Projects / Programmes
Development and evaluation of radiolabelled bio-molecules for targeted radionuclide therapy and imaging of neuroendocrine tumours
| Code |
Science |
Field |
Subfield |
| 3.04.00 |
Medical sciences |
Oncology |
|
| Code |
Science |
Field |
| B000 |
Biomedical sciences |
|
| Code |
Science |
Field |
| 3.01 |
Medical and Health Sciences |
Basic medicine |
targeted molelcular radiotherapy, somatostatin, octreotid, 90Y-DOTATAOC, 177Lu-DOTATATE, 99mTc-HYNIC TOC, radiolabelled octreotide analogs, neuroendocrine tumours, scintigraphy
Researchers (15)
Organisations (2)
Abstract
Number of cancer and cancer deaths in western countries continuously increases over the past few decades. The fact that it is the third leading cause of deaths in the developed countries, makes cancer a major research challenge over the past two decades. Use of systemic chemotherapy agents for treatment in systemic disease is often limited by serious side effects to normal tissues and lack of their selectivity. Sub-optimal doses result in therapeutic failure and the development of drug resistance. Tumour-targeting therapeutics, based on bio-molecules such as peptides and antibodies, are becoming increasingly important in therapy regiments due to their high selectivity and relative low toxicity to normal tissues. When such a bio-molecule is used as a vector for delivery of radioactive isotope to affected tissue, its therapeutic power is greatly improved because of radiation dose, specifically directed to cancer cells.
Targeted molecular radiotherapy is a new therapeutic modalitiy for patients with inoperable neuroendocrine tumours, who are not suitable chemotherapy. Indications for treatment with radiolabelled octreotide analogs are: inoperable, metastatic neuroendocrine carcinomas with high somatostatin expression confirmed by diagnostic octreotide scintigraphy, normal bone marrow reserve (Hb ) 10g/l, WBC ) 3.0*109/l, platelets ) 100*109/l), adequate renal function and good performance status. Majority of neuroendocrine tumours express receptors for somatostatin on their cell membrane. Besides somatostatin, also its analogs, like octreotide can bind to the receptors.
For imaging of neuroendocrine tumours in Slovenia radiolabelled 99mTc labelled somatostatin analog (hydrazinonicotinyl-[D-Phe1, Tyr3]-octereotid - (99mTc-HYNIC-TOC) is used since 2002. In 2006-2009 University medical centre in Ljubljana has implemented targeted molecular radiotherapy of neuroendocrine tumours with radiolabelled analogs 1,4,7,10-tetraazocyclododekan-1,4,7,10-tetraacetic acid-[D-Phe1, Tyr3]-octreotid (90Y-DOTATOC) and 177Lu-1,4,7,10-tetraazocyclododekan-1,4,7,10-tetraacetic acid-[D-Phe1, Tyr3]-octreotate (177Lu-DOTATATE).
In cell biology there is a well konwn sindrom, where number of available binding sites on a celll membrane is decreased – so called down-regulation. The mechanism is not entirely understood, data in the literature shows that amount of the substrate and possible saturation of binding sites can cause the down-regulation. There is not conclusive data on amount or concentration of peptide, where down-regulation of somatostatine receptors occurs. It is postulated that if the concentration of peptide on affected sites is too high, accumulation of radiolabelled peptide is diminished resulting in decreased sensitivity of imaging procedure or sub-optimal succes of treatment of neuroendocrine tumours.
The basis of this proposal is optimisation of targeted molecular radiotherapy of patients with neuroendocrine tumours using radiolabelled octreotide analogs. We will study influence of amountg of total peptide mass and receptor binding sites on accumulation of radiolabelled octreotide analog on somatostatin receptor. Further on we will investigate the effect of classical therapy with longacting somatostatin analogs on efficiency of imaging of somatostatine receptors using 99mTc-HYNICTOC and/or targeted molecular radionuclide therapy using radiolabelled analogs 90Y-DOTA-TOC and/or 177Lu-DOTATATE.
Significance for science
1.Better understanding of influence of total peptide mass on binding of radiolabelled octreotide analogs on somatostatin receptors in vitro 2. Better understanding of influence of internalization of somatostatin receptors on number of binding sites on cell bembrane in vitro 3. Better understanding of inflluence of total peptide mass on accumulation of radiolabelled octreotide analogs in vivo 4. Improved diagnostic value of somatostatin receptor scintigraphy and imprived algoritm for PRRT.
Significance for the country
As in 9.1 and additionally: 1. New therapeutic and diagnostic modalities for patients with neuroendocrine tumours 2. Individualisation of managements of patients with neuroendocrine tumours 3. Optimisation of expenses for therapy of neuroendocrine patients by means of ptimal use of biological medicines.
Most important scientific results
Annual report
2011,
2012,
2013,
final report,
complete report on dLib.si
Most important socioeconomically and culturally relevant results
Annual report
2012,
2013,
final report,
complete report on dLib.si
