HASPIN: Potencial nueva diana terapéutica

Carralero Llano, Juan María (2020). HASPIN: Potencial nueva diana terapéutica. Proyecto Fin de Carrera / Trabajo Fin de Grado, E.T.S. de Ingeniería Agronómica, Alimentaria y de Biosistemas (UPM), Madrid.

Description

Title: HASPIN: Potencial nueva diana terapéutica
Author/s:
  • Carralero Llano, Juan María
Contributor/s:
  • Blanco Aparicio, Carmen
  • Oñate Sanchez, Luis
Item Type: Final Project
Degree: Grado en Biotecnología
Date: June 2020
Subjects:
Faculty: E.T.S. de Ingeniería Agronómica, Alimentaria y de Biosistemas (UPM)
Department: Biotecnología - Biología Vegetal
Creative Commons Licenses: Recognition - No derivative works - Non commercial

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Abstract

Cancer is one of the biggest upcoming health problems in our current society. It has been related with developed countries lifestyle and it is a disease with an estimated burden of 18.1 million of new cases and 9.6 deaths in 2018 becoming, progressively, one of the biggest challenges of our healthcare system. Biologically, the most common feature of cancer disease is the aberrant cell growth and proliferation caused by mutations accumulation in oncogenes and/or tumour suppressor genes. Etiologically, the relationship between our lifestyle and cancer disease remains unknown, but several etiological factors have been correlated with cancer in different studies. Biological factors such as common genetic mistakes during cell division or steroid hormones levels, environmental factors such as geography, ultraviolet radiation, smoking or even viral infections such as papillomavirus have been correlated with the onset of cancer, showing the intrinsic difficulties of cancer investigation. Although oncology investigation faces one of the most difficult clinical challenges; it has been progressing throughout the years, and several advances have been made in cancer treatment. To be concrete, cancer treatment has evolved from treatments based on cellular routes such as chemotherapy to a new clinical approach based on the knowledge of a therapeutic target, that allow us to develop more selective and safe therapies. The process of new therapeutic agents’ development is called Drug Discovery, and it requires from 12 to 15 years of investigation and the investment of more than a billion of dollars. Having several important phases, the essential part of the process is the selection of the biologic target. This target has to fulfil biological and economic criteria, as it has to be a druggable target, which modulation needs to be trackable and have therapeutic effects, and it has to be practical in an economic perspective, according to the operational and strategic standards established by the promotor of the investigation project. In this project, our goal is to review the state-of-the-art of the validation process of HASPIN, an interesting emerging antitumoral target, as well as evaluate the data available of the most important HASPIN inhibitors, in order to assess their properties aswell as compare them to some experimental compounds that are being developed at CNIO. Validation of an antitumoral target is a very complex process in which several complementary studies need to be done with different chemical and biological probes in order to determine target function in tumor development and progression and confirm therapeutic effects obtained by target inhibition. HASPIN is a serine/threonine kinase structurally different from other kinases, whose function is required to normal cell division. Specifically, it phosphorylates Threonine 3 in Histone 3, creating an epigenetic mark that triggers the localization of the chromosome passenger complex in the centrosome, allowing correct chromatids segregation and, hence, normal cell division. Being an epigenetic kinase related to cell division, HASPIN has attracted lot of attention due to its therapeutic potential, and a lot of research has been done towards it. As a mitotic regulator, several studies claim that HASPIN role could be crucial in cancer progression and HASPIN inhibition could be the key to cancer growth inhibition in some cancer types. Whereas, other studies showed that HASPIN role is redundant as well as non-essential for cell division, which creates a contradiction that could only be solved by studying the effect of HASPIN inhibition in different cellular contexts. Given the importance of the studies carried out with HASPIN inhibitors (or HASPIN-i), these have shown several limitations. The best known HASPIN inhibitors in the literature, 5-Itu, Sangivamycin, CHR-6494 and CX-6258, are not selective enough to be used as molecular probes, as many off-targets had been found for all of them, preventing HASPIN validation. Secondly, the complementary studies made with other biological probes; such as siRNA, shRNA or CRISPR-Cas9, show that some of the antitumoral effects seen with HASPIN inhibitors are not due to HASPIN inhibition itself but to off-target effects, which means that new high-selectivity compounds are needed to complete HASPIN validation. In this regard, CNIO has developed compounds such as compound 1, that is a high-selectivity HASPIN-i that could help with the final validation of HASPIN and, subsequently, with the development of new cancer therapies that could allow us to find a solution to this major disease.

More information

Item ID: 65807
DC Identifier: http://oa.upm.es/65807/
OAI Identifier: oai:oa.upm.es:65807
Deposited by: Biblioteca ETSI Agrónomos
Deposited on: 21 Dec 2020 12:09
Last Modified: 21 Dec 2020 12:09
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