Targeting SUMOylation with TAK-981 in BRAF-mutant melanoma: Therapeutic relevance for brain metastases
Melanoma is an aggressive malignancy characterized by a high frequency of BRAF mutation, which drive oncogenic signaling and contribute to therapeutic resistance. Despite advances in targeted and immunotherapies, disease progression remains common, particularly in patients who develop brain metastases, a major cause of morbidity and mortality. Emerging evidence suggests that SUMOylation, a post translational modification regulating protein stability, stress responses, and transcriptional activity, plays an important role in tumor progression and adaptation to therapeutic pressure. Therefore, targeting SUMOylation represents a promising therapeutic strategy. TAK-981 is a selective small-molecule inhibitor of the SUMO activating enzyme that has demonstrated anti-tumor and immunomodulatory effects in preclinical models. However, its role in BRAF-mutant melanoma, especially in the context of brain metastatic disease, remains insufficiently explored.
In this project, we aim to investigate the therapeutic potential of TAK-981 in BRAF-mutant melanoma models by evaluating its effects on tumor cell proliferation, oncogenic signaling pathways, and stress-response mechanisms, with exploratory relevance to brain metastasis biology. Understanding the impact of SUMOylation inhibition may provide new insights into resistance mechanisms and support the development of novel therapeutic strategies for advanced melanoma.
Key words:
Melanoma, BRAF, SUMOylation, TAK-981, Brain metastases
Development and Evaluation of Biomaterial Scaffolds for Cardiac Regeneration and Repair
Ischemic heart disease is the leading cause of death and is responsible for approximately one third of deaths in the developed countries; >64 million people are living with heart failure. Myocardial infarction (MI) leads to the rapid loss of cardiomyocytes (CMs), adverse cardiac remodelling, weakened mechanical properties, and scar tissue formation. Unlike neonatal heart, postnatal heart exhibits negligible regeneration ability partly due to altered mitochondrial energy metabolism and cell-cycle arrest, Strategies aimed at ameliorating the lost function of CMs and orchestrating endogenous regeneration may help alleviate MI dysfunction and promote cardiac health. Biomaterials can offer an intriguing avenue to alleviate cardiac dysfunction, and they can additionally offer an invaluable platform to incorporate bioactive molecules.
An overarching objective of my research is to design and develop biomaterial scaffolds which can leverage a conducive environment to promote in situ cardiac regeneration and repair. We aim to utilise biomaterial scaffolds to promote the processes linked to cardiac regeneration and repair, including regeneration-promoting processes in different cell types central to the cardiac tissue repair.
I will utilize biomaterials to develop an artificial extracellular matrix (a-ECM) through micro/nanofabrication techniques and demonstrate the ability of a-ECM for cardiac regeneration and repair. Human pluripotent stem cell (hPSC)-derived CMs and endothelial cells (ECs-) will be used for the preliminary cell culture studies in vitro, while both natural and synthetic biomaterials will be used as material components to obtain user-tailorable a-ECM.
I will first screen for the effect of modular bioactive molecules to promote angiogenic network formation of ECs in vitro. Thereafter, I will further elucidate the effect of these bioactive cues to enhance CMs self-renewal (proliferation) and cardiac regeneration. If we find a promising approach to enhance ECs angiogenesis or CMs self-renewal (proliferation) in vitro, we will potentially delineate their assessment in a myocardial infarction (MI) model in rats in vivo. This intelligent yet smart a-ECM-based platform may have broad implications for cardiovascular tissue repair and potentially drug development for therapeutic gains in cardiac health.