DNA methylation as a therapeutic target in RB1 deficient and neuroendocrine prostate cancer and rational co-targeting with B7-H3 [RNA-Seq 1]

Aberrant DNA methylation has been implicated as a key driver of prostate cancer lineage plasticity and histologic transformation to neuroendocrine prostate cancer (NEPC). DNA methyltransferases (DNMT) are highly expressed, and global DNA methylation levels are elevated in NEPC. We identified that deletion of DNMT genes decreases expression of neuroendocrine lineage markers and markedly reduced NEPC tumor development and metastasis in vivo. Decitabine, a global DNMT inhibitor, significantly attenuated tumor growth in NEPC patient-derived xenograft (PDX) models, as well as RB1-deficient castration-resistant prostate adenocarcinoma (CRPC) models compared with RB1-proficient CRPC. We further discovered that DNMT inhibition increased expression of B7-H3, an emerging druggable target, via demethylation of B7-H3 CpG islands. We tested DS-7300a, a novel antibody-drug conjugate (ADC) targeting B7-H3, alone and in combination with decitabine. There was potent single agent antitumor activity of DS-7300a in both CRPC and NEPC models bearing high expression of B7-H3. In B7-H3 low models, combination therapy of decitabine plus DS-7300a resulted in a synergistic response. Overall, we report that DNMT inhibition is a novel therapeutic target for NEPC and RB1-deficient CRPC and may sensitize B7-H3-low prostate cancer to the ADC DS-7300a through increasing target expression. NEPC and RB1-deficient CRPC represent prostate cancer subgroups with poor prognosis. The development of novel biomarker-driven therapeutic strategies for this population may ultimately help improve patient outcomes.