Targeting CUB domain containing protein 1 (CDCP1) with radioligands for the treatment of Metastatic Castration Resistant Prostate Cancer (mCRPC)

Introduction: As mCRPC is uniformly lethal, there is an urgent need to develop new therapies to cure this disease. We have previously demonstrated that the cell surface antigen CDCP1 is highly overexpressed in mCRPC, including PSMA-null disease and small cell neuroendocrine cancer. Moreover, we have shown that ⁸⁹Zr and ¹⁷⁷Lu-labeled antibodies targeting the ectodomain of CDCP1 can be used to image and treat models of mCRPC, including patient derived xenografts. We are now testing if (1) CDCP1 directed RLT combines with antiandrogen therapy to produce more durable tumor responses, (2) CDCP1 directed RLT using alpha emitters produce more durable responses compared to beta emitters, and (3) if SCNC is comparatively more sensitive to RLT than adenocarcinoma.

Methods: Mice bearing LTL-545 and C4-2B xenografts were treated with ²²⁵Ac-4A06 monotherapy. In vitro, flow cytometry was done in order to access the change in CDCP1 expression in cells which were treated with anti-androgen drugs. Currently, the relationship between acute androgen receptor inhibition with antagonists or siRNA and downstream modulation of CDCP1 expression is being studied (CDCP1 has been reported to be an androgen repressed gene). Additionally, androgen receptor positive cell line is being transfected in order to silence the AR gene to deduce if this silencing changes the CDCP1 expression. In vivo, mice bearing adenocarcinoma tumors are being treated with enzalutamide and ²²⁵Ac-4A06 in order to access the therapeutic benefits of combination therapy.

Results: Preliminary results suggest that acute androgen receptor inhibition or stimulation does not impact cell surface expression of CDCP1. ²²⁵Ac-4A06 proved to be a promising therapeutic in mice bearing LTL-545. On this basis, a combination treatment study is underway in castrate male nude mice bearing C4-2B tumors. More results will be presented.

Conclusions: Early data suggests CDCP1 directed RLT can be added to androgen receptor antagonists to augment anti-tumor effects. Moreover, ²²⁵Ac-4A06 may be a safe and effective therapeutic.

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