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Targeting treatment induced relapse for patients with aggressive prostate cancers

Nearly 20% of advanced prostate cancer patients relapse on potent androgen receptor (AR) targeted therapies with a highly aggressive disease called treatment induced neuroendocrine prostate cancer (NEPC).

In NEPC, cancer cells commit what Dr. Amina Zoubeidi, professor and Canada Research Chair in Cancer Therapy Resistance at the University of British Columbia, calls “an identity shift” where cancer cells adapt and escape treatment.  In scientific terms it’s called “lineage plasticity.” For patients with this cancer, chemotherapy is the only treatment and survival is measured in months.  

A six-year, $6-million renewal award in the form of a Terry Fox New Frontiers Program Project Grant will help them to tackle the problem, says Dr. Zoubeidi, the new PPG project leader.

“The problem with the current paradigm of targeted prostate cancer therapy is that treatments fail to target tumour cell plasticity. Even worse, these therapies can trigger the emergence of highly plastic phenotypes that are responsible for the most dynamic and lethal aspects of advanced prostate cancer,” she explains.

A former holder of a Terry Fox New Investigator Award, the renewal grant means a lot to Dr. Zoubeidi and her team at the Vancouver Prostate Centre. The 2022 PPG is Dr. Zoubeidi’s first as project leader for the group; the team received numerous multiple renewals previously under longtime project leader Dr. Martin Gleave.

The current objective of the PPG team is to use the renewed funding to uncover how prostate cancer cells evade contemporary therapies, reveal dependencies and implement new strategies to target these dependencies clinically.  To do so, they’ll use their state-of-art core facility containing patient samples used in previous clinical trials as well as liquid biopsies in ctDNA repositories of more than 4,000 relevant blood samples collected from patients with metastatic prostate cancer across Canada.

Under previous PPG funding, the prostate team focused on developing new and innovative strategies to understand the molecular mechanisms that drive treatment resistance in prostate cancer patients, initiated four clinical trials, and established treatment frameworks specifically targeting emergent vulnerabilities.

Under the team’s four new projects, they will:  

  • define adaptive pathway activation after acute AR pathway inhibition (ARPI) in genomically-segmented castrate-naive PCa, and clinically evaluate
    effects of an EZH2 inhibitor in neo-adjuvant setting
  • investigate how distinct treatment strategies influence genomic evolution in metastatic PCa and define the proportion of patients that show evidence of AR- negative/low PCa using nucleosome footprints in ctDNA
  • uncover metabolic and epigenetic dependencies in an ASCL1-high segmented population and decipher how metabolic changes function to shape the epigenome and promote NEPC; and
  • investigate the early signals that reshape the translatomic, transcriptomic and epigenomic landscapes to prime cells for lineage plasticity.

In addition to improving patient outcomes, Dr. Zoubeidi is personally driven by the legacy of Terry Fox, and its transcendent effects on individual lives, community, and future scientists. “This is very important to me and I can see how Terry Fox (through its funded programs) has, in general, invested in human capital. The funding shaped not only the landscape for cancer research in general, but also for the scientists at BC Cancer, and in Canada, and we [now] have a lifeline of people who are part of this legacy.”

The team will also continue to mentor new investigators, following in the new project leader’s own footsteps. “I am an example of a young investigator who worked on a Terry Fox-funded project in 2006. I became a young independent investigator, a co-investigator, a lead investigator, and now I am the principal investigator for the whole program. The mentoring that we do in our program now continues the legacy forward into future generations of scientists. Terry Fox played an important role in my career. It means a lot to receive this grant and do this work.”