Tumor-Activated Dual Payload-Drug Conjugates

PROJECT SUMMARY/ABSTRACT
Targeting the hallmark biomarker prostate specific membrane antigen (PSMA) has been a successful small
molecule drug-delivery strategy for various payloads to prostate tumor cells, which is evident in the FDA's
recent approval of 177Lu-PSMA-617 and the clinical advancement of our 18F-CTT1057 (an irreversible-binding
phosphoramidate-based) PSMA-targeted PET-imaging agent (NCT04838626, NCT04838613). However,
efforts to develop PSMA-targeted chemotherapeutic nanomedicine have had limited clinical therapeutic
efficacy. Our long-term goal is to develop a versatile and intelligently designed platform for the selective
delivery of synergistic therapeutic payloads to offer novel treatment options for lengthening and improving the
quality of life for metastatic castration-resistant prostate cancer (mCRPC) patients. The overall objective of this
project is to develop a PSMA-targeted small-molecule dual drug conjugate (SMDDC) to serve as a companion
therapeutic to our PSMA-targeted PET-imaging agent (NCT02916537, NCT03427476). Our central hypothesis
is that tumor-site activation and release of two distinct chemotherapeutic payloads for prostate cancer can be
achieved and will be more effective than small molecule drug conjugates (SMDCs) releasing only a single
chemotherapeutic payload. The rationale for developing SMDDCs is to set the groundwork for a new, dual-
drug therapeutic strategy for patients with mCRPC and advanced malignancies with PSMA(+) neovasculature.
Two specific aims will be pursued to test the central hypothesis: 1) Assess the spatio-temporal cargo-release in
prostate tumor cells with a PSMA-targeted small-molecule dual probe conjugate (SMDPC); and 2) Determine
the potency enhancement of a SMDDC bearing dual payloads in prostate cancer cell lines. For Aim 1,
PSMA(+) and PSMA(-) prostate cancer cell lines will be used to assess the spatio-temporal cargo-release of a
PSMA-targeted SMDPC bearing two distinct turn-on probes, 7-Amino-4-methylcoumarin and hydroxymethyl
rhodamine green. Established PSMA activity assays will be used to determine the IC50 and mode of binding for
the PSMA-targeted SMDPC. In Aim 2, in vitro effectiveness of an SMDDC bearing both MMAE and Exatecan
vs. an SMDC bearing either MMAE or Exatecan alone will be evaluated in PSMA(+) and PSMA(-) prostate
cancer cell lines. The proposed work is innovative because it aims to utilize a unique combination of drug-
delivery strategies; PSMA-ligand promoted internalization, a novel acid-labile linker for pH-triggered drug
release, and two distinct chemotherapeutic drugs with differing mechanisms of action. This will be a significant
achievement because it will provide proof-of-concept for developing clinically relevant chemotherapy for
mCRPC and other malignancies with PSMA(+) neovasculature. Future plans include expanding the selection
of drug payloads for PSMA-targeted SMDDCs and initiate preclinical IND-enabling studies. The expected
positive impact of these studies is that they will, in all likelihood, set the foundation for a general, dual-drug
strategy for targeted chemotherapy for other biomarker-characterized diseases.

Grant Number: 1R21CA292338-01
NIH Institute/Center: NIH
Principal Investigator: Clifford Berkman