (PCa). My main goal is to sharpen diagnostics and to develop rationally designed novel targeted therapeutic strategies for the detection and treatment of PCa. Using frontline nuclear medicine approaches and optical and molecular imaging I plan to use theranostics, a combination of therapeutics and diagnostics, to establish tools for specific molecular targeting. Moving from a conventional medicine platform to a personalized and precision targeted methodology through theranostics, my ultimate goal is to develop a curative and well tolerated therapeutic approach aiming to improve the clinical outcome for patients with PCa. To achieve these purposes, I will work in a strategic stepwise procedure with the aims to:

• Assess the in vivo and ex vivo tumor targeting ability of newly generated antibodies designed to specifically target cancer cells in solid tumor and advanced prostate cancer-based mouse models.
• Evaluate the therapeutic efficacy of the most promising antibodies as an antibody-drug conjugate (ADC) or antibody-based radiopharmaceutical, alone or in combination with other pharmacological approaches, like immunotherapy and small molecules therapy (e.g. PARP inhibitors, PARPi).
• Verify the antibody targeting efficiency in human cancer and benign tissues, using as a platform our systematic biobanking of human tissues from representative population-based cohorts with long-term follow-up and full clinical dataset. 

State-of-the-art

Prostate cancer (PCa) is the second most frequently diagnosed solid-organ malignancy (after lung cancer) in men1. Scientists continue to rapidly elucidate the therapeutic landscape of PCa, and as a result, several therapeutic agents targeting specific pathways of the disease have been approved. For metastatic castration-resistant PCa (mCRPC), many treatment options are available, including next generation androgen receptor targeting agents (ARTAs) like abiraterone and enzalutamide, and taxane-based chemotherapies like docetaxel and cabazitaxel. However, de novo resistance to the ARTAs is often observed and cross-resistance is also common for these drugs2. Recently, mCRPC patients harboring DNA repair gene mutations have responded well to new PARPi niraparib and olaparib in clinical trials3. Additionally, great advances have been made in radioactive drug-based imaging and treatment of PCa; however, its optimal use in the clinic is still unclear. PSMA targeted theranostics using 68-Gallium/18-Flouride and lutetium-177 labeled PSMA ligands are currently under investigation, but not yet approved for use4. Radioligand therapy (RLT) with 177Lu-PSMA, is a novel, effective and well-tolerated RLT option for mCRPC patients, however, as a single treatment approach it is not curative, and relapses occur after delays in disease progression5. Though there are a number of options clinically available for PCa imaging, there are no clinically available options for therapy with radiolabeled antibodies of PCa at any stage. Thus, there is an urgent need to investigate new therapeutic targets to develop curative, well-tolerated therapies for patients with advanced prostate cancer. 

Theranostics is an emerging field of nuclear medicine that combines diagnostic and therapeutic applications to generate a single agent to facilitate diagnosis, drug delivery and treatment response monitoring. Antibodies are often used in nuclear medicine as they provide an ideal platform for targeted imaging and therapy (Radioimmunotherapy, RIT) of cancer due to their high specificity to detect any tumor-associated or tumor-specific antigen. Preclinical testing for targeted imaging and therapy using antibodies has proved successful in a variety of cancers, yet only a limited number have reached the clinic. In PCa, some promising results have been obtained in clinical trials using RIT alone or in combination with other approaches (immunotherapy, chemotherapy) indicating a potential therapeutic value of RIT in advanced PCa6. 

References

1. Bray et al. CA Cancer J Clin 2018,
2. Chi et al. Ann Oncol 2015,
3. Mateo et al. NEJM 2015,
4. Weinesen et al. J Nucl Med 2015,
5. Fendler et al. J Nucl Med 2017,
6. Evans-Axelsson et al. Semin Nucl Med 2016.