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2021 Republic National Distributing Company-PCF Young Investigator Award

Delineating Clonal Evolution of Resistance to Androgen Deprivation Therapy and Metastasis in Newly Diagnosed Early Metastatic Prostate Cancer

Yuehui Zhao, PhD
The University of Texas MD Anderson Cancer Center

Mentors: Nicholas Navin, PhD, Amado Zurita, MD

Description:

  • In contrast to most solid malignancies which evolve from a single cell, primary prostate cancer can evolve from multiple independent normal cells in the prostate. The evolution of multiple tumor lineages may lead to distinct clones with diverse malignant traits and result in multi-clonal seeding events to metastatic sites.
  • A greater understanding of how multifocal prostate cancer and different prostate cancer clones contribute to therapeutic resistance and metastasis is needed to improve the outcomes of metastatic prostate cancer patients. Additionally, identifying new clinical markers is essential for stratifying patients to improve treatment strategies.
  • Dr. Yuehui Zhao is using novel genomic technologies to study tumor evolution and metastasis.
  • In this project, Dr. Zhao will use novel single cell DNA and RNA sequencing technologies combined with spatial transcriptomics, to reconstruct the tumor subclonal structure and characterize the tumor microenvironment in a primary and metastatic prostate tumor, and resolve how the tumor evolved. These data will be used to develop a machine learning-based method to investigate the spatial distribution of tumor subclones.
  • How clonal evolution may contribute to the development of resistance to androgen deprivation therapy (ADT) as well as biomarkers of response to ADT will be identified. The mechanisms by which metastatic sites can be seeded by different tumor clones will be investigated.
  • If successful, this project will provide new insights into how different tumor clones evolve, drive disease progression, adapt to the metastatic niche, and promote treatment resistance.

What this means to patients: To better understand metastasis in prostate cancer and develop more effective new treatments, it is necessary to trace tumor evolutionary trajectories and identify genomic drivers of metastasis. Dr. Zhao will use single-cell multi-omics approaches to resolve tumor heterogeneity and evolution and identify mechanisms of metastasis and treatment resistance. These understandings will accelerate the identification of new biomarkers and treatments for prostate cancer.