Small-cell neuroendocrine prostate cancer (SCNPC) is an aggressive variant form of prostate cancer that is resistant to androgen receptor(AR)-directed targeted therapies. SCNPC has molecular and morphological features in common with other aggressive small-cell tumors such as small-cell lung cancer (SCLC) and Merkel cell carcinoma (MCC). We recently conducted a pan-cancer transcriptomic analysis to identify “druggable” targets that display conserved expression patterns across small-cell tumors. Using this method, we identified and subsequently determined that BCL2 inhibitors (BCL2i) are lethal in SCNPC cell lines and repress the growth of a subset of SCNPC patient-derived xenograft models (PDXs). In this study, we profile the expression of an additional candidate target identified by this method, L1CAM.
We compiled transcriptomic data from prostate cancer metastases (including SCNPC and AR-pathway driven tumors), SCLC and MCC metastases. We identified druggable targets similarly expressed amongst small-cell tumors using differential expression analysis. We then profiled RNA and protein expression of individual candidates in a panel of cell lines and prostate cancer PDX models.
We identified 875 genes previously determined to contain druggable features as commonly expressed across SCNPC, SCLC, and MCC. L1CAM is amongst these genes and is highly expressed across all small-cell tumors profiled. L1CAM is also positively correlated with a 10-gene neuroendocrine signature across small-cell tumors and PDX models. L1CAM protein levels are elevated in small-cell tumor cell lines and SCNPC PDX models compared to non-neuroendocrine prostate models. L1CAM protein in small-cell cell lines and PDX models can be detected by the CE7 epitope. Initial co-culture experiments with prostate lines and the L1CAM-CE7R-BBζ chimeric antigen receptor (CAR) T cells demonstrate IFNˠ release in the presence of SCNPC cell lines.
We identify L1CAM as highly expressed in SCNPC patient metastases, cell lines, and PDX models. A CAR targeting L1CAM is currently under investigation for the treatment of another neuroendocrine tumor type, neuroblastoma. Here we provide evidence for the pre-clinical assessment of the L1CAM-CE7R CAR in SCNPC.
The authors.
PNW SPORE: CA097186, W81XWH-18-1-0347, PC170350P1, Prostate Cancer Foundation and Kelsey Dickson Challenge Award, Movember Foundation/Prostate Cancer Foundation Challenge Award, Department of Defense Prostate Cancer Research Program Physician Research Award PC160018, Ford Foundation Dissertation Fellowship, Chromosome Metabolism and Cancer Training Grant 2T32CA009657.
P.S. Nelson: Advisory/Consultancy, employee/paid consultant: Astellas; Advisory/Consultancy, employee/paid consultant: Janssen. All other authors have declared no conflicts of interest.