Publications

Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive, inborn error of bile acid metabolism characterized by diarrhea in infancy, juvenile cataracts in childhood, tendon xanthomas developing in the second to third decades of life, and progressive neurologic dysfunction in adulthood. The condition is caused by mutations in the CYP27A1 gene that result in decreased production of chenodeoxycholic acid (CDCA) and elevated levels of cholestanol and bile alcohols. We present a 36-year-old male of Han ethnicity who developed xanthomas of his Achilles tendons and suffered neurocognitive declines and gait deterioration in his second decade. The diagnosis of CTX was confirmed by marked elevation of the serum cholestanol level. Sequencing of CYP27A1 showed a paternally inherited splice mutation, c.446 + 1G>T, and a maternally inherited nonsense mutation, c.808C>T, predicting p.(Arg270*). Despite the advanced disease in this patient, treatment with CDCA reduced the xanthoma size and improved his cognition and strength, and the patient made significant gains in his ambulation and coordination. We report this case to illustrate the potential benefits of therapy in patients with CTX who have advanced disease at the time of diagnosis.

Noninvasive biomarkers that detect the activity of important oncogenic drivers could significantly improve cancer diagnosis and management of treatment. The goal of this study was to determine whether Ga-citrate (which avidly binds to circulating transferrin) can detect MYC-positive prostate cancer tumors, as the transferrin receptor is a direct MYC target gene. PET imaging paired with Ga-citrate and molecular analysis of preclinical models, human cell-free DNA (cfDNA), and clinical biopsies were conducted to determine whether Ga-citrate can detect MYC-positive prostate cancer. Importantly, Ga-citrate detected human prostate cancer models in a MYC-dependent fashion. In patients with castration-resistant prostate cancer, analysis of cfDNA revealed that all patients with Ga-citrate avid tumors had a gain of at least one copy number. Moreover, biopsy of two PET avid metastases showed molecular or histologic features characteristic of MYC hyperactivity. These data demonstrate that Ga-citrate targets prostate cancer tumors with MYC hyperactivity. A larger prospective study is ongoing to demonstrate the specificity of Ga-citrate for tumors with hyperactive MYC. Noninvasive measurement of MYC activity with quantitative imaging modalities could substantially increase our understanding of the role of MYC signaling in clinical settings for which invasive techniques are challenging to implement or do not characterize the biology of all tumors in a patient. Moreover, measuring MYC activity noninvasively opens the opportunity to study changes in MYC signaling in patients under targeted therapeutic conditions thought to indirectly inhibit MYC. .