BCAM Gene and Ovarian Cancer

Several therapeutic antibodies are approved for the treatment of specific cancers. Some of these antibodies target proteins essential for the malignant phenotype, such as Human epidermal growth factor receptor 2 (HER2); while others target proteins aberrantly expressed by tumor cells, such as Vascular endothelial growth factor (VEGF). More recently, antibodies, such as those that target Programmed cell death protein 1 (PD1), that modulate immune activity have exhibited dramatic responses in subsets of patients. Most efforts to identify new antigens for antibody-based therapies require prior knowledge of targets or arduous validation schemes.

HGSOC is the most common and deadly subtype of cancer of the ovaries, and the vast majority of women are diagnosed with advanced disease stage. The current standard of care is surgical debulking plus chemotherapy. Although standard therapy induces an initial response, tumors eventually recur, and 70% of patients die within 5 years of diagnosis. To achieve better results, new therapeutic targets are needed. The screen led to the identification of CADM1 and BCAM, two adhesion proteins that are highly expressed on the surface of HGSOC cell lines. Previous studies have demonstrated that CADM1 can act as tumor suppressor and is frequently inactivated by promoter hypermethylation in many solid tumors, including pancreatic, lung, melanoma, esophageal, and cervical cancer.

BCAM, first shown to be highly expressed on sickle RBCs, is overexpressed in a number of tumors, notably highest in HGSOC, while its expression appears relatively low in normal tissues, with moderate expression in the kidney and the thyroid. Detection with BCAM antibody found that BCAM was highly expressed in about 35-40% of primary HGSOC tumors and low to undetectable in the kidneys and thymus. BCAM has previously been suggested as an ovarian-specific target. We found that BCAM expression is very low or undetectable on the surface of healthy RBCs, alleviating potential off-tumor toxicity concerns. A recurrent BCAM-AKT2 fusion has also been described in some HGSOC.

Fig1. BCAM is a potential therapeutic target in HGSOC.
(Proc Natl Acad Sci USA,2023)

To evaluate BCAM as a potential target for ovarian cancer, western blotting analysis was first performed using BCAM antibody in ovarian cancer cell lines and patient-derived organoids. Together, these observations demonstrate that BCAM is preferentially expressed in HGSOC cell lines and on a large fraction of organoids derived from ovarian cancer patients. To detect BCAM levels in primary tumors, ovarian tissue BCAM microarrays are analyzed. IHC staining of ovarian tumor tissue microarrays using BCAM antibody. The results showed that strong staining was visible on the surface of HGSOC tumor cells, while BCAM expression was not seen or weak on adjacent stromal cells or tumor nuclei of other tumor subtypes. Cell staining shows BCAM expression on the cell surface. Comparing the percentage of tumor cells expressing BCAM between HGSOC and other cancer subtypes (positive score), it was found that the expression of BCAM on HGSOC was highly and significantly enriched. Of note, BCAM expression was weak or absent in healthy ovarian, kidney, and thyroid tissues. BCAM has been reported to be expressed on red blood cells (RBCs), in particular RBCs in patients with Sickle cell anemia. Similar results were obtained with the BCAM antibody, and low level expression of BCAM on red blood cells was confirmed by western blotting. The data suggest BCAM as an attractive therapeutic target in a subset of HGSOC.

All in all, BCAM is a transmembrane glycoprotein with 5 immunoglobulin-like domains that acts as a receptor for LAMA5. Their interaction was demonstrated to promote adhesion and migration of carcinoma cells. Accordingly, inhibition of BCAM-LAMA interaction has been demonstrated to have an inhibitory effect on migration. Surprisingly, Surprisingly, no correlation between Laminin 5 and BCAM expression in HGSOC was observed in tissue microarrays by the use of BCAM antibody, raising the question as to whether laminin 5 is the primary ligand for BCAM in ovarian cancer. In agreement with this, although our mutagenesis data suggest that the 6N2_22 epitope at least partially overlaps with the LAMA5-binding region, it does not have an apparent effect on cell adhesion. Further in vivo studies, which require antibody engineering and suitable cancer models, are necessary to assess the consequences of targeting BCAM with this suitable BCAM antibody.

BCAM Antibodies

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