Vladimir Tolmachev's projects on scaffold protein-based radionuclide tumour targeting
Targeted cancer therapy
Therapy of disseminated cancer can be improved by increasing treatment specificity with the use of molecular recognition of proteins that are aberrantly expressed in malignant cells. Antibodies, tyrosine kinase inhibitors and small interfering RNAs are just a few examples of novel specific therapeutics.
However, the expression of a particular molecular target can vary from patient to patient and between lesions within the same patient. Therefore, molecular testing is becoming part of the paradigm of targeted therapy to choose drugs on an individual patient basis.
Patient stratification and personalised treatment
Radionuclide molecular imaging of tumour-associated targets has the clear advantages of being global, minimally invasive and easily repeatable to follow changes in a target expression. Therefore, radionuclide molecular imaging might be used for patient stratification, identifying patients who would most likely benefit from particular targeting therapy due to sufficient target expression. Thus, radionuclide molecular imaging may be a powerful and convenient tool to make treatment of disseminated cancer more personalised.
Targeted delivery of cytotoxic nuclides
Predictive biomarkers identify only high probabilities of response to a targeting therapy. Some patients with positive predictive biomarkers will inevitably not respond. Targeted delivery of cytotoxic nuclides (e.g. beta- or alpha-emitters) may provide selective destruction of malignant cells sparing healthy tissues. The use of radionuclides offers the advantage of crossfire effect (when nuclides delivered to one cancer cell irradiate its malignant neighbours) and absence of multidrug resistance phaenomenon.
Enhancing the anti-tumour effect of scaffold protein-based radionuclide therapy
Supported by Swedish Cancer Society (Cancerfonden)
Maryam Oroujeni, Ivan Zelepukin, Eleftherios Papalanis, Anna Orlova, Fredrik Frejd, Vladimir Tolmachev
Engineered scaffold proteins (ESP) are a new type of targeting vectors capable of delivering radionuclides to malignant tumours by specific recognition of cancer-associated molecular abnormalities. Targeting of cytotoxic radionuclides may enable treatment of disseminated tumours resistant to other therapies.
We have developed and validated in preclinical studies approaches for radionuclide therapy using ESP, such as a fusion of ESP with albumin-binding domain (ABD) or pre-targeting. Currently, these therapeutics are being translated into clinics. The overall purpose of the project is to investigate approaches that permit further increase the anti-tumour efficacy of ESP-based radionuclide therapy. We are testing the following approaches:
- the use of radionuclides emitting alpha-particles or abundant Auger electrons;
- co-targeting using radiolabelled agents with different toxicity profiles;
- co-targeting of radionuclides and cytotoxic drugs; and
- co-treatment with ESP-targeted nanocarriers loaded with a cytotoxic payload.
CEASE cancer: CarcinoEmbryonic Antingen-targeting Scaffold protein Engineering for precision targeted therapy of carcinomas
Supported by Swedish Research Council (Vetenskapsrådet)
Eleftherios Papalanis, Maryam Oroujeni, Ivan Zelepukin, Anna Orlova, Vladimir Tolmachev
CEACAM5 is a pan-carcinoma antigen, which is overexpressed in a variety of malignant tumours. The overall purpose of the project is to investigate factors influencing targeting properties of derivatives of CEACAM5-targeting affibody C9 (ZCEA:C9) and provide rationale for molecular design of novel agents for imaging and therapy of cancer.
We investigate factors influencing:
- biodistribution of CEACAM5-targeting affibody ZCEA:C9,
- targeted drug delivery using CEACAM5-targeting affibody ZCEA:C9, and
- targeted radionuclide therapy using CEACAM5-targeting affibody ZCEA:C9,
to find solutions improving uptake in tumours and decreasing uptake in normal tissues. The project is multidisciplinary and translational.