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Molecular Evolution of Treatment-Resistant Prostate Cancer: Study

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Prostate cancer, a prevalent malignancy affecting the male population, often exhibits a disturbing tendency to become more aggressive and resistant to treatment over time. Among the various forms of prostate cancers, a particularly challenging subtype is the small cell neuroendocrine (SCN) cancer, characterized by its rapid growth and resistance to conventional therapies.

In a groundbreaking study led by Dr. Owen Witte and Thomas Graeber from the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, researchers have successfully documented the molecular steps that transform common prostate cancers into the elusive and treatment resistant SCN cancers. This unprecedented insight offers a promising avenue for developing targeted therapies to impede the evolution of these aggressive tumours. 

The research, published in Cancer Cell, marks a significant milestone in understanding the transformation process from typical prostate adenocarcinomas to SCN cancers. While SCN cancers constitute a minority of newly diagnosed prostate cancers, their prevalence increases among tumours that persist and proliferate after treatment. These tumours pose a formidable challenge due to their aggressive nature and resistance to standard treatments. 

Dr. Witte emphasizes the groundbreaking nature of this research, stating, “For the first time, we have a real opportunity to define the process that leads these very, very aggressive tumours.” The researchers utilized a unique model, implanting healthy human prostate cells into mice and manipulating them to progress from adenocarcinomas to SCN cancers. This model allowed the team to observe and analyze the genetic changes occurring at various stages of tumour development. 

Over a span of at least 10 weeks, biopsies were collected every two weeks, providing a comprehensive dataset for analyzing the molecular evolution of the tumours. Despite the numerous molecular distinctions between prostate adenocarcinomas and SCN cancers, the researchers identified only two major pathways through which the transformation occurred. Remarkably, the study also found that some lung cancers followed similar pathways to evolve into SCN cancers. 

Olga Chia-Chun Chen, the first author of the study and a graduate student at the UCLA Broad Stem Cell Research Center Training Program, highlighted the significance of tracking the progression from normal cells to aggressive cancers. This unique approach allowed the researchers to discern key molecular changes and identify the critical junctures in the evolution of SCN cancers. 

Thomas Graeber expressed his surprise at the findings, stating, “It was a real surprise that there were just two major pathways. And it gives us a lot of hope for therapeutics because it’s much easier to figure out how to block two paths than hundreds.” The identification of these specific pathways provides a tangible target for therapeutic interventions, offering hope for the development of drugs that can disrupt the evolution of SCN cancers. 

The researchers are now gearing up for future studies aimed at devising methods to block these identified evolutionary pathways. Importantly, several of the molecular changes critical for the evolution of SCN cancers are potential targets for drug intervention. Rather than tackling fully developed SCN cancers, the researchers envision a strategy where drugs could halt the progression of less aggressive subtypes, preventing the emergence of SCN cancers altogether. 

In essence, the study delivers a crucial message: the process of cancer becoming more aggressive is reproducible and predictable. Armed with this knowledge, the researchers are optimistic about the prospect of predicting and preventing the transformation of less aggressive cancers into highly malignant forms. The findings open up new possibilities for therapeutic strategies that could revolutionize the approach to managing and treating aggressive prostate and lung cancers. 

Journal Reference  

Chia-Chun Chen et al, Temporal evolution reveals bifurcated lineages in aggressive neuroendocrine small cell prostate cancer trans-differentiation, Cancer Cell (2023). DOI: 10.1016/j.ccell.2023.10.009. 

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