Periodic Reporting for period 1 - InterTask (Therapeutic molecules and druggable sites to suppress aberrant ion channel activity in cancer.)
Okres sprawozdawczy: 2021-10-01 do 2024-09-30
Ion channels are membrane proteins, i.e. cellular components, involved in a variety of physiological processes and they have been deeply studied for their role in excitable cells and transmission of the electric signal. Building on these early studies, it has been possible to correlate ion channels malfunctions with many pathological conditions affecting the nervous and cardiac systems. More recently, evidences accumulated highlighting a role of ion channels in cancer. Hence ion channels have emerged as pharmacological targets to contrast angiogenesis and tumor growth.
The present study focused on a class of proteins known as K2P channels. They have attracted a lot of interest for their ability to respond to a large number of chemical and physical cues in the cell and malfunction of K2Ps have been linked to many pathological conditions such as depression, autoimmune and degenerative diseases, mental retardation, migraine, ischemia, epilepsy and tumorigenesis. The subject of this study, TASK-3 (TWIK-related Acid-Sensitive K+ channel), has been also implicated in cancer for its aberrant presence with a frequency of 44% among the breast cancer and it was also found in 35% of lung cancers. This evidence strongly supports the idea that TASK-3 may constitute an important therapeutic target in malignancies in which the ion channel is aberrantly expressed.
The development of a novel TASK-3 specific therapeutic tool, which could be used to treat tumors as well as to unravel the underlining contribution of TASK-3 at the molecular level, heavily relies on structural and functional information on the channel, especially in complex with partners known to reduce or modulate its activity.
The overall objectives of the study consisted of approaching TASK-3 at the molecular level, by studying the three-dimensional structure of this cellular component and to develop therapeutic tools based on antibodies to control its presence in cancer phenotypes. Another objective of the proposed research was to directly control the presence of the protein by acting on other cellular components that directly interact with it. The approach was to understand the interaction between the two components to have a starting point for the design of therapeutics capable of controlling the presence of the TASK-3 protein in different organs.
The execution of the study let to achieve most of the first objective with the determination of the structure of TASK-3 together with an IgG that recognizes the channel and cause its internalization in breast cancer metastasis. The second objective was only partially achieved and more progress will be required to understand the molecular basis on TASK-3 presence due to its interaction with other cellular components.
The present study focused on a class of proteins known as K2P channels. They have attracted a lot of interest for their ability to respond to a large number of chemical and physical cues in the cell and malfunction of K2Ps have been linked to many pathological conditions such as depression, autoimmune and degenerative diseases, mental retardation, migraine, ischemia, epilepsy and tumorigenesis. The subject of this study, TASK-3 (TWIK-related Acid-Sensitive K+ channel), has been also implicated in cancer for its aberrant presence with a frequency of 44% among the breast cancer and it was also found in 35% of lung cancers. This evidence strongly supports the idea that TASK-3 may constitute an important therapeutic target in malignancies in which the ion channel is aberrantly expressed.
The development of a novel TASK-3 specific therapeutic tool, which could be used to treat tumors as well as to unravel the underlining contribution of TASK-3 at the molecular level, heavily relies on structural and functional information on the channel, especially in complex with partners known to reduce or modulate its activity.
The overall objectives of the study consisted of approaching TASK-3 at the molecular level, by studying the three-dimensional structure of this cellular component and to develop therapeutic tools based on antibodies to control its presence in cancer phenotypes. Another objective of the proposed research was to directly control the presence of the protein by acting on other cellular components that directly interact with it. The approach was to understand the interaction between the two components to have a starting point for the design of therapeutics capable of controlling the presence of the TASK-3 protein in different organs.
The execution of the study let to achieve most of the first objective with the determination of the structure of TASK-3 together with an IgG that recognizes the channel and cause its internalization in breast cancer metastasis. The second objective was only partially achieved and more progress will be required to understand the molecular basis on TASK-3 presence due to its interaction with other cellular components.
The work consisted first in the execution of the first scientific Aim of the proposal, focusing on biochemical experiments that allowed us to produce enough TASK-3 sample for our structural studies. The studies were based on an electron microscopy technique that allow to visualize a single particle, in this case a protein, and to collect large datasets of movies where all the particles are classified until it is possible to define the protein structure at atomic level. We spent the first two years to optimize the conditions to obtain reliable data. The information that we have now are the structure of the protein alone and in complex with an IgG, a humanized antibody, that has a therapeutic effect on breast cancer metastasis. We shared these results with our collaborator at the John Hopkins University, the lab of Prof. Latorre, who developed the IgG. The general scope is to provide a framework to develop more therapeutic agents based on the structural information obtained from this work. Once published, the structure will be available for all the scientific community for structure-based drug design.
To reach all the interested scientific community members we disseminated the results in some conferences, both national and international, to anticipate the data before the publication. At the same time, we tried to interest the local community with outreach activities that get the public closer to what the lab is working on and how our basic research can turn into a translational outcome on spreading pathological conditions.
To reach all the interested scientific community members we disseminated the results in some conferences, both national and international, to anticipate the data before the publication. At the same time, we tried to interest the local community with outreach activities that get the public closer to what the lab is working on and how our basic research can turn into a translational outcome on spreading pathological conditions.
The project resulted in novel structural information on TASK-3, a cellular component which has a crucial role in several neuronal processes and whose aberrant presence in other body tissues is linked to oncogenesis and metastasis processes. These information will soon be available to the scientific community through open access publication and they will impact future design and development of therapeutic agents acting on TASK-3. Since the project has been focusing on basic research on ion channel mechanisms the results produced will impact several fields of the life science (physiology, pharmacology, medicine) and they will have a long-term influence on aspects related to the production of drugs for pathologies with high incidence on western countries and not only.