Chemoligand therapy for metastatic castration-resistant prostate cancer

<p>The disease of >70% of patients with metastatic castration-resistant prostate cancer (mCRPC) has moderate to high nonphysiological levels of a transmembrane protein known as prostate-specific membrane antigen (PSMA) and creates opportunities for precision medicine approaches. Using PSMA as a mechanism of disease selection, I conceptualized, designed, coordinated and contributed to the synthesis of, and tested a precision chemotherapy with on-demand nuclear properties. Conceptually, the strategy fused into a single drug the benefits of microtubule inhibition and theranostics, which are both standard of care in mCRPC. To achieve this, the design of the drug built on the general structure of chelator-containing glutamate-ureido-based radiopharmaceuticals for radioligand therapy. After screening taxanes, auristatins, and maytansinoids as candidates for drug development, I conjugated the next-generation microtubule inhibitor monomethyl auristatin E into glutamate-ureido-based small molecules via a multimodality chelator pioneered in our laboratory. Using a combination of radiopharmaceutical-guided drug development and molecular pharmacology <em>in vitro</em>, I discovered a chemoligand with high affinity to PSMA (<em>K</em>_d= 2.5 [1.5-3.9] nM) that disrupts the mitotic spindle, causes erratic mitosis, and induces cell and clonal death. Image-guided drug development using ⁶⁸Gallium-positron emission tomography contextualized the accumulation of the chemoligand in PSMA⁺C4-2 (7.1 ± 0.9 %ID/g) and 22R<em>v</em>1 (2.1 ± 0.3 %ID/g) tumors, but not PSMA^- PC-3 counterparts (0.2 ± 0.1 %ID/g), relative to its low nonspecific processes and rapid renal excretion. Without exceeding a specificity threshold dosage of 0.5 mg/kg qw x3 (empirically determined in PSMA^- PC-3 tumors), the chemoligand more than doubled the median survival (<em>P </em>= 0.04) of male mice bearing PSMA^highC4-2 tumors at a low cumulative dose (1.5 mg/kg). Using a dosage of 0.125 mg/kg qw x3 in castrated male mice bearing PSMA^low22R<em>v</em>1 tumors, the chemoligand caused tumor growth delay and improved the median survival (31 vs. 42 days, <em>P </em>= 0.009) in a manner that correlated with the observed reduction in Ki-67 proliferation index. I termed this therapeutic strategy as <em>chemoligand therapy</em>, a precision medicine that uses an advanced drug design for advanced theranostics.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2025

Authors dc:creator

• Hernandez Vargas, Servando
• <p>0000-0003-1614-7966</p>

Contributors dc:contributor

• Ali Azhdarinia, Ph.D.
• Kendra S. Carmon, Ph.D.
• Daniel E. Frigo, Ph.D.

• Chemoligand
• chemoligand therapy
• drug conjugate
• image-guided drug development
• mCRPC
• microtubule inhibition
• multimodality chelator
• theranostics
• PSMA
• radiopharmaceutical-guided drug design
• specificity threshold
• Oncology
• Pharmacology
• Therapeutics

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1492

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2549