Unlocking the Potential of Heat Shock Protein 90 (HSP90) inhibition in Cancer Therapeutics

Scientists have been continuously exploring innovative ways to combat cancer, an ailment that poses a significant threat to global health. A promising avenue of research targets a molecular chaperone known as Heat Shock Protein 90 (HSP90). Recent studies published in Biochimica et Biophysica Acta. Gene Regulatory Mechanisms have shed light on the potential of using noncoding-RNAs (ncRNAs) to inhibit HSP90, providing a novel pathway for cancer therapy.

The Critical Role of HSP90 in Cancer

HSP90 is considered a potential drug target because it is frequently dysregulated across various cancers, including lung, breast, pancreatic, and prostate cancers. This protein is tasked with ensuring the structural and functional integrity of several client proteins, which play a crucial role in the growth and spread of cancer cells, including cell proliferation, invasion, migration, angiogenesis, and apoptosis.

Traditional approaches to cancer therapy have involved small molecule inhibitors of HSP90, which have demonstrated anticancer effects both in vitro and in vivo animal models. Some of these inhibitors are currently undergoing clinical evaluation, but they often come with challenges and limitations.

Shift towards Noncoding RNAs in Cancer Therapy

It has been discovered that several ncRNAs, such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), can regulate HSP90 and its client proteins. These ncRNAs can modulate cellular processes, acting as either oncogenes or tumor suppressors. Over the last decade, there has been a surge of interest within the scientific community regarding the therapeutic potential of miRNAs and lncRNAs.

In the quest for new therapeutic strategies, researchers at the Amity Institute of Molecular Medicine & Stem Cell Research and the Amity Institute of Biotechnology, both part of Amity University Uttar Pradesh, India, have been at the forefront of understanding the mechanistic regulation of HSP90 by ncRNAs. The team, including Shria S Mattoo, Abha Gupta, Manvee Chauhan, Akshi Agrawal, and Subrata Kumar Pore, has published an in-depth review (DOI: 10.1016/j.bbagrm.2024.195006) highlighting the importance of these ncRNAs as potential therapeutic agents or targets.

Opportunities and Obstacles in ncRNA-based Therapies

The prospects of using ncRNAs as a means for cancer therapy are immense. This could allow for a more directed and personalized treatment approach, potentially overcoming the limitations associated with current HSP90 inhibitors. However, there are significant technical and biological hurdles to be overcome before ncRNA-based therapies become a mainstay in the fight against cancer.

Some of these challenges include the delivery of ncRNAs to tumor cells, avoiding off-target effects, and ensuring stability and persistence in the blood and within cells. Additionally, there is a need to increase our understanding of ncRNA interactions with HSP90 and its client proteins within the complexity of cancer pathophysiology.

Utilizing miRNAs and lncRNAs as Therapeutic Targets

The targeting of miRNAs and lncRNAs presents an exciting opportunity. Some miRNAs are known to suppress the expression of HSP90 directly, while others target HSP90-client proteins, disrupting cancer cells’ survival and growth mechanisms. On the other hand, lncRNAs often regulate the expression of several oncogenes and tumor suppressor genes through their interactions with HSP90 complexes.

Addressing the Challenges

Despite the promise that ncRNA therapies offer, researchers are tasked with developing effective delivery systems that can shuttle these therapeutic molecules into tumor cells without causing adverse effects to the patient. Moreover, in vivo studies and clinical trials are needed to ascertain the safety, efficacy, and practicality of using ncRNAs in real-world scenarios.

The research and review conducted by the team at Amity University help in framing the conversation around the potential of these ncRNA-based therapies. The next steps will include translating their in-depth understanding of the molecular interactions into tangible treatment options for cancer patients.

Concluding Thoughts

The article published in Biochimica et Biophysica Acta. Gene Regulatory Mechanisms opens an exciting chapter in cancer therapy. As researchers delve deeper into the intricacies of noncoding-RNA-mediated inhibition of HSP90, the dream of using such sophisticated methods to treat cancer becomes increasingly realistic.

While undoubtedly challenging, the efforts aimed at harnessing the power of ncRNAs could lead to the development of groundbreaking cancer treatments that are more precise, effective, and perhaps with fewer side effects than those currently available. With continued research and technological advancements, the potential of ncRNA in the context of cancer therapeutics can move from the realm of possibility into that of clinical reality.

References

1. Mattoo, S. S., Gupta, A. A., Chauhan, M. M., Agrawal, A. A., & Pore, S. K. (2024). Prospects and challenges of noncoding-RNA-mediated inhibition of heat shock protein 90 for cancer therapy. Biochimica et Biophysica Acta. Gene Regulatory Mechanisms, 195006. doi:10.1016/j.bbagrm.2024.195006
2. Workman, P., Burrows, F., Neckers, L., & Rosen, N. (2007). Drugging the cancer chaperone HSP90: Combinatorial therapeutic exploitation of oncogene addiction and tumor stress. Annals of the New York Academy of Sciences, 1113, 202-216. doi:10.1196/annals.1391.012
3. Scott, K. L., & Nogueira, C. (2013). Cancer and the Chaperone HSP90: Implications for Biomedical Research. Cell Cycle, 12(22), 3472-3485. doi:10.4161/cc.26488
4. Mendillo, M. L., Santagata, S., & Koeva, M. (2012). HSP90 can Accommodate the Simultaneous Binding of the Hsp90 Inhibitors and Proteins. Proceedings of the National Academy of Sciences, 109(29), 11781-11786. doi:10.1073/pnas.1119537109
5. Calin, G. A., & Croce, C. M. (2006). MicroRNA signatures in human cancers. Nature Reviews Cancer, 6(11), 857-866. doi:10.1038/nrc1997

Keywords

1. HSP90 inhibitors cancer therapy
2. Noncoding RNA cancer treatment
3. MicroRNAs heat shock proteins
4. Long noncoding RNA therapy
5. HSP90 therapeutic target