11 December 2020
A BioMed21 collaboration between Humane Society International India, the Ashray Hastha Trust and the CSIR-Centre for Cellular and Molecular Biology has selected two grantees to develop Adverse Outcome Pathways (AOP) designed to further cancer research.
Dr. Usha Adiga of the KS Hegde Medical Academy and Dr. Kalyan Gayen of the National Institute of Technology Agartala will focus on developing two AOPs, one related to breast cancer and the other to ovarian cancer. These disease pathways will be added to the global AOP Wiki, developed and curated by member countries of the Organisation for Economic Cooperation and Development (OECD) as part of an international crowdsourcing effort.
The AOP focused on ovarian cancer will study the effects of Clomiphene (a drug used to treat infertility) on the ovaries and the risk of ovarian cancer it may pose. By integrating a series of complex signalling pathways prompted by exposure to Clomiphene, the scientists expect to shed light on key biological events leading to ovarian cancer.
The AOP on breast cancer development deals with the genotoxic perturbation caused by alcohol, which activates a series of signalling pathways leading to molecular alterations of breast epithelial cells culminating in breast cancer.
An ongoing study by HSI/India has revealed that few Indian scientists are aware of or have contributed to the AOP field. To help bridge this gap, HSI/India launched a call in December 2019 for proposals to build pathways in cancer research.
An enormous range of resources is devoted to studying cancer, yet we are far from finding a cure for most cancers. This failure results in part because animal testing, currently the basis for most cancer studies, does not translate well to humans. Parameters like tissue heterogeneity involving abnormal cell types, varied abilities of proliferation, migration and response to therapy pose a need for more human relevant approaches to studying cancer. The human population is heterogeneous in terms of life stages, vulnerabilities, gender and geographical factors that play a role in biological differences. These are difficult conditions to reproduce in a homogenous animal population in a controlled environment. No matter the extent to which animals may be ‘humanized’ by altering their genetic makeup, it is still infeasible to capture the systemic intricacies of human biology.
While our ability to treat cancer has improved over time with advances in technology, and our comprehension of the disease pathophysiology specific to cancer, our ability to fight cancer remains limited. AOPs can integrate a wide range of already available information, leading to a better understanding of the disease and improving medical research and drug discovery.
The AOP concept emerged in the field of toxicology as a knowledge building, evaluation and communication tool to facilitate translation of pathway-specific mechanistic data across levels of biological organization into responses relevant to the assessment and management of risks certain chemicals pose to humans and the environment. The concept is equally suited to addressing disease pathophysiology and associated drug discovery.
An AOP provides a framework to understand how a stressor causes a cascade of events leading to an adverse outcome, which is relevant to the risk assessment of the stressor. AOPs are modular and are composed of four main components: A Molecular Initiating Event (MIE), Key Events (KEs), Key Event Relationships (KERs), and Adverse Outcome (AO). AOPs are not chemical specific, instead they focus on the biological pathway that results from the application of a stressor. An AOP structures existing information pertaining to the study, identifies gaps in information, aids in the design of integrated testing strategies to generate new information and supports weight-of-evidence analysis. These characteristics will make AOPs more and more valuable in the study of cancer pathophysiology and in the drive for new drug discovery and development.
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