Periodic Reporting for period 3 - TOPAS (Exploiting the Tumor Proteome Activity Status for Future Cancer Therapies)
Periodo di rendicontazione: 2022-09-01 al 2024-02-29
Despite the fact that the treatment of cancer patients has substantially improved over the past decades, the incidence of cancer is still rising and the prognosis remains grim for many patients. As the risk of developing cancer increases with age, the societal challenges in providing adequate care will also grow in the coming years. Hence, there is a continuous need for improving cancer care and research is necessary in order to find new cancer vulnerabilities that can be targeted by existing or novel drugs. One important concept in this context is precision oncology. The idea is to understand the tumor biology of an individual patient well enough to derive an evidence-based individually tailored treatment.
Today, precision oncology makes use of genomic and transcriptomic profiling of cancer patients. Physicians and scientists come together in interdisciplinary molecular tumor boards to evaluate the druggability of any genetic abnormalities in order to recommend a treatment. However, the majority of genomic aberrations detected in cancer patients are functionally not understood so they do not lend themselves as biomarkers for treatment. In addition, the measurement of transcriptomes is a poor proxy for the activity of proteins. As the malignant activity of most cancers is driven by malfunctioning proteins, and the fact that most targeted cancer drugs act on proteins by modulating so-called post-translational modifications, notably phosphorylation, a logical next step is to add a proteomic component to the molecular profiling data. Hence, the overall goal of this project is to establish the tumor proteome activity status (TOPAS) of individual patients as an evidence-based criterion for treatment recommendations by molecular tumor boards. For this idea to work out, it is important to understand what patient proteomes look like, what cancer drugs do to patient proteomes and how this information can be put together to guide treatment recommendations.
To achieve this, the overall objectives of TOPAS are: 1) To show that modulating the TOPAS of cancer models by kinase inhibitors functionalizes the phosphoproteome and reveals the cellular mechanisms of action of these important medicines. 2) To develop and validate drug-, protein- and pathway-centric TOPAS scores able to make treatment suggestions based on the proteomes and phosphoproteomes of cancer cell lines and patients. 3) To demonstrate that phosphoproteomic analysis and TOPAS scoring of sarcoma patients complements information from genomic profiling and aids in decision making by molecular tumor boards.
Today, precision oncology makes use of genomic and transcriptomic profiling of cancer patients. Physicians and scientists come together in interdisciplinary molecular tumor boards to evaluate the druggability of any genetic abnormalities in order to recommend a treatment. However, the majority of genomic aberrations detected in cancer patients are functionally not understood so they do not lend themselves as biomarkers for treatment. In addition, the measurement of transcriptomes is a poor proxy for the activity of proteins. As the malignant activity of most cancers is driven by malfunctioning proteins, and the fact that most targeted cancer drugs act on proteins by modulating so-called post-translational modifications, notably phosphorylation, a logical next step is to add a proteomic component to the molecular profiling data. Hence, the overall goal of this project is to establish the tumor proteome activity status (TOPAS) of individual patients as an evidence-based criterion for treatment recommendations by molecular tumor boards. For this idea to work out, it is important to understand what patient proteomes look like, what cancer drugs do to patient proteomes and how this information can be put together to guide treatment recommendations.
To achieve this, the overall objectives of TOPAS are: 1) To show that modulating the TOPAS of cancer models by kinase inhibitors functionalizes the phosphoproteome and reveals the cellular mechanisms of action of these important medicines. 2) To develop and validate drug-, protein- and pathway-centric TOPAS scores able to make treatment suggestions based on the proteomes and phosphoproteomes of cancer cell lines and patients. 3) To demonstrate that phosphoproteomic analysis and TOPAS scoring of sarcoma patients complements information from genomic profiling and aids in decision making by molecular tumor boards.
We have optimized the proteomic methodology such that cancer patient proteomes can be analysed in time for becoming part of making treatment recommendations in molecular tumor boards. More than 150 cancer patient tumors have been analysed so far.
In parallel, we have quantitatively characterized the activity of about 130 cancer drugs on the phosphoproteomes of four cancer models, representing more than 10 million data points for mining and sharing with the scientific community and the general public via https://www.proteomicsdb.org/. Based on patient proteome profiles, we have developed scoring schemes that reduce the enormous quantities of data to what is clinically actionable and implemented the use of the proteomic data as well the scores in a molecular tumor board. More than 100 patients have already been analysed this way and the results show that adding the proteomic angle provides more confidence for treatment recommendations.
In parallel, we have quantitatively characterized the activity of about 130 cancer drugs on the phosphoproteomes of four cancer models, representing more than 10 million data points for mining and sharing with the scientific community and the general public via https://www.proteomicsdb.org/. Based on patient proteome profiles, we have developed scoring schemes that reduce the enormous quantities of data to what is clinically actionable and implemented the use of the proteomic data as well the scores in a molecular tumor board. More than 100 patients have already been analysed this way and the results show that adding the proteomic angle provides more confidence for treatment recommendations.
The systematic profiling of cancer patient phosphoproteomes in a molecular tumor board setting unique feature of the TOPAS project. Once this approach becomes better known, we anticipate to motivate many other to follow this example. The work performed so far also represents by far the most comprehensive molecular characterization of targeted cancer drugs and that will be of outstanding value for the scientific community, drug companies and physicians around the world. By the time the TOPAS project ends, we expect to have analysed at least 200 retrospective cases of sarcoma patients which fuels the development of clinically actionable patient classifications. In addition, we expect to have analysed at least 200 prospective cases. This is important as the proteomic data for these patients can be used in molecular tumor boards for their individual treatments. If successful, the TOPAS project will set an important example for how precision medicine can be improved and, eventually, be more broadly implemented into cancer patient care.