Synergistic Ferroptosis Induction to Maximize DS-7300a Efficacy in TP53-Deficient Prostate Cancer

Javier Leo (Advisor: Di Zhao, PhD)

The tumor suppressor TP53 plays a central role in regulating cell cycle progression, apoptosis, and the cellular response to DNA damage. Genetic alterations or deletions of TP53 occur in more than half of all human cancers and are associated with increased metastatic potential and poor clinical outcomes. Besides this, prostate cancer is the most diagnosed malignancy and the second leading cause of cancer-related death among men in the United States. Although most patients initially respond to androgen deprivation therapy (ADT), many eventually progress to castration-resistant prostate cancer (CRPC). In conjunction with PTEN and RB1, TP53 alterations define a clinically and biologically distinct subset of androgen-indifferent prostate tumors, collectively referred to as aggressive variant prostate cancers (AVPCs). Treatment options for advanced prostate cancers harboring TP53 defects remain limited, underscoring the urgent need for novel therapeutic strategies. Loss of TP53 function can lead to the accumulation of DNA damage due to impaired regulation of cell-cycle arrest, apoptosis, and senescence. Given that TP53 alterations occur in approximately 60% of prostate cancer cases, therapies that exploit this molecular vulnerability are of significant clinical interest.

To address this unmet need, we evaluated DS-7300a, a next-generation B7-H3–targeting antibody–drug conjugate (ADC), for the treatment of TP53-deficient prostate cancer. DS-7300a has demonstrated clinical activity across multiple refractory malignancies, including metastatic CRPC. Our findings indicate that the anti-tumor efficacy of DS-7300a is highly dependent on functional p53 in prostate cancer cells. Mechanistically, the topoisomerase I inhibitor payload (DXd) induces single-stranded DNA breaks and activates the ATM/ATR/CHK signaling cascade, leading to p53 stabilization and transcriptional activation of pro-apoptotic and senescence-associated genes. In contrast, TP53-deficient cells fail to adequately sense DXd-induced DNA damage, maintain unchecked proliferation, and exhibit intrinsic resistance to both DXd and DS-7300a.

Notably, TP53 loss also enhances the expression of glutathione peroxidase 4 (GPX4), an antioxidant enzyme that mitigates lipid peroxidation, and this effect is further amplified upon DS-7300a treatment. We demonstrate that pharmacological inhibition of GPX4 synergizes with DS-7300a to suppress tumor growth in TP53-deficient models, including syngeneic immunodeficient mice and a novel humanized B7-H3 C57BL/6 mouse model. Collectively, our results suggest that inducing ferroptosis is a promising therapeutic approach to overcome resistance to DXd-based ADCs in malignancies harboring TP53 defects.

Advisory Committee:

• Di Zhao, PhD, Chair
• Kendra Carmon, PhD
• Eleonora Dondossola, PhD
• Daniel Frigo, PhD
• Sangeeta Goswami, MD

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