Potential Clinical Applications Explained for Students (Easy Guide)

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Original Question

Potential Clinical Applications of Targeting CDCP1 in Cancer CDCP1 is expressed by the epithelium of a limited number of normal tissues, including prostate, breast, lung, colon, and endome- trium (22, 63, 64) and while its normal function is unknown, several findings suggest that toxicities associated with its detection and/or therapeutic disruption in patients with cancer will be clinically man- ageable. A key finding is that CDCP1 knockout mice develop and reproduce normally, indicating that its functions are not essential for normal physiology (65). Also, immunization of immune-competent mice with mouse CDCP1 peptides triggered antitumor immunity against primary and metastatic tumors of a mouse breast cancer cell line without overt toxicity, indicating that therapeutic disruption of CDCP1 will likely have a manageable adverse event profile (45). In addition, the marked upregulation of CDCP1 expression in a range of cancers, compared with the corresponding normal tissues, suggests that a therapeutic window will be achievable for CDCP1-targeted agents. The data suggest the exciting possibility that targeting CDCP1 for certain cancers will be as important as the clinically established receptor targets HER2, nectin 4, TROP-2, and PSMA, and emerging candidates such as HER3 and folate receptor a (66, 67). Importantly, based on its roles and elevated expression in a variety of malignant settings, employing CDCP1 as a biomarker or a treatment target could be beneficial for a significant number of patients with cancer. Figure 2 summarizes potential applications of targeting CDCP1 and CDCP1- mediated signaling in cancer, including as a biomarker, a direct target for therapeutic intervention, as well as a target for tumor delivery of agents to detect and treat cancer. CDCP1 as a potential cancer biomarker Reports indicating that CDCP1 can be detected at elevated levels in the serum of patients with colorectal (43) and gastric (68) cancer and urine of patients with prostate cancer, and on the surface of circulating Figure 2. Potential applications of CDCP1 in cancer. A, CDCP1 as a cancer biomarker. 1. Measurement of CDCP1-ATF levels in patient body fluids as a potential biomarker for diagnosis and prognosis and to monitor response to treatment or relapse. The graph is adapted with permission from Chen and colleagues (43). 2. Measurement of CDCP1 expression levels in patient tumors for cancer diagnosis or prognosis. The survival curve is adapted with permission from He and colleagues (9). B, CDCP1 as a target for delivery of PET radiotracers for cancer imaging. To date, anti-CDCP1 antibodies have been used to deliver the radionuclide 89Zr for PET-CT-based detection of xenograft tumors in mice. The PET-CT image is adapted with permission from Kryza and colleagues (14). White arrow, orthotopic pancreatic ductal adenocarcinoma xenograft detected using 89Zr chemically linked to anti-CDCP1 antibody 10D7. DFO, desferrioxamine; DOTA, 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; 225Ac, actinium-225. C, Disruption of cancer by targeting CDCP1 and CDCP1-mediated signaling. 1. Inhibition of proteases that cleave and activate CDCP1 using a chlorinated analogue of kempopeptin B. 2.Disruption of CDCP1 signaling via PKCd using the low molecular weight glycoconjugated palladium compound, Pd-Oqn. 3.Antibodies disrupting CDCP1 cell surface expression and downstream signaling.D, CDCP1 as a target for delivery of cytotoxic agents for cancer treatment. Anti-CDCP1 antibodies have been used to deliver cytotoxic payloads, such as Saporin, MMAE, and 177Lu, for treatment of preclinical models of cancer. Receptor-mediated internalization of the bound antibody following lysosomal-mediated release of the payload and apoptosis results in significant reductions in tumor burden and increased survival of mouse models of cancer. The graph is adapted with permission from Kryza and colleagues (14). The CDCP1 Signaling Hub AACRJournals.org Cancer Res; 81(9) May 1, 2021 2265Downloaded from http://aacrjournals.org/cancerres/article-pdf/81/9/2259/3094450/2259.pdf by guest on 11 June 2022 leukemic cells (16, 17), suggest that it may be suitable as a cancer biomarker as summarized in Fig. 2A. Proteolytic cleavage at the cell surface generates CDCP1-ATF that can remain tethered to the cell surface or released into the extracellular space (14, 34) and detectable in human serum with levels elevated in several cancers (Fig. 2A). An example is colorectal cancer where CDCP1-ATF levels are significantly higher in stage II- IV patients, suggesting that it could be used to distinguish early- stage cases or monitor response to treatment or relapse (43). Also, as part of a panel of 19 proteins from patient serum, elevated CDCP1 distinguishes earlier stage from later-stage gastric cancers and the panel may be useful for identifying patients suitable for curative intent surgery (68). Mass spectrometry analysis of proteins enriched from urine of patients with prostate cancer revealed markedly higher levels of CDCP1 in cases at high risk of treatment failure, defined as those with serum PSA > 20 ng/mL, Gleason score 8 to 10, or clinical stage T2c-3a, suggesting that elevated CDCP1 could be used to identify patients requiring closer monitoring and/ or more aggressive treatment (69). In addition to CDCP1-ATF present in patient body fluids, cell expressed CDCP1 may be useful as a biomarker for leukemia. Flow cytometry analysis detected cell surface CDCP1 in acute myeloid leukemia, acute lymphoid leukemia, and chronic myeloid leukemia in blast crisis but not normal circulating immune cells (17). In the leukemic patient cohorts, elevated CDCP1 levels correlated inversely with overall survival in patients receiving anthracycline-based induc- tion therapy or best available alternative therapy, suggesting its use as a negative prognostic marker for these treatments (17). Transcriptomic profiling and IHC analysis are well established for detection of CDCP1 mRNA and protein, respectively, in cancer (4-17). For many cancers, altered CDCP1 expression correlates with patient outcomes such as disease-free and overall survival (4-17) and it is possible that the level of expression may be useful for diagnosis or prognosis of a range of these malignancies (Fig. 2A). Furthermore, with the development of CDCP1-targeted treatments, assays detecting the presence of CDCP1 mRNA or protein in biopsies, resected tumors or circulating tumor cells would be useful for prognosticating patient response to those agents. Also, as shown in Fig. 2B, recent preclinical studies have provided promising data that PET-CT imaging using CDCP1-targeted radiotracers could be effective at stratifying patients with cancer suitable for CDCP1-targeted therapies (14, 31, 49, 61). These preclinical studies have employed mAbs, which induce cellular internalization of CDCP1, to deliver the radionuclide zirconium-89 (89Zr) for PET-CT-based detection of subcutaneous and orthotopic tumors in mouse models of high-grade serous ovarian cancer, clear cell ovarian carcinoma, and pancreatic ductal adenocarcinoma demonstrating impressive sensitivity to detect low-burden disease in particular for clear cell ovarian carcinoma (14, 31, 49, 61). As discussed below, in two of these studies, PET-CT imaging has been coupled to a treatment arm to therapeutically target CDCP1-positive lesions, following a theranostic paradigm, with the antigen-targeting antibody linked to a cytotoxic payload such as has been successfully translated clinically for the receptor PSMA for detection and treatment of advanced prostate cancer (49, 61). Emerging CDCP1-targeted treatment approaches Two approaches have to date been employed to target CDCP1 in cancer: function-blocking approaches that seek to disrupt CDCP1- signaling nodes, and theranostic approaches that exploit tumor- enriched expression of the receptor. As shown in Fig. 2C, several low molecular weight compounds that disrupt CDCP1 molecular interactions have been tested in preclinical models of cancer. Kempopeptin C, a chlorinated analogue of kempopeptin B, isolated from a marine cyanobacterium, that inhibits the CDCP1-cleaving proteases trypsin, plasmin, and matriptase, was effective at reducing proteolysis of CDCP1 and migration of the breast cancer cell line MDA-MB-231 in vitro (49, 70). Also, a low molecular weight glycoconjugated palladium compound, Pd-Oqn, that inhibits inter- actions between PKCd and tyrosine phosphorylated CDCP1, reduces proliferation, colony formation and invasion in vitro, and peritoneal dissemination and orthotopic tumor growth of 44As3 gastric adenocarcinomas and MiaPaCa-2 pancreatic adenocarcino- ma cells in vivo (71). Also, anti-CDCP1 antibodies that disrupt CDCP1 cell surface expression and downstream signaling have achieved significant slowing of tumor growth in intraperitoneal mouse models of high-grade serous ovarian cancer (8), subcutane- ous xenografts of lung cancer H322M, and breast cancer KPL4 and MDA-MB231 cells in mice (72). While anti-CDCP1 antibodies have slowed progression of preclin- ical models of cancer, significantly more promising effects have been achieved through employment of these biomolecules as theranostic agents for delivery target of cytotoxic payloads to cancer, as shown in Fig. 2D. An internalizing human/mouse chimeric anti-CDCP1 antibody, 25A11, conjugated to the ribosomal-inactivating toxin saporin inhibited subcutaneous growth and lymph node metastases of prostate cancer PC3 cells (63). Also, immunoliposomes incorpo- rating the antibody-binding fragment of anti-CDCP1 mAb CUB4 linked with liposomes loaded with doxorubicin, blocked the emer- gence in vitro and in mice of androgen-deprivation-independent prostate cancer LNCAP cells when combined with the androgen- deprivation therapy enzalutamide (12). In addition, a single treatment with the high-affinity internalizing mouse anti-CDCP1 mAb 10D7 conjugated to the tubulin polymerization inhibitor monomethyl aur- istatin E (MMAE) was effective at causing marked regression of intraperitoneal mouse xenografts of HEY high-grade serous ovarian cancer cells and significantly improving survival of the mice (49). CDCP1 expression in xenografts was first confirmed by PET-CT imaging using zirconium-89-labelled 10D7 (49). A single treatment with the same 10D7-MMAE antibody-drug conjugate also blocked growth of patient-derived pancreatic cancer cells grown subcutane- ously in mice. This treatment was significantly more effective than four treatments with the standard-of-care chemotherapy gemcitabine at blocking tumor growth and improving survival of xenografted mice (14). Importantly, the pancreatic cancer study revealed that proteolytic cleavage of CDCP1 does not interfere with antibody- mediated delivery of radionuclides or cytotoxins to cancer in vivo (14). Another more recent preclinical pancreatic cancer study also reported efficacy of another anti-CDCP1 antibody, 4A06, con- jugated with cytotoxic lutetium-177 against subcutaneous xenografts of the HPAC cell line (61). This antibody was also effective at delivering 89Zr for PET-CT imaging of this preclinical model (61). While promising results against preclinical models of cancer have been achieved with CDCP1-directed antibodies (14, 49, 61, 63), some cancer settings may require the use of high-affinity peptides for theranostic targeting of CDCP1, analogous to peptide-based agents for detection and treatment of advanced prostate cancer that target the receptor PSMA (67). It is important to note that implementation of the theranostic approach requires enrichment of the target on the surface of malignant Khan et al. 2266 Cancer Res; 81(9) May 1, 2021 CANCER RESEARCH Downloaded from http://aacrjournals.org/cancerres/article-pdf/81/9/2259/3094450/2259.pdf by guest on 11 June 2022 cells and the kinetics of internalization of the theranostic agent. Because it is independent of the role of the receptor in cancer, questions about the role of CDCP1 as an oncogene or tumor suppressor in particular cancers are less relevant. A critical issue is whether an approach is available to select patients who could benefit from treatment with a theranostic against a cancer-enriched receptor such

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