Periodic Reporting for period 1 - ICG68-PROG (Imaging of c-Met aberrant cancers with Gallium-68 chelators for positron emission tomography)
Período documentado: 2020-05-01 hasta 2022-04-30
Aberrant hepatocyte growth factor/hepatocyte growth factor receptor (HGFR or c-Met) signalling is involved in the development of several tumor types. Monitoring of c-Met expression in real time will assist in the diagnosis and in the monitoring of response to therapy. The overall objective of the ICG68-PROG was to create a library of novel molecular agents able to effectively target c-Met and to efficiently bind gallium-68, and therefore to be exploited as c-Met PET imaging tracers. The expected results of the ICG68-PROG were to select the most promising and effective tracers among the library of synthesized compounds for further preclinical development. The objective of the ICG68-PROG will be achieved thanks to a rational design and synthesis of the novel peptide-chelator bioconjugates. Firstly, the gallium binding units will be developed, then c-Met binding peptides will be synthesized. The two chemical moieties will then be conjugated and the gallium chelating capabilities, as well as the c-Met binding capabilities, will be evaluated. It is logical to believe that, in future clinical practice, non-invasive PET imaging with the developed tracers will support not only the diagnosis of c-Met overexpressed cancers but also the selection of patients for c-Met–targeting drugs (Met inhibitors and anti-Met antibodies), as well as identifying responding and nonresponding patients for such therapeutic agents. According to the European Cancer Information System, the most common estimated and lethal causes of cancer are breast, prostate, lung and bronchus, and colon & rectum. In these tumors, the c-Met receptor is often overexpressed. In this context the products derived from the development of the ICG68-PROG will create powerful tools for the detection and monitoring of the most common and lethal cancers among Europe and worldwide, making the ICG68-PROG at the forefront for the fighting of a major public health problem and of primary interest for the European citizens.
Since the beginning of the project the work was developed as initially planned. Several peptide sequences (c-Met binding peptides) have been selected from literature data. The gallium binding units were then produced and joined to the selected c-Met binding peptides. The actual binding activity of the radioactive element (gallium-68) was then measured for each produced molecule. The stability in solution and in serum was also measured and then each peptide was screened against cancer cellular models to verify the binding to the target receptor (c-Met). The products of the project are now under revision for a patent application. Further studies will guarantee a next future application of the produced pharmaceutical in clinical environment.
The project aims to accelerate the exploitation of a kit-based THP technology to produce a PET tracer for c-Met aberrant cancers using the advantages of gallium-68. Differently from the already reported c-Met PET tracers, the products derived from the ICG68-PROG have the advantages of using THP as the chelating unit for the gallium-68. This ensures a quantitative radiolabelling under mild conditions without eluate pre-processing or post-labelling purification to produce a single species. In fact, THP can complex gallium rapidly at room temperature and neutral pH, with high radiochemical yield and purity, reducing the costs of the production of the radiotracers. Moreover, the use of gallium-68, thanks to its availability from commercially available generators, will reduce the cost of the infrastructures associated with 18F and 11C tracer production and make it possible to use PET even for hospitals without an on-site cyclotron. Finally, the production of a peptide-based tracer, in contrast to an antibody-based one, will also reduce the cost of the production and, therefore, the cost of the final product. The combination of targeted imaging agents with PET allows non-invasive diagnosis of specific cancer types with precise delineation of tumors and metastases and thus disease staging. It is logical to believe that, in future clinical settings, non-invasive PET imaging with the developed radiolabeled tracers will support the diagnosis of c-Met overexpressed cancers, the selection of patients for c-Met–targeting drugs, and identify responding and nonresponding patients for such therapeutics. According to the ECIS (European Cancer Information System), cancer has a significant impact on society in Europe and worldwide. The three most common estimated new cancer cases are breast, lung/bronchus, colon/rectum for females and prostate, lung/bronchus, and colon/rectum for males. These types of cancer are also the ones that produce each year the highest number of deaths. Notably, many human tumor types, including the already cited, often have the c-Met receptor overexpressed. Considering only these four cases of cancer, each year, almost 7 million new cases worldwide are diagnosticated (2 million lung cancer, 1.3 million prostate cancer, over 2 million breast cancer and 1.8 million colon/rectum cancer); among them, 318,327 new cases of lung cancer, 335,514 of prostate cancer, 355,457 of breast cancer and 341,419 of colon/rectum cancer were estimated for 2020 for EU-27 countries by the European Cancer Information System. In these cancers, the overexpression of c-Met is well documented, resulting in a vast target clinical population per year of millions of potential patients worldwide and hundreds of thousands in Europe who will benefit from the results of the project. In this context, the products derived from the development of the project are creating powerful chemical tools for the detection of the most common and lethal cancers among Europe and worldwide, doing the project at the forefront for the fighting of a significant public health problem and primary interest for European citizens.
Notably, the ICG68-PROG falls into the scope of the recent 2020 document by the European Commission Proposed Mission CONQUERING CANCER: MISSION POSSIBLE Report of the Mission Board for Cancer, particularly into the intervention area for action optimize diagnostics and treatments under the recommendation 5: Advance and implement personalised medicine approaches for all cancer patients in Europe and the under recommendation 6: Develop an EU-wide research programme on early diagnostics and minimally invasive treatments. The overall and ambitious goal of the Mission on Cancer of the European Commission has been formulated as: “By 2030, more than 3 million lives saved, living longer and better”. This is consistent with United Nations Sustainable Development Goal (SDG) 3: Ensure healthy lives and promote well-being for all, at all ages. The target of this SDG for non-communicable diseases for 2030 is “to reduce by one-third premature mortality through prevention and treatment and promote mental health and well-being.”
Notably, the ICG68-PROG falls into the scope of the recent 2020 document by the European Commission Proposed Mission CONQUERING CANCER: MISSION POSSIBLE Report of the Mission Board for Cancer, particularly into the intervention area for action optimize diagnostics and treatments under the recommendation 5: Advance and implement personalised medicine approaches for all cancer patients in Europe and the under recommendation 6: Develop an EU-wide research programme on early diagnostics and minimally invasive treatments. The overall and ambitious goal of the Mission on Cancer of the European Commission has been formulated as: “By 2030, more than 3 million lives saved, living longer and better”. This is consistent with United Nations Sustainable Development Goal (SDG) 3: Ensure healthy lives and promote well-being for all, at all ages. The target of this SDG for non-communicable diseases for 2030 is “to reduce by one-third premature mortality through prevention and treatment and promote mental health and well-being.”