Authored by Tanya Keenan

Dr. Juric led an inspiring session about discovering therapeutic resistance with serial biopsies, rapid autopsies, and blood-based biomarkers. The key learning points he discussed are outlined below:

• Make it real by finding the reasons that make you excited and passionate.
• Don’t make yourself busy – make yourself effective.
• Precision oncology means having the right treatment for the right patient at the right time.
• PIK3CA is both a biomarker and a target.
  • It is not an oncogene or a tumor suppressor.
  • Instead, it acts as an amplifier. It is similar to a gas pedal in a car that requires a foot to push it to make a car go.
  • PTEN loss is also needed, and two PIK3CA mutations provide even more gas.
  • The important question to always ask is: what else is going on?
• Alpelisib alone did not have the same waterfall plot as BRAF inhibitors.
  • PI3K inhibition in ER-positive tumors led to increased ER.
  • Dual inhibition with an estrogen blocker, namely a SERD that inhibits ER and not just estrogen, was required for efficacy.
  • ORR as an endpoint does not matter as much in breast cancer. PFS and OS are much more important.
• Sequencing of therapies is so poorly studied but very important in drug development.
• Liquid biopsies are better at detecting acquired resistance and tumor heterogeneity than tissue biopsies.
• Rapid autopsies allow the combination of multiple tissue and blood biopsies that facilitate scientific discovery.
  • Align stakeholders and get funds by making yourself look bigger than you are.
    • Listing connections on a website will attract more people to work for your program.
    • All you need to start a program is a colleague.
  • Acquired PTEN loss mediates cross-resistance to both CDK4/6 inhibitors and PI3K-alpha inhibitors.
    • PTEN loss is a cross resistance marker indicating that second line therapy with alpelisib will likely not work.
    • Don’t study just resistance. Instead study cross-resistance, specifically why later lines of therapy work less effectively.
    • PTEN loss leads to AKT activation and p27 sequestration, resulting in increased CDK2 activity, which compensates for CKD4/6 inhibition.
      • CDK2 phosphorylates Rb to drive resistance.
      • Lose PTEN protein only without a DNA change, and RNA is still expressed in some.
      • CDK4/6 inhibitor, PI3K inhibitor, and SERD together lead to better responses.
• Think of yourself as faculty and not junior faculty, as the latter will limit what you think you can do.