CUB domain containing protein 1 (CDPC1) is a target for radioligand therapy in castration resistant prostate cancer

Zhao, N.; Trepka, k.; Wang, Y.-h.; Chopra, S.; Hooshdaran, N.; Kim, H.; Yang, J.; Zhuo, J.; Lim, S.; Leung, K. K.; Egusa, E.; Zhang, L. K.; Foye, A.; Chou, J.; Feng, F. Y.; Small, E. J.; Evans, M. J.; Wells, J. A.; Aggarwal, R.

doi:10.1101/2021.06.17.448569

bioRxiv · 10.1101/2021.06.17.448569

CUB domain containing protein 1 (CDPC1) is a target for radioligand therapy in castration resistant prostate cancer

Zhao, N.·Trepka, k.·Wang, Y.-h.·Chopra, S.·Hooshdaran, N.·Kim, H.·Yang, J.·Zhuo, J.·Lim, S.·Leung, K. K.·Egusa, E.·Zhang, L. K.·Foye, A.·Chou, J.·Feng, F. Y.·Small, E. J.·Evans, M. J.·Wells, J. A.·Aggarwal, R.

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Abstract

PurposeRadioligand therapy (RLT) is relatively unexplored in metastatic castration resistant prostate cancer (mCRPC), with much of the focus having been on bone seeking radionuclides and PSMA-directed RLT. Herein, we evaluated if CUB domain containing protein 1 (CDCP1) can be exploited to treat mCRPC with RLT, particularly for subsets like small cell neuroendocrine prostate cancer (SCNC) that would not be expected to respond to current options. Experimental DesignCDCP1 mRNA levels were evaluated in the RNA-seq data from 119 recent mCRPC biopsies. Protein expression was assessed in twelve SCNC and adenocarcinoma patient derived xenografts. Saturation binding assays were performed with 4A06, a recombinant human antibody that targets the CDCP1 ectodomain. The feasibility of imaging and treating mCRPC in vivo was tested with 89Zr-4A06 and 177Lu-4A06. ResultsCDCP1 mRNA expression was observed in over 90% of mCRPC biopsies, including SCNC and in adenocarcinoma with low FOLH1 (PSMA) levels. A modest anticorrelation was observed between CDCP1 and PTEN. Overall survival was not significantly different based on CDCP1 mRNA levels, regardless of PTEN status. Full length and/or cleaved CDCP1 was expressed in ten of twelve PDX samples. Bmax values of ~22,000 and ~6,200 fmol/mg were calculated for two human prostate cancer cell lines. Five prostate cancer models were readily detected in vivo with 89Zr-4A06. 177Lu-4A06 significantly suppressed the growth of DU145 tumors compared to control. ConclusionsThe antitumor data and the overexpression of CDCP1 reported herein provide the first evidence promoting CDCP1 directed RLT as a treatment strategy for mCRPC. Statement of Translational RelevanceNew targets for RLT are needed to address the subset of mCRPC that cannot be treated with bone seeking radionuclides or PSMA directed RLT. We report herein the first data credentialing CDCP1 as a target for mCRPC, in both adenocarcinoma and neuroendocrine subtypes. Combined with low expression in normal human tissues, these data provide a compelling scientific rationale for testing CDCP1 directed RLT clinically in mCRPC patients alone or in combination with other systemic therapies.

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Zhao, N., Trepka, k., Wang, Y.-h., Chopra, S., Hooshdaran, N., Kim, H., Yang, J., Zhuo, J., Lim, S., Leung, K. K., Egusa, E., Zhang, L. K., Foye, A., Chou, J., Feng, F. Y., Small, E. J., Evans, M. J., Wells, J. A., Aggarwal, R.. 2021-06-17. CUB domain containing protein 1 (CDPC1) is a target for radioligand therapy in castration resistant prostate cancer. https://doi.org/10.1101/2021.06.17.448569

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