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2023 Alison and Jim Casey – PCF Young Investigator Award

Rational Antibody-Drug Conjugate (ADC) Combinations for Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Galina Semenova, MD, PhD
Fred Hutchinson Cancer Center

Mentors: John Lee, Peter Nelson

Description:

  • Antibody-Drug Conjugates (ADC) are a class of treatments that consist of cancer antigen-targeting antibody attached to a cytotoxic drug (payload) via a chemical linker.
  • While single agent ADC therapies are established treatments for several tumor types, none have been approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Challenges associated with ADC therapy in mCRPC include tumor heterogeneity, treatment resistance, and toxicity.
  • Dr. Galina Semenova and team have found that these challenges can be addressed by co-targeting multiple mCRPC cell surface antigens and using complementary payload combinations.
  • In this project, Dr. Semenova and team will rationally design combinatorial ADC therapies for CRPC.
  • To identify which tumor targets may be optimally co-targeted, the landscape of tumor antigen expression in lethal mCRPC specimens will be characterized. Antigen pairs that are present in different prostate cancer subsets but are not expressed together in normal tissues will be prioritized for subsequent therapeutic development.
  • ADCs against prostate cancer antigen pairs such as PSMA and CEACAM5 will be evaluated as single agents and together in heterogeneous mCRPC models.
  • ADCs bearing different classes of payloads will be tested in combinations to identify those that achieve synergistic cytotoxicity in a variety of prostate cancer models, without increasing side effects. The mechanisms of drug synergy will be investigated, and molecular markers of response will be determined.
  • If successful, this project will result in the development of rationally designed ADC combination treatments that target multiple tumor antigens and carry different payloads, setting the stage for testing these in clinical trials.

What this means to patients: Prostate cancer commonly develops resistance to targeted therapies by losing expression of the therapeutic target. Dr. Semenova and team are developing an assortment of rationally designed combination ADC treatments that target multiple tumor antigens and deliver complementary payload combinations. This could lead to new treatment strategies for patients that have increased efficacy with reduced toxicity.