Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients.

BACKGROUND: Temozolomide (TMZ) is one of the most potent chemotherapy agents for the treatment of glioblastoma. Unfortunately, almost half of glioblastoma tumors are TMZ resistant due to overexpression of methylguanine methyltransferase (MGMT(hi)). Coadministration of O6-benzylguanine (O6BG) can restore TMZ sensitivity, but causes off-target myelosuppression. Here, we conducted a prospective clinical trial to test whether gene therapy to confer O6BG resistance in hematopoietic stem cells (HSCs) improves chemotherapy tolerance and outcome. METHODS: We enrolled 7 newly diagnosed glioblastoma patients with MGMT(hi) tumors. Patients received autologous gene-modified HSCs following single-agent carmustine administration. After hematopoietic recovery, patients underwent O6BG/TMZ chemotherapy in 28-day cycles. Serial blood samples and tumor images were collected throughout the study. Chemotherapy tolerance was determined by the observed myelosuppression and recovery following each cycle. Patient-specific biomathematical modeling of tumor growth was performed. Progression-free survival (PFS) and overall survival (OS) were also evaluated. RESULTS: Gene therapy permitted a significant increase in the mean number of tolerated O6BG/TMZ cycles (4.4 cycles per patient, P < 0.05) compared with historical controls without gene therapy (n = 7 patients, 1.7 cycles per patient). One patient tolerated an unprecedented 9 cycles and demonstrated long-term PFS without additional therapy. Overall, we observed a median PFS of 9 (range 3.5-57+) months and OS of 20 (range 13-57+) months. Furthermore, biomathematical modeling revealed markedly delayed tumor growth at lower cumulative TMZ doses in study patients compared with patients that received standard TMZ regimens without O6BG. CONCLUSION: These data support further development of chemoprotective gene therapy in combination with O6BG and TMZ for the treatment of glioblastoma and potentially other tumors with overexpression of MGMT. TRIAL REGISTRATION: Clinicaltrials.gov NCT00669669. FUNDING: R01CA114218, R01AI080326, R01HL098489, P30DK056465, K01DK076973, R01HL074162, R01CA164371, R01NS060752, U54CA143970.

Urinary 3-(3,5-dihydroxyphenyl)-1-propanoic acid, an alkylresorcinol metabolite, is a potential biomarker of whole-grain intake in a U.S. population.

5-n-Alkylresorcinols (AR) are a major group of phenolic compounds in whole-grain wheat, rye, and barley. As such, they may serve as potential biomarkers of whole-grain intake, because they are quantifiable intact in plasma and as metabolites in urine. We examined relationships between 12-h urinary excretion of AR metabolite 3-(3,5-dihydroxyphenyl)-1-propanoic acid (DHPPA) and self-reported habitual intake of whole-grain foods measured by 3-d food record (3DFR) and FFQ. Urine samples from 100 men and women were analyzed for DHPPA using HPLC with coularray detection. DHPPA excretion ranged from 1.3 to 99.4 (mean +/- SE, 14.0 +/- 1.5) mumol/12 h. Whole-grain food intake, as determined by 3DFR and FFQ and adjusted for BMI and energy and fiber intake, was significantly associated with 12-h urinary DHPPA excretion. Based on 3DFR, whole-grain wheat + rye consumers had a 44% higher DHPPA excretion than nonconsumers [ratio of excretion (95% CI) = 1.44 (1.04, 1.97); P = 0.029]. Using whole-grain intake estimated by FFQ, a serving increase in whole-grain wheat + rye intake increased DHPPA excretion by 94% [ratio of excretion (95% CI) = 1.94 (1.35, 2.78); P = 0.001] and a serving increase in whole grains as defined more broadly in epidemiologic studies of whole-grain intake and disease risk (whole-grain wheat, rye, oats, and corn) increased DHPPA by 67% [ratio of excretion (95% CI) = 1.67 (1.28, 2.17); P < 0.0001]. This study supports the potential utility of urinary DHPPA as a biomarker of whole-grain intake in a U.S. population.