Prostate-specific Inhibitors of Membrane Antigen as a Base for Radiopharmaceuticals for Diagnostics and

Therapy of Prostate Cancer

German Konstantin a,b, Vlasova Oksanad, Petriev Vladimire, Obruchnikova Yana a,c , Krilov Vladimir, Epshtein Natalia, Tananaev Ivana, Myasoedov Borisa,

Afanasiev Andrey a,b, Kryzhovets Olga a,

a Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences, Leninsky pt, Moscow GSP-1, b Medical University REAVIZ, Krasnobogatyrskaya,2; Moscow, Russia

c Mendeleev Russian Chemical Technology University, Miusskaya sq.1, Moscowd- MEPhI, Obninsk

• Corresponding author: guerman_k@mail.ru Dec 3, 14-50

3rd Japan-China Academic Symp. on Nuclear Fuel Cycle

December 2-5, 2015

Prostate specific membraneantigen as a candidate biomarkers

for diagnosis and therapy• As a radiopharmaceutical for the diagnosis and

treatment of prostate cancer useful to consider the PSMA, which is a membrane abusive and glycoprotein produced in high concentrations in the epithelial cells of healthy individuals and patients with prostate cancer.

• PSMA is normally found in secreted prostate epithelial cells, but very weakly expressed in cells of other organs (kidney, salivary cancer, small intestine), and practically does not occure in benign prostatic cancer.

Consortium organigram

DireсtorateA.N. Frumkin

Institute of Physical Chemistry and

Electrochemistry RAS, Moscow

Medical Institute Reaviz, Moscow branch,

Russia

Burnazyan Federal Medical Biological Center of FMBA, Moscow, Russia

National Research Nuclear University MEPhI, Obninsk,

Russia

Medical Radiological Research Center of

Ministry of Health of Russia, Obninsk, Russia

A. I. Leipunsky Institute for Physics and Power

Engineering, Obninsk, Russia

Tc-99m for prostate cancerdiagnostics and

Re-188 for treatment

A.N. Frumkin Institute of Physical Chemistry and Electrochemistry

RAS, MoscowTechnetium chemistry laboratory

• K. German, Project CEO, Head of Tc laboratory, PhD , Doc., Prof.

• A. Safonov, Deputy head of Tc laboratory, PhD• Ya. Obruchnikova, PhD• V. Tregubova, PhD student • M. Glazkova

Innovation department• V. Lebedev, General manager for innovations

Laboratory of new physical-chemical problems• A. Tsivadze, Director of IPCE RAS, Academician• A. Filyanin, liquid extraction group, PhD• V. Tarasov, NMR analysis, Professor

Laboratory of substance radiation chemistry• B. Ershov, Head of laboratory, corr. member

RAS, Professor• E. Abkhalimov, PhD• R. Solovov, PhD student

Laboratory of interphase boundaries and electocatalysis

• V. Andreev, Head of laboratory, Professor

Laboratory of radioactive material analysis• M. Grigoriev, Head of laboratory, Professor

Sci. review on New Radiopharmaceuticals Based on Prostate-Specific Inhibitors of Membrane Antigen for Diagnostics and Therapy of Metastatic Prostate Cancer

byO.P. Vlasova1, K.E. German2, V.V. Krilov3, V.M. Petriev3, N.B. Epstein4

• 1 State Scientifi c Centre of the Russian Federation Institute for Physics and Power Engineering n.a. A.I. Leypunsky ,≪ ≫ Obninsk, Russian Federation• 2 A.N. Frumkin Institute of Physical Chemistry and Electrochemistry RAS, Moscow, Russian Federation• 3A. Cyb Scientifi c Research Centre of Radiology, Obninsk, Russian Federation• 4 National Research Nuclear University MEPhI, Obninsk, Russian Federation

About 10.7% cases of prostate cancer were registered in Russia in 2011 (40 000 patients). More than half of cancer cases were revealed in advanced (III–IV) stages when metastases inevitably developed quickly. Clinical problem of early diagnostics and treatment of metastatic prostate cancer is still not solved. Anatomical imaging techniques have low sensitivity and specificity for the detection of this disease. Metabolic visualization methods which use prostate specific antigen (PSA) as a marker are also ineffective. This article describes prostate-specific membrane antigens (PSMA) that are proposed as a marker for diagnostics and therapy of prostate cancer.The most promising PSMA-based radiopharmaceutical agent for diagnostics has been developed and clinically tested in the European countries. These pharmaceuticals are based on small peptide molecules modified with urea, and have the highest affinity to PSMA. Favorable pharmacokinetics, rapid accumulation in the tumor and rapid excretion from the body are beneficial features of these pharmaceuticals.

• Annals of the Russian Academy of Medical Sciences. 2015; 70 (3): 360–365. Doi: 10.15690/vramn.v70i3.1334) (Vestnik Rossiiskoi Akademii Meditsinskikh Nauk)

99m Tc-labeled peptide inhibitor of PSMA

• a new RFP is based on the peptide inhibitor of PSMA ,

• labeled with 99mTc is developed for diagnosis • and labeled with 188Re - for radionuclide

therapy.• Results of the Studies (Phase I and II) showed

that these RFP quickly "discover" the tumor and its metastases including in lymph nodes and skeletal size less 1 cm [16-18].

• The main purpose of the Institute is to carry out fundamental and applied scientific research in various fields of physical chemistry, electrochemistry, chemical resistance of materials, radiochemistry and radiation chemistry.

A. I. Leipunsky Institute for Physics and Power Engineering, Obninsk, Russia

• O. Vlasova, N. Nerozin, Yu. Shevko, I. Zhuk• multidisciplinary scientific organization,

conducting complex investigations of physical and technical problems of nuclear science and technology.

Medical Radiological Research Center of Ministry of Health of Russia, Obninsk,

Russia

• V. Skvortsov, V. Petriev• Mission: Development of concepts, regulatory

documents related to radiation safety of a human and the environment, health security and reduction of socioeconomic prejudice caused by radiation.

• The Institute was founded in 1962 to develop and improve methods of radiation diagnostics and radiation therapy, prevention and treatment of radiation injury, the study of the biological and medical effects of ionizing radiation.

National Research Nuclear University MEPhI, Obninsk, Russia

• N. Airapetova, N. Epshtein• Development of analytical procedures for

quality control of radiopharmaceuticals and staff training

• Mission: to generate, disseminate the use and to preserve scientific knowledge aiming to address global challenges of the XXI century, as well as to provide innovative transformations in Russia accompanying development of the country competitiveness in the global energy and non-energy high-tech markets.

Burnazyan Federal Medical Biological Center of FMBA, Moscow, Russia

• G. Kodina, PhD, Department head• A. Maruk, PhD, Laboratory Head• Production of Tc-99m (for radiodiagnostics) and Re-188

(for radiotherapy) isotopes and preclinical medicine tests

• Fundamental and applied research in the field of radiation medicine, radiobiology and radiation protection; • Research in the field of biomedical technologies, radiopharmacy;• Development of new radiation technologies (including photon and neutron capture therapy); • Research in the field of chemical and radiation safety in the use of technology for special applications.

Medical Institute Reaviz, Moscow branch, Russia

• K. German, Chair of Natural science, Professor • A. Safonov, docent, PhD• Ya. Obruchnikova, assistant prof., PhD• V. Tregubova, PhD student

• Training of medical staff for modern medicine

“The main aim of Reaviz is the training of health care staff, of young people who should become highly professional physicians in the nearest future. The most important quality for these professionals should be the integration of the greatest responsibility and the inner freedom of this profession, of scientific research and practical achievements.” Rector of Samara Medical Institute “REAVIZ”, Doctor of Medical Science, professor Nikolay A. Lyssov

What we intend to obtain

In the course of this project should be developed• production technologies of 99mTc generators and high-

value 188Re generators with reduced transport index,• technologies of 188Re concentration, development of

analytical methods for detection of radioactive and chemical impurities in the 188Re preparation,

• quality assurance of 99mTc and 188Re generator eluates in accordance with the requirements of potential radiopharmaceuticals based on them, specifically binds to the receptor tissue of prostate cancer.

What we already have for radionuclide imaging

• 2-18F-fluoro-2-deoxy-D-glucose (FDG); • 111In-7E11 antibody (ProstaScint);• 18F-fluorodihydrotestosterone (18F-FDHT); • radioacetate analogs; • radiocholine analogs; • anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid

(anti-[18F]FACBC)Production of Tc-99m (for radiodiagnostics) and Re-188 (for radiotherapy) isotopes were improved with optimized generator design aimed to high specific activity production.

• Potential consumer of radiopharmaceuticals (RPh): medical institutions at various levels, cancer medical centers, cancer clinics, licensed to work with sources of ionizing radiation and equipped with diagnostic equipment, SPECT or PET.

• Objects of RPh application: patients with the disease of prostate cancer (about 30 thousand pers. / year).

• Over the past few years in Russia approximately 40,000 new cases of prostate cancer per year were recorded, and only for 30% of them brachytherapy is performed with an efficiency of 75%

Effective diagnostics and therapy of prostate cancer is an important issue for

Russia due to constantly increasing number of decease cases herein.

Rational development of new radiopharmaceuticals for the management of advanced and metastatic prostate cancer requires an improved cooperation of the organization thus involved. For this reason an interdisciplinary consortium collaboration for the development of radiopharmaceutical approach is established with principle aim to improve the situation within the 3 coming years.

The development of new radiopharmaceuticals and generators for the management of advanced prostate cancer will help to improve the treatment of this disease in Russia.

• Special educational interdisciplinary program for specialist training for technetium application to prostate radiodiagnostics is elaborated.

• The development of new radiopharmaceuticals and generators for the management of advanced prostate cancer will help to improve the treatment of this disease in Russia.

• Innovative character of this project requires special attention on staff training.

• New technologies worked out by Igor Zhuk and Yury Shevko (A.I. Leipunsky Institute for Physics and Power Engineering, Obninsk, Russian Federation) are to be used in this project

Thank you !