Reid Michalski

Background: Annually there were over 1.4 million new cases of prostate cancer and 375,000 related deaths worldwide.^1,2 When prostate cancers can’t be controlled with the first-line androgen depravation therapy, they are termed resistant prostate cancer (CRPC), which happens in about 3.4% of all prostate cancer.^1,2 Prostate specific membrane antigen (PSMA) is a transmembrane protein that increases up to 1000-fold in CRPC.² Accordingly, CRPC can be treated with radioligands of PSMA such as 177Lu-PSMA-617 that delivers fatal radiation to CPRC cells.^3,4  The problem is that 15-20 percent of CRPC patients lose PSMA expression, making PSMA targeted therapies ineffective.⁵ Neuroendocrine Prostate Cancer (NEPC) in particular tends to lose PSMA expression and is a rather aggressive cancer clinically.⁵

Objective: Because some CRPC patients develop resistance to radiolabeled PSMA ligand therapies, likely due to PSMA-negative lesions, more research is needed to determine what biomarkers predict success with such therapies.³ This study aims to find a biomarker that is effective in treating NE PSMA negative CRPC.

Search Methods: Data was sourced through PubMed searches including combinations of keywords “PSMA”, “Prostate Cancer”, “Castration Resistant”, “HoxB13” and “DLL3” and the timeframe is 2017-2025. Articles were then screened for relevance and reliability.

Results: HOXB13 is a key regulator of PSMA expression and synergizes with H3K27 (lysine 27 on histone H3) acetylation to regulate expression of PSMA.^5,6 H3K27 acetylation also affects the expression of other cellular markers such as DLL3. Further studies showed that  DLL3 is a specific and sensitive cell marker of neuroendocrine (NE) CRPCs and expressed in about 83% of  PSMA-negative NEPC tumors.⁷ A DLL3 targeting antibody used in small cell lung cancer treatment was then repurposed to target DLL3 in PSMA-negative NE-CRPC.⁸ 177Lu-labeled DLL3 antibody showed complete responses in all mice carrying NE-CRPC in a dose-dependent manner and with few side effects.⁹

Conclusion: DLL3 can serve as a biomarker that can be safely targeted for the treatment of PSMA negative NE CRPC. These results indicate human trials are warranted and future clinical application of this drug can provide lifesaving changes to the prognosis of NEPC patients. Research should continue to find novel sensitive and specific biomarkers of different tumors to further the reach of precision medicine.

Works Cited:

1. Ismuha RR, Ritawidya R, Daruwati I, Muchtaridi M. Future Prospect of Low-Molecular-Weight Prostate-Specific Membrane Antigen Radioisotopes Labeled as Theranostic Agents for Metastatic Castration-Resistant Prostate Cancer. Molecules. 2024;29(24):6062. Published 2024 Dec 23. doi:10.3390/molecules29246062
2. Patell K, Kurian M, Garcia JA, et al. Lutetium-177 PSMA for the treatment of metastatic castrate resistant prostate cancer: a systematic review. Expert Rev Anticancer Ther. 2023;23(7):731-744. doi:10.1080/14737140.2023.2213892
3. Kostos L, Buteau JP, Hofman MS, Azad AA. Determinants of outcome following PSMA-based radioligand therapy and mechanisms of resistance in patients with metastatic castration-resistant prostate cancer. Ther Adv Med Oncol. 2023;15:17588359231179309. Published 2023 Jun 6. doi:10.1177/17588359231179309
4. Zhou J, Wu R, Wang W, Zhao Y, Liu X. ⁶⁸Ga-PSMA PET/CT for the evaluation of metastasis in patients with prostate cancer: A systematic review and meta-analysis. Hell J Nucl Med. 2022;25(3):297-311. doi:10.1967/s002449912525
5. Bakht MK, Yamada Y, Ku SY, et al. Landscape of prostate-specific membrane antigen heterogeneity and regulation in AR-positive and AR-negative metastatic prostate cancer. Nat Cancer. 2023;4(5):699-715. doi:10.1038/s43018-023-00539-6
6. Nguyen DT, Yang W, Renganathan A, et al. Acetylated HOXB13 Regulated Super Enhancer Genes Define Therapeutic Vulnerabilities of Castration-Resistant Prostate Cancer. Clin Cancer Res. 2022;28(18):4131-4145. doi:10.1158/1078-0432.CCR-21-3603
7. Ajkunic A, Sayar E, Roudier MP, et al. Assessment of TROP2, CEACAM5 and DLL3 in metastatic prostate cancer: Expression landscape and molecular correlates. NPJ Precis Oncol. 2024;8(1):104. Published 2024 May 17. doi:10.1038/s41698-024-00599-6
8. Tully KM, Tendler S, Carter LM, et al. Radioimmunotherapy Targeting Delta-like Ligand 3 in Small Cell Lung Cancer Exhibits Antitumor Efficacy with Low Toxicity. Clin Cancer Res. 2022;28(7):1391-1401. doi:10.1158/1078-0432.CCR-21-1533
9. Korsen JA, Gutierrez JA, Tully KM, et al. Delta-like ligand 3-targeted radioimmunotherapy for neuroendocrine prostate cancer. Proc Natl Acad Sci U S A. 2022;119(27):e2203820119. doi:10.1073/pnas.2203820119