Clifton-Bligh, Roderick

Abstract This study explores parallels between systemic hypoxia adaptation in high-altitude populations and tumorigenesis. We identified EPAS1, a gene critical for hypoxia adaptation in populations such as Tibetans and Sherpas, as playing a similar adaptive role in tumors arising under hypoxic conditions. Tumors from patients with chronic hypoxia displayed impaired DNA repair and frequent emergence of EPAS1 variants, with frequencies reaching up to 90%, echoing the positive selection seen in high-altitude dwellers. Mechanistically, EPAS1 gain-of-function mutations promote COX4I2 expression, reducing cellular oxygen consumption and supporting tumor proliferation in hypoxia. Analysis of clinical data from patients with hypoxia revealed tissue-specific and time-sensitive tumorigenic effects, particularly impacting oxygen-sensitive cells in the postnatal period. Our findings suggest that EPAS1-driven adaptation mechanisms in high-altitude populations provide a model for understanding tumor evolution under hypoxic stress, highlighting how genetic adaptations to diverse stressors in natural populations may yield insights into tumorigenesis and cancer progression. Significance: This study reveals a broad convergence in genetic adaptation to hypoxia between natural populations and tumors, suggesting that insights from natural populations could enhance our understanding of cancer biology and identify novel therapeutic targets. See related commentary by Lee, p. 875

Abstract Disclosure: S.W. Ing: Advisory Board Member; Self; Ultragenyx, Amolyt. Grant Recipient; Self; Alexion Pharmaceuticals, Inc.. Research Investigator; Self; BridgeBio Pharma, Takeda, Amolyt, Radius Health, Inc, Ultragenyx. P. Harmatz: Research Investigator; Self; BridgeBio Pharma. S. Mora: Research Investigator; Self; BridgeBio Pharma. E.A. Imel: Research Investigator; Self; BridgeBio Pharma. P.J. Tebben: Research Investigator; Self; BridgeBio Pharma. M.L. Warren: Research Investigator; Self; BridgeBio Pharma, Ascendis, Amolyt. Speaker; Self; Ascendis. N. Ma: Research Investigator; Self; Calcilytix Therapeutics, Ultragenyx, Inozyme. Other; Self; Up To Date. A.A. Khan: Research Investigator; Self; BridgeBio Pharma, Ascendis. A. Palermo: Research Investigator; Self; BridgeBio Pharma. B. Decallonne: Research Investigator; Self; BridgeBio Pharma. S. Lemoine: Research Investigator; Self; BridgeBio Pharma, Kyowa Kirin. G. Mantovani: Research Investigator; Self; BridgeBio Pharma. A. Linglart: Consulting Fee; Self; Alexion, Novo Nordisk, Merck, Pfizer, Inc.. Research Investigator; Self; BridgeBio Pharma, Kyowa Kirin. H. Wasserman: Research Investigator; Self; BridgeBio Pharma. A.P. Barbosa: Research Investigator; Self; BridgeBio Pharma. C. Cardot-bauters: Research Investigator; Self; BridgeBio Pharma. M. Roberts: Employee; Self; BridgeBio Pharma. A. Mathew: Employee; Self; BridgeBio Pharma. S. Adler: Employee; Self; BridgeBio Pharma. M.C. Zillikens: Research Investigator; Self; BridgeBio Pharma. R.J. Clifton-Bligh: Consulting Fee; Self; Ipsen, Kyowa Kirin, Amgen Inc, Eisai. Research Investigator; Self; BridgeBio Pharma. L. Rejnmark: Research Investigator; Self; BridgeBio Pharma, Ascendis, Amolyt, Takeda, Kyowa Kirin. Autosomal dominant hypocalcemia type 1 (ADH1), caused by gain-of-function calcium-sensing receptor gene (CASR) variants, is characterized by low parathyroid hormone (PTH) concentrations, hypocalcemia, hypercalciuria, hyperphosphatemia and hypomagnesemia. While a rare disease, ADH1 is one of the more frequently identified causes of genetic hypoparathyroidism. Conventional therapy includes calcium (Ca) and/or active vitamin D, but this regimen incompletely corrects the hypocalcemia and is associated with persistent hypercalciuria, which may result in renal complications including nephrocalcinosis (NC), nephrolithiasis (NL), and chronic kidney disease (CKD). The CLARIFY disease monitoring study [NCT05227287] is a global, multicenter, longitudinal study to understand disease burden, management, and progression in children and adults with ADH1 over a 5-year period. Here we report data on the characteristics of adult participants at study entry. As of November 2023, 45 adults (≥18 years) with ADH1 were enrolled, with a mean±SD age of 42.1±16.5 years (range 18-80). The mean±SD age of a hypocalcemia diagnosis was 19.1±19.1 years, while the mean±SD age for a diagnosis of ADH1 was 28.2±20.6 years. As reported on medical history, in decreasing order of prevalence, 36% (16) had NC, 22% (10) had intracranial calcifications, 11% (5) had history of seizures, 11% (5) had CKD, 9% (4) had cataracts, 7% (3) had NL, and 4% (2) had undergone renal transplant. Treatment data were available for 43 participants and included the following: 74% (32) Ca and active vitamin D, 9% (4) Ca alone, 9% (4) active vitamin D alone, 37% (16) magnesium, 33% (14) thiazide diuretics, 26% (11) potassium, 7% (3) phosphate binder, 7% (3) PTH, and 5% (2) no treatment. Mean±SD fasting values collected prior to conventional therapy dose are presented. PTH concentrations (10.1±8.2 pg/mL [nl 15-65]) and albumin-corrected calcium ([cCa]=7.5±1.0 mg/dL [nl 8.5-10.5]) were low. Despite the low mean cCa, the mean 24-hr urine calcium was elevated (268±183 mg/d, [nl <250 women, <300 men]). Blood phosphate was 4.8±0.8 mg/dL [nl 2.5-4.8] while blood magnesium was 1.8±0.2 mg/dL [nl 1.8-2.4]. 25-OH vitamin D was 35.0±13.5 ng/mL [nl 30-80]. Renal function as assessed by CKD-EPIcr_R showed eGFR of 86±23 mL/min/1.73m² (range 36-123). This study represents the largest cohort of adults with ADH1 described to date. These data highlight variability in therapeutic approaches in a real-world setting with some participants receiving up to 6 different medications/supplements. Despite being followed in expert centers, and treated with available therapies, patients on average have low cCa with relatively high 24-hr urine calcium excretion. The CLARIFY study provides an opportunity to better understand the progression and burden of disease in participants with ADH1. Presentation: 6/3/2024

Abstract Disclosure: S.W. Ing: Research Investigator; Self; BridgeBio Pharma. P. Harmatz: Research Investigator; Self; BridgeBio Pharma. S. Mora: Research Investigator; Self; BridgeBio Pharma. E.A. Imel: Research Investigator; Self; BridgeBio Pharma. P.J. Tebben: Research Investigator; Self; BridgeBio Pharma. M.L. Warren: Research Investigator; Self; BridgeBio Pharma, Ascendis, Amolyt. Speaker; Self; Ascendis. N. Ma: Research Investigator; Self; Calcilytix Therapeutics, Ultragenyx, Inozyme. Other; Self; Up To Date. A.A. Khan: Research Investigator; Self; BridgeBio Pharma, Ascendis. A. Palermo: Research Investigator; Self; BridgeBio Pharma. B. Decallonne: Research Investigator; Self; BridgeBio Pharma. S. Lemoine: Research Investigator; Self; BridgeBio Pharma, Kyowa Kirin. G. Mantovani: Research Investigator; Self; BridgeBio Pharma. A. Linglart: Consulting Fee; Self; Alexion, Novo Nordisk, Merck, Pfizer, Inc.. Research Investigator; Self; BridgeBio Pharma, Kyowa Kirin. H. Wasserman: Research Investigator; Self; BridgeBio Pharma. A.P. Barbosa: Research Investigator; Self; BridgeBio Pharma. C. Cardot-bauters: Research Investigator; Self; BridgeBio Pharma. M. Roberts: Employee; Self; BridgeBio Pharma. A. Mathew: Employee; Self; BridgeBio Pharma. S. Adler: Employee; Self; BridgeBio Pharma. M.C. Zillikens: Research Investigator; Self; BridgeBio Pharma. R.J. Clifton-Bligh: Consulting Fee; Self; Ipsen, Kyowa Kirin, Amgen Inc, Eisai. Research Investigator; Self; BridgeBio Pharma. L. Rejnmark: Research Investigator; Self; BridgeBio Pharma, Ascendis, Amolyt, Takeda, Kyowa Kirin. Autosomal dominant hypocalcemia type 1 (ADH1), caused by gain-of-function calcium-sensing receptor gene (CASR) variants, is characterized by low parathyroid hormone (PTH) concentrations, hypocalcemia, hypercalciuria, hyperphosphatemia and hypomagnesemia. While a rare disease, ADH1 is one of the more frequently identified causes of genetic hypoparathyroidism. Conventional therapy includes calcium (Ca) and/or active vitamin D, but this regimen incompletely corrects the hypocalcemia and is associated with persistent hypercalciuria, which may result in renal complications including nephrocalcinosis (NC), nephrolithiasis (NL), and chronic kidney disease (CKD). The CLARIFY disease monitoring study [NCT05227287] is a global, multicenter, longitudinal study to understand disease burden, management, and progression in children and adults with ADH1 over a 5-year period. Here we report data on the characteristics of adult participants at study entry. As of November 2023, 45 adults (≥18 years) with ADH1 were enrolled, with a mean±SD age of 42.1±16.5 years (range 18-80). The mean±SD age of a hypocalcemia diagnosis was 19.1±19.1 years, while the mean±SD age for a diagnosis of ADH1 was 28.2±20.6 years. As reported on medical history, in decreasing order of prevalence, 36% (16) had NC, 22% (10) had intracranial calcifications, 11% (5) had history of seizures, 11% (5) had CKD, 9% (4) had cataracts, 7% (3) had NL, and 4% (2) had undergone renal transplant. Treatment data were available for 43 participants and included the following: 74% (32) Ca and active vitamin D, 9% (4) Ca alone, 9% (4) active vitamin D alone, 37% (16) magnesium, 33% (14) thiazide diuretics, 26% (11) potassium, 7% (3) phosphate binder, 7% (3) PTH, and 5% (2) no treatment. Mean±SD fasting values collected prior to conventional therapy dose are presented. PTH concentrations (10.1±8.2 pg/mL [nl 15-65]) and albumin-corrected calcium ([cCa]=7.5±1.0 mg/dL [nl 8.5-10.5]) were low. Despite the low mean cCa, the mean 24-hr urine calcium was elevated (268±183 mg/d, [nl <250 women, <300 men]). Blood phosphate was 4.8±0.8 mg/dL [nl 2.5-4.8] while blood magnesium was 1.8±0.2 mg/dL [nl 1.8-2.4]. 25-OH vitamin D was 35.0±13.5 ng/mL [nl 30-80]. Renal function as assessed by CKD-EPIcr_R showed eGFR of 86±23 mL/min/1.73m² (range 36-123). This study represents the largest cohort of adults with ADH1 described to date. These data highlight variability in therapeutic approaches in a real-world setting with some participants receiving up to 6 different medications/supplements. Despite being followed in expert centers, and treated with available therapies, patients on average have low cCa with relatively high 24-hr urine calcium excretion. The CLARIFY study provides an opportunity to better understand the progression and burden of disease in participants with ADH1. Presentation: 6/3/2024