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Study of the radiobiological basis of therapeutic and toxic responses of prostate cancer radiation therapy

Context

 

Current cancer treatment options may include surgery, medicines and/or radiotherapy. New cancer treatment modalities focus on immunotherapy, hadron therapy or targeted radionuclide therapy and hold promise to be more effective and to reduce the detrimental effects on the healthy tissues. Radiopharmaceuticals for targeted radionuclide therapy consist of a cancer-seeking molecule, such as antibodies or antibody fragments, peptides or low molecular weight ligands, labeled with an appropriate radionuclide to deliver therapeutic doses of ionizing radiation directly to the cancer sites, both in the primary tumor as well as in metastatic lesions. When injected into the patient’s bloodstream, the radiopharmaceuticals diffuse in the whole body, concentrate in the disease, and progressively destroy the disease.

 

Prostate-specific membrane antigen (PSMA) is a promising target in prostate cancer. The potential of PSMA-targeted radionuclide therapy for advanced, castrate-resistant prostate cancer is being demonstrated by a growing number of reports detailing institutional experience with various agents and prospective clinical trials are in progress to further establish the safety and efficacy of this approach. Although extremely promising, PSMA-ligand therapy remains a non-curative treatment and, therefore, the prolongation in survival and amelioration of disease-related symptoms must be balanced against the direct toxicities of the treatment and their impact on quality of life. Of these, xerostomia, due to radiation injury of the salivary glands, is amongst the most common and debilitating, particularly for Ac225-PSMA. The nature of this dysfunction is incompletely understood and strategies for its prevention and treatment are still under evaluation.

 

In addition, radiation-resistance is an issue in current prostate cancer treatments. Following a prostate cancer diagnosis, approximately 50 percent of men will receive external beam radiation therapy. However, recurrence rates in these patients remain high (20-30%) and are associated with a limited chance of cure [1,2]. Therefore, the development of potent agents that increase the sensitivity of malignant prostate cells to radiation is urgently required. Also treatment modalities based on targeted radionuclide therapy may benefit from radiosensitizers for prostate cancer cells.

 

Characterization of the biological basis for therapeutic and cytotoxic responses is essential to guide the evaluation of current as well as novel therapeutic options for prostate tumor, including prevention strategies for salivary gland toxicity and radiosensitizing strategies. It may also provide a means to select patients most likely to benefit from these strategies.

 

Therefore, this PhD project aims at a better understanding of the molecular mechanisms underlying (i) salivary gland toxicity after PSMA-targeted radionuclide therapy and (ii) prostate cancer cell radioresistance.

 

Importance of the research for SCK•CEN

 

This PhD project is fully embedded in the SCK•CEN mission to conduct research and provide services in the field of peaceful applications of nuclear technology and ionising radiation, and to assure safety of man and the environment in this context.

 

On top, “the use of radioactive substances for primarily therapeutic but also diagnostic purposes” and “the development in medicine” are listed as one of the general strategic lines for SCK•CEN (“A strategy for SCK•CEN”, Dec 2016; SCK•CEN/20508627), and “Nuclear medicine and development of a Campus for Nuclear Medicine Research” is stated as “highest priority”. Furthermore, it is mentioned that “SCK•CEN intends to actively profile itself as a Contract Research Organisation (CRO) in the development of innovative radionuclides, testing of new vector molecules and conducting pre-clinical studies.” In accordance, “Knowledge of (bio)medical and pharmaceutical aspects of the use of radionuclides” and “Nuclear technology in medicine, including radiobiology, biochemistry and dosimetry” are indicated as two of the main content-related competencies that will gain importance in the implementation of the Strategic Plan. The underlying PhD project proposal sprouted from a discussion with the Belgian company ANMI – Advanced Nuclear Medicine Ingredients, and can be considered as first of a kind CRO service.

 

Finally, the SCK•CEN strategy emphasizes to maintain “Radiobiological research” investigating the effect of radiation on man. The underlying PhD project proposal is embedded in the research priorities of SCK•CEN as expressed in the EHS program lines PL1 “Biological effects of ionising radiation” and PL8 “Medical applications of ionizing radiation”.

 

 

State of the art

 

The potential use of targeted radionuclide therapy has been recognized for many decades. The first application in oncology was in the 1940s when patients with thyroid disease were treated with I131. More recently, in 2002 and 2003, the radiolabeled anitobodies Y90-ibritumomab tiuxetan (Zevalin; Spectrum Pharmaceuticals, Inc.) and I131-tositumomab (Bexxar; GlaxoSmithKline, Inc.) were approved for treatment of patients with non-Hodgkin lymphoma. However, they never came close to their full marketing potential, and Bexxar even has been totally phased-out. Nevertheless, interest from the medical community for targeted radionuclide therapy has been growing. In 2013, Ra223 dichloride (Xofigo, Bayer HealthCare Pharmaceuticals, Inc.) was approved for palliative pain relief and anti-tumour effect on bone metastases in patients with advanced prostate cancer. In January 2018, Lu177-DOTATATE (Lutathera, Advanced Accelerator Applications S.A.) was approved for the treatment of gastroenteropancreatic neuroendocrine pancreatic tumors. In addition, several radiopharmaceuticals for targeted radionuclide therapy are currently being studied in clinical trials and many more are investigated in discovery projects. Also alpha-emitters are in this context increasingly studied.

 

Gaps identified for (targeted) radiation therapy for prostate cancer:

  • Prostate cancer patients treated with targeted radiation therapy, particularly with Ac225-PSMA therapy,  suffer from xerostomia, due to radiation injury of the salivary gland, which is vastly impacting their quality of life post treatment. The nature of this dysfunction is incompletely understood and strategies for its prevention and treatment are still under evaluation.
  • In addition, radiation-resistance is an issue in current prostate cancer treatments with external beam radiation therapy. Following a prostate cancer diagnosis, approximately 50 percent of men will receive radiation therapy. However, recurrence rates in these patients remain high (20-30%) and are associated with a limited chance of cure. Both treatment modalities based on external beam radiotherapy as well as targeted radionuclide therapy may benefit from radiosensitizers for prostate cancer cells.

 

Treatment with Lu177-PSMA revealed only mild to moderate reversible xerostomia in prostate cancer patients [3,4]. In contrast, although leading to excellent therapeutic effects, even with complete remissions in a considerable number of cases, Ac225-PSMA treatment also lead to destruction of the salivary glands [5]. As such, severe xerostomia became the dose-limiting toxicity. It is known that also salivary glands do express PSMA epitopes in normal, non-malignant, conditions [6]. However, the exact molecular principles of tracer accumulation, in particular the ratio of nonspecific over specific uptake in salivary glands, are still insufficiently understood. Targeted radionuclide therapy, unlike external beam radiotherapy, offers potential routes to prevent radiation exposure to salivary gland tissue by avoiding or reducing radionuclide uptake [7]. Preclinical animal data on potential radioprotective substances injected into the salivary glands, such as botulinum toxin A, appear promising [8], and the first proof-of-concept was published rencently showing a 64 % decrease in Ga68-PSMA uptake in a patient [9]. Other radioprotectors have also been tested, such as histamine, vitamin E, statins, and amifostine, exploiting mechanisms of radiation resistance [7]. Local appplication of cold compounds or inhibitors of PSMA are also being investigated [7]. However, none of the above mentioned strategies was shown to be succesfull. Finally, strategies for regeneration of salivary tissues are exploited, including gene therapy and stem cell therapy [10]. With respect to the potential survival benefit of PSMA-directed radionuclide therapies, severe reduction in quality of life will gain more significance in the future, and more work is required in order to balance the risk of salivary gland toxicity against therapeutic effectiveness.

 

One main reason for failures prostate cancer therapy following external beam radiation therapy is because of radioresistance of a subpopulation of clones within tumor [11]. Therefore, radioresistance is a major challenge for current prostate cancer radiation therapy. Radioresistant prostate cancer cells often show aberrant growth signaling pathways, such as the PI3K-Akt/mTOR or Jak-STAT pathways, resulting in easier DNA double strand break repair together with apoptosis evasion [12]. In addition, prostate cancer stem cells can provide a cellular reservoir to promote tumor recurrence after therapy [13,14]. Specific gene mutation-dependent over-activation of stem cell specific pathways, such as Wnt/beta catenin-, Hedgehog- and Notch pathways, play an important role in facilitating both self-renewal and radioresistance of prostate cancer stem cells. Preclinical attempts were made to interfere with these pathways with varying succes [11,12]. Thus, modalities to further improve the therapeutic efficacy of radiation therapy are warranted to increase sensitivity of radiation treatment in optimizing radiation effect and minimizing radioresistance influence.

 

 

Research hypothesis:

 

We hypothesize that:

(i) Interaction of PSMA-targeting compounds to salivary gland cells and induction of cell death in salivary gland cells by PSMA-targeting compounds are underlying causes of the observed salivary gland dysfunction after targeted radionuclide prostate cancer therapy using PSMA-targeting compounds. More specifically, we hypothesize that:

  • differrent types of PSMA-targeting compounds show different degrees of binding to salivary gland and prostate tumor cells, allowing to select PSMA-targeting compounds with optimal binding profiles (i.e. low salivary gland and high prostate tumor binding).
  • different types of  PSMA-targeting compounds show different degrees and mechanisms of salivary gland cell killing, allowing to select PSMA-targeting compounds with minimal toxicity for salivary gland cells
  • based on the identified salivary gland cell killing mechanisms of the PSMA-targeting compounds we can select molecules counteracting or mitigating salivary gland (stem) cell toxicity
     

(ii) Prostate cancer cells exploit cell survival mechanisms that underly the observed prostate cancer cell radioresistance. More specifically, we hypothesize that:

  • prostate tumors cells or tissues develop mechanisms to circumvent the cell inhibiting effects from ionizing radiation
  • based on the identified radioresistance molecular mechanisms we can select (a coctail of) molecules radiosensitizing prostate cancer cells
  • radiosensitizing agents for prostate cancer cells can provide a means to lower the required dose for targeted radionuclide therapy as such reducing the dose burden for healthy tissus, such as the salivary glands

 

 

Feasibility/risk analysis/risk mitigation

 

  • Difficulties in supply of Ac225
    Mitigation: Contact several centres within Europe and outside
     
  • Delay of the building of the SCK-CEN Hot Animal Facility
    Mitigation: Contact collaboration partners with established hot animal facilities
     
  • Ethical approval for the animal studies not obtained on time
    Mitigation: Start early
     
  • Difficulties with animal breeding and establishing xenografts
    Mitigation: Start early to optimize processes
     
  • Difficulties in setting up salivary gland cell lines
    Mitigation: Deep literature study and contacts with experienced laboraties

 

 

References

 

[1] McDermott et al. Sci Rep. 2016 6:34796;

[2] Rukstalis et al. Rev Urol. 2002 4(Suppl 2): S12–S17

[3] Rahbar et al. J Nucl Med. 2017 58(1):85-90;

[4] Langbein et al. Eur J Nucl Med Mol Imaging 2017 44(Suppl 2):238

[5] Kratochwil et al. J Nucl Med. 2016 57(12):1941-1944

[6] Klein Nulent et al. Oral Surg Oral Med Oral Pathol Oral Radiol. 2018 125(5):478-486

[7] Langbein et al. J Nucl Med. 2018 59(8):1172-1173

[8] Hakim et al. Int J Radiat Oncol Biol Phys. 2012 82:e623–e630

[9] Baum et al. Nucl Med Mol Imaging 2018 52:80-81

[10] Thaïeb et al. J Nucl Med. 2018 May;59(5):747-748

[11] Chang et al. Cell Death Dis. 2014 5:e1437

[12] Alberti Eur Rev Med Pharmacol Sci. 2014 18(16):2275-82

[13] Xiao et al. Clin Exp Metastasis. 2012 29(1):1-9

[14] Kim et al. Anticancer Res. 2013 33(10):4469-74

University UGENT
Phd started on

Mentor

Vermeulen Koen

Promotor

Baatout Sarah

Candidate

Heynickx Nathalie