Cancer is a disease that afflicts millions of people each year. While there are many drugs available to treat certain subsets of cancer, there still remain many types of cancer that do not have tailored therapy available to treat them. Mesothelioma and Pediatric Medulloblastoma are two such cancers that the NIH classifies as rare and aggressive neoplasms. As such, both cancers display unmet needs, and are the subject of much research to improve the chemotherapy available for treatment. Our laboratory has found that both cancers express a protein called Prostaglandin F2 Receptor Negative, or PTGFRN. PTGFRN is a member of the Tetraspanin family, which are transmembrane proteins. Previously, PTGFRN expression has been found to correlate with a more aggressive phenotype. Additionally, when its expression is inhibited, cellular processes essential for cancer metastasis were also found to be impacted. To better understand how PTGFRN affects cancer progression, we looked at the effects of PTGFRN with various in vitro functional assays to assess phenotypic changes. We also performed a global proteome and pathway analysis using mass spectrometric methods to better understand what pathways were most affected by PTGFRN expression, and identify proteins that are complexed, or in direct interaction, with PTGFRN. In parallel to these studies, we also developed monoclonal antibodies that are capable of binding cell-surface PTGFRN, and inducing endocytosis to the cytoplasm. Conjugation of our prototype antibody, the mouse mAb 33B7, to the ribosome-inactivating protein Saporin results in an Antibody-Drug Conjugate (ADC) of moderate¬ efficacy. Due to the success of this first ADC attempt, we then developed a fully human antibody, denoted as 8C7, and conjugated it to the payload Duocarmycin via a cleavable linker, resulting in our second generation ADC. This new ADC exhibits improved, highly potent in vitro anti-cancer effect, as well as in in vivo models with mice bearing mesothelioma and medulloblastoma tumors. The work detailed here lays the groundwork for a tailored therapy to treat the aforementioned cancers, and expands our knowledge of proteins and protein interactions involved in cancer metastasis.