title: Parathyroid Hormone-Related Peptide-Linked Hypercalcemia in a Melanoma Patient Treated With Ipilimumab: Hormone Source and Clinical and Metabolic Correlates.
abstract: A patient diagnosed with metastatic melanoma developed the paraneoplastic syndrome of humoral hypercalcemia of malignancy and cachexia after receiving ipilumumab. The cause of the hypercalcemia was thought to be secondary to parathyroid hormone-related peptide (PTHrP) as plasma levels were found to be elevated. The patient underwent two tumor biopsies: at diagnosis (when calcium levels were normal) and upon development of hypercalcemia and cachexia. PTHrP expression was higher in melanoma cells when hypercalcemia had occurred than prior to its onset. Metabolic characterization of melanoma cells revealed that, with development of hypercalcemia, there was high expression of monocarboxylate transporter 1 (MCT1), which is the main importer of lactate and ketone bodies into cells. MCT1 is associated with high mitochondrial metabolism. Beta-galactosidase (β-GAL), a marker of senescence, had reduced expression in melanoma cells upon development of hypercalcemia compared to pre-hypercalcemia. In conclusion, PTHrP expression in melanoma is associated with cachexia, increased cancer cell lactate and ketone body import, high mitochondrial metabolism, and reduced senescence. Further studies are required to determine if PTHrP regulates cachexia, lactate and ketone body import, mitochondrial metabolism, and senescence in cancer cells.
authors.affiliation: Sidney Kimmel College of Medicine Thomas Jefferson University, Philadelphia, PA.
authors.forename: Teresa Anne
authors.initials: TA
authors.lastname: Mills
authors.affiliation: Department of Medical Oncology Thomas Jefferson University, Philadelphia, PA.
authors.forename: Marlana
authors.initials: M
authors.lastname: Orloff
authors.affiliation: Department of Medical Oncology Thomas Jefferson University, Philadelphia, PA.
authors.forename: Marina
authors.initials: M
authors.lastname: Domingo-Vidal
authors.affiliation: Department of Pathology Thomas Jefferson University, Philadelphia, PA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Cotzia
authors.affiliation: Department of Pathology Thomas Jefferson University, Philadelphia, PA.
authors.forename: Ruth C
authors.initials: RC
authors.lastname: Birbe
authors.affiliation: Department of Pathology Thomas Jefferson University, Philadelphia, PA.
authors.forename: Rossitza
authors.initials: R
authors.lastname: Draganova-Tacheva
authors.affiliation: Department of Medicine Thomas Jefferson University, Philadelphia, PA.
authors.forename: Maria P
authors.initials: MP
authors.lastname: Martinez Cantarin
authors.affiliation: Department of Pathology Thomas Jefferson University, Philadelphia, PA.
authors.forename: Madalina
authors.initials: M
authors.lastname: Tuluc
authors.affiliation: Department of Medical Oncology Thomas Jefferson University, Philadelphia, PA. Electronic address: ubaldo.martinezoutschoorn@jefferson.edu.
authors.forename: Ubaldo
authors.initials: U
authors.lastname: Martinez-Outschoorn
mesh_terms: D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D002100:Cachexia / Q000139:chemically induced; D005260:Female; D006801:Humans; D006934:Hypercalcemia / Q000139:chemically induced / Q000378:metabolism*; D000074324:Ipilimumab; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism; D010257:Paraneoplastic Syndromes / Q000139:chemically induced; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism*; D027981:Symporters / Q000378:metabolism; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D000911:Antibodies, Monoclonal; D000074324:Ipilimumab; D027501:Monocarboxylic Acid Transporters; D044162:Parathyroid Hormone-Related Protein; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C470121:PTHLH protein, human