Delta-like Protein 3 Is a Target in Neuroendocrine Prostate Cancer

A subset of castration-resistant prostate cancers (CRPC) evades androgen receptor (AR)–targeted therapies by circumventing AR signaling dependencies or acquiring neuroendocrine (NE) features. Castration-resistant small cell neuroendocrine prostate cancer (CRPC-NE) is clinically aggressive and refractory to standard prostate cancer therapies, and it exhibits molecular features similar to small cell lung cancer. Preclinical studies in small cell lung cancer and neuroendocrine carcinoma utilized the antibody–drug conjugate SC16LD6.5 (rovalpituzumab tesirine), which targets the Notch pathway signaling protein delta-like protein 3 (DLL3), to achieve complete and durable eradication of tumors. Given the similarities between CRPC-NE and SCLC, Puca and colleagues assessed the expression of DLL3 and potential efficacy of SC16LD6.5 in neuroendocrine prostate cancer. Although no DLL3 expression was detected in benign and localized prostate cancers, the majority of CRPC-NE and a small percentage of CRPC adenocarcinoma expressed DLL3, and expression was associated with RB1 loss and poor overall survival. DLL3 expression correlated with the neuroendocrine markers SYP, chromogranin A, and ASCL1 as well as Notch signaling genes. In patients with CRPC-NE, DLL3 expression was lower in primary tumors than in circulating tumor cells and in tumors from multiple sites of metastasis. Treatment of DLL3-expressing CRPC-NE xenografts with SC16LD6.5 resulted in complete responses by 35 days after treatment, whereas xenografts with low DLL3 expression failed to respond to therapy. In a patient with DLL3-expressing CRPC-NE enrolled in a phase I basket trial of SC16LD6.5 for DLL3-expressing advanced solid tumors, treatment with SC16LD6.5 induced significant reductions of target nodal metastases, complete and partial responses of nontarget lesions, and no disease progression after 2 cycles of therapy. Collectively, these data highlight DLL3 as a marker for aggressive clinical features including neuroendocrine morphology and poor survival. Furthermore, they demonstrate the therapeutic potential of targeting DLL3 in patients with advanced DLL3-positive CRPC-NE, providing a possible alternative to conventional chemotherapy in the treatment of recurrent disease.

Puca L, Gavyert K, Sailer V, Conteduca V, Dardenne E, Sigouros M, et al. Delta-like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer. Sci Transl Med 2019;11:eaav0891.

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