Autophagy and Mitochondria Influence Susceptibility of Lymphoma Cells to Target-Therapy
Project location: ITALY, Rome
Project start date: September 2019 - Project end date: September 2022
Project number: 2019-042
Beneficiary: Istituto Superiore di Sanità
Istituto Superiore di Sanità (ISS), the technical/scientific unit of the Ministry of Health, is a public research and control institution with a supervisory role on all aspects of public health. ISS is responsible for quality control of drugs, food and vaccines, promotes and participates in biomedical and social research in all areas of human health and interfaces with the health ministry to guide health policies based on the needs of the population emerging from the epidemiological studies. It manages the registers of rare diseases and organ transplantation, and has the role of protecting the health of the people by informing them, also through a Knowledge portal continuously updated, on the correct lifestyles to be adopted to favor the maintenance of the state of health. In addition, the ISS evaluates and authorizes studies conducted throughout Italy on animal models, thus ensuring that they are performed in accordance with European guidelines that provide for the use of the minimum number of animals with the least suffering possible in compliance with the Animal Research: Reporting of In Vivo Experiments guidelines (McGrath, Drummond, McLachlan, Kilkenny, & Wainwright, 2010; McGrath & Lilley, 2015) and the European directives (2010/63/EU).
ISS is equipped with laboratories and qualified personnel to carry out experiments in all fields of human and veterinary pathology for the benefit of public health.
In particular, ISS's research group, which is part of the Oncology unit of the Center for Gender-specific Medicine, has been involved in cancer research for years and has produced numerous works published in prestigious international journals.
Lymphomas and leukemias are the most commonly found tumors in children. Despite the enormous progress in the treatment of these oncological pathologies, a certain number of them remain incurable due to the mechanisms of resistance to chemo and radiotherapy developed by cancer cells. These resistance mechanisms are also established towards biological molecules potentially useful in the therapy of leukemias and lymphomas, such as that based on the use of the cytokine TRAIL.
This biological molecule binds to specific receptors on the cell membrane and triggers a signal of death that leads, through the formation of a protein platform inside the cancer cell, to its elimination.
Unfortunately, cancer cells can develop mechanisms that make them resistant to death.
In particular, some of these mechanisms, shortly illustrated below, will be the subject of this project.
1. In cancer cells the protein platform that transfers the death signal from the external receptor into the cell is defective. As a consequence, the cancer cell becomes resistant to TRAIL.
2. Although the mechanism of death is properly triggered, the cancer cell carries out some protective mechanisms, such as autophagy, which counteract the toxic effects of treatment removing damaged cellular components, and allow the tumor cell to survive.
3. Mitochondria, intracellular organelles responsible for the energy supply of the cell, can switch their metabolism to promote the survival of cancer cells.
The molecular mechanisms underlying the resistance to therapy acquired by tumor cells will be studied and analyzed essentially in vitro and only in the final phase of the project will they be validated in vivo on appropriate animal models. Importantly, in vivo studies will be conducted on the smallest possible number of animals capable of giving statistical validity to the data obtained, and in compliance with European rules on animal welfare and ethics statement to minimize animal suffering (Animal Research: Reporting of In Vivo Experiments guidelines (McGrath, Drummond, McLachlan, Kilkenny, & Wainwright, 2010; McGrath & Lilley, 2015) and the European directives (2010/63/EU).
The understanding of the mechanisms underlying the resistance of cancer cells to traditional (chemotherapy and radiotherapy) and innovative (biological and immunological) therapies may allow, in the not too distant future, the development of innovative pharmacological strategies to overcome resistance.
It should not be forget that the enormous increase in the survival to the oncological diseases observed in recent years, due to the introduction of new drugs and personalized therapeutic strategies, is also the result of the translation of the laboratory findings into clinically applicable therapeutics in an ever increasing collaboration close between oncologists and researchers (from bench to bedside).
Based on the preliminary results, ISS expects to identify the biochemical pathways involved in tumor cell death induced by chemotherapy. In fact, this is a fundamental step in order to identify possible target proteins for the development of innovative therapies or the refining of the standard therapeutic protocols, especially for cancers for which there is no effective therapy.
In this respect ISS will perform in vitro experiments to clarify the molecular mechanisms responsible for resistance or sensitivity of cancer cells to different drugs and in vivo experiments on mice SCID in order to confirm or refute results obtained in vitro.
This project, which received a grant from the Nando and Elsa Peretti Foundation, aims at understanding the mechanisms underlying the resistance of cancer cells to traditional (chemotherapy and radiotherapy) and innovative (biological and immunological therapies) therapies in order to proceed to the development of innovative pharmacological strategies to overcome resistance.