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Overcoming Tazemetostat Resistance in Epithelioid Sarcoma and Rhabdoid Tumors: A Potential Breakthrough

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Medriva Correspondents
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Overcoming Tazemetostat Resistance in Epithelioid Sarcoma and Rhabdoid Tumors: A Potential Breakthrough

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In 2020, the FDA approved a targeted therapy named tazemetostat for certain patients with epithelioid sarcoma and rhabdoid tumors. Despite its initial success, the drug has not been effective in many patients carrying a mutation in the SMARCB1 gene, leading to the development of resistance. However, a promising breakthrough has been made in overcoming this resistance by a research team led by Dr. Alex Kentsis.

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Understanding the Mechanisms of Resistance

The team at Dr. Kentsis's lab identified the mechanisms that activate resistance to tazemetostat. The mutations in the SMARCB1 gene lead to an overactive EZH2 protein, causing cells to grow uncontrollably and become cancerous. After treatment with tazemetostat, another group of mutations emerged, creating further complications. However, understanding these mechanisms has been pivotal in developing a new therapeutic approach.

Combination Therapy: An Epigenetic Treatment Strategy

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With the understanding of the resistance mechanisms, the researchers designed a combination therapy that overcomes this resistance. This novel approach uses an epigenetic treatment strategy, which focuses on altering the expression of genes, rather than their sequence. This involves using tazemetostat in combination with an experimental drug named barasertib, which targets mutations in the relevant pathway.

Initial Success of the Combination Therapy

Initial testing of this combination therapy has shown promising results. In a lab setting, the researchers found that this approach could slow tumor growth in mice, indicating its potential effectiveness in human treatment. The research, reported in Cancer Discovery, brings renewed hope for patients resistant to tazemetostat.

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Future Research and Therapeutic Approaches

With the success of the combination therapy, the team is not stopping there. They are also exploring the possibility of combining tazemetostat with immune checkpoint inhibitors. This could potentially provide a more lasting therapeutic response, improving patient outcomes. Philanthropy plays a significant role in funding this ongoing research, highlighting the importance of continued support in the fight against cancer.

Role of Epigenetic Therapy and Degradation Technologies

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While the combination therapy shows promise, it's important to note that the field of epigenetic therapy is continuously evolving. The use of degradation technologies, such as proteolysis targeting chimeras (PROTACs), and lysosome-based strategies, is gaining prominence. These strategies aim to target and degrade the proteins involved in cancer development. The challenge lies in developing potent, selective, and drug-like epigenetic drugs for clinical applications. However, the potential of these strategies in cancer treatment is immense.

Conclusion

The approval of tazemetostat marked a milestone in the treatment of epithelioid sarcomas and rhabdoid tumors. Yet, the emergence of resistance has presented a significant challenge to its effectiveness. Thankfully, the work of Dr. Kentsis and his team in understanding these resistance mechanisms and developing a promising combination therapy offers renewed hope. As research and technology continue to advance, the future of cancer treatment looks bright.

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