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2024 Lucy Shostak – PCF Young Investigator Award In Honor of Eliott Abramowitz, PhD

Investigation of a Novel NSD2 Inhibitor KTX-1001 in Targeting Lineage Plasticity and Treatment Resistance in NEPC and mCRPC Subtypes

Jia Li, PhD
Columbia University Medical Center

Mentors: Michael Shen, PhD; Charles Sawyers, MD

Description:

  • Treatment with highly potent anti-androgen receptor signaling inhibitors (ARSIs) promotes lineage plasticity in metastatic castration-resistant prostate cancer (mCRPC), which results in intra-tumor heterogeneity and emergence of mCRPC subtypes. These mCRPC have lost a dependency on lineage-survival signals, leading to targeted drug resistance. A typical example is the transformation from adenocarcinoma to neuroendocrine prostate cancer (NEPC). 
  • NEPC is a highly aggressive form of mCRPC, for which no effective therapies are available. NEPC arises through lineage plasticity, in which prostate cancer lose adenocarcinoma features and transform into histologically distinct tumors expressing neuroendocrine markers. Understanding the mechanisms of lineage plasticity and transition to NEPC is critical for identifying new therapeutic strategies.
  • Except for NEPC, there are other AR independent mCRPC subtypes do not exhibit neuroendocrine features, such as double negative prostate cancer.
  • Dr. Jia Li and team are studying the mechanisms of prostate cancer lineage plasticity. They have previously identified the epigenetic regulatory enzyme NSD2 as a key driver of NEPC and found that NSD2 inhibition have therapeutic potential for preventing or reversing NEPC.
  • In this project, Dr. Li will evaluate the anti-tumor activity and mechanisms of action of the NSD2 inhibitor KTX-1001, a clinical drug in phase I clinical trial (NCT05651932) to treat people with Multiple Myeloma, in models of NEPC and mCRPC subtypes.
  • The mechanisms by which NSD2 inhibitor KTX-1001 can reverse lineage plasticity in NEPC and mCRPC subtypes and reinstate sensitivity to androgen receptor-targeted therapy will be determined.
  • The mechanisms of synergy and synthetic lethality between KTX-1001 with anti-androgens will be identified.
  • Biomarkers will be developed to predict treatment response to KTX-1001 and identify patients with mCRPC who would respond to a treatment combination of KTX-1001 and anti-androgens.
  • If successful, this project will define mechanisms of lineage plasticity in NEPC and mCRPC, and determine the potential and biomarkers for the use of NSD2-inhibitors for the treatment of patients with lethal disease subtypes.

What this means to patients: Dr. Li and team have established NSD2 as a key driver and promising therapeutic target in NEPC and subtypes of mCRPC. This project will establish the mechanisms of action of NSD2 inhibitor, KTX-1001 in reversing lineage plasticity and ARSI-resistance in NEPC, AR-dependent and AR-independent mCRPC subtypes and define biomarkers that can identify patients who may benefit from treatment with NSD2-inhibitors, setting the stage for clinical trials testing this intervention.