Howard Colman

BACKGROUND: Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas. METHODS: We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes. RESULTS: Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma. CONCLUSIONS: The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.).

AIMS: Cancer diagnosis may increase the risk of developing prediabetes/diabetes and subsequently worsen survival in cancer patients. However, it is unclear whether this association is influenced by the timing of hyperglycemia onset or the use of antihyperglycemic medications. MATERIALS AND METHODS: This study leveraged a retrospective cohort, constructed using electronic health record data, of solid tumour patients at the Huntsman Cancer Institute, a comprehensive cancer centre in Utah, USA. Adjusted Cox proportional-hazards regression models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) to evaluate the association between new-onset prediabetes/diabetes and overall survival. RESULTS: Of the 7300 patients included, 23% developed prediabetes/diabetes after cancer diagnosis (mean time-to-onset = 2.6 years). Patients with new-onset prediabetes/diabetes had worse overall survival compared to patients without prediabetes/diabetes [HR (95% CI): 2.97 (2.48-3.55)]. Compared to patients without prediabetes/diabetes, patients who were not prescribed antihyperglycemic medications had poorer survival than those who were prescribed antihyperglycemic medications (n = 665) [HR (95% CI): 2.52 (2.17-2.93) and 1.70 (1.40-2.06), respectively]. Ever use of metformin was associated with better survival [HR (95% CI): 0.32 (0.15-0.66)] compared to individuals with prescriptions of other non-insulin antihyperglycemic medications, while ever use of insulin was associated with worse survival [HR (95% CI): 1.67 (1.16-2.42)], compared to individuals with prescription of non-insulin antihyperglycemic medications. CONCLUSIONS: Improving clinical practice guidelines for appropriate hyperglycemia monitoring and management, especially in the first 3 years after cancer diagnosis, may improve cancer survival. Early intervention with non-insulin antihyperglycemic medications for control of new-onset prediabetes/diabetes may be crucial in preventing the need for insulin prescription and worsening of survival.

Introduction: Multiple case studies have reported diabetic ketoacidosis (DKA) in recently-diagnosed cancer patients, especially those taking immune checkpoint inhibitors. The prevalence of DKA and other acute diabetes complications (ADC), including hypoglycemia and hyperosmolarity, and their relationship with the onset of systemic cancer therapy is unclear. Methods: This study utilized data from n=9,588 cancer patients from the Huntsman Cancer Institute, UT. Data on clinicodemographic characteristics, biomarkers, and cancer diagnoses were extracted from electronic medical records (EMR) and tumor registry. Patients included in this analysis received an ICD diagnosis of hypoglycemia, hyperosmolarity with or without coma, and/or DKA with or without coma. Systemic therapy was defined as any chemotherapy, immunotherapy or hormone therapy resulting from a specific first primary cancer diagnosis. Results: There were 243 instances of ADC within this cohort, occurring in 211 (2.2%) unique patients. Of these 211 unique patients with an ADC, 106 (50.0%) experienced their first ADC within one year after cancer diagnosis, with a median time to ADC diagnosis of 88 days. Forty-seven (44%) of these patients experienced the ADC following the onset of systemic therapy, with a median time from systemic therapy onset to ADC diagnosis of 120 days. In these 47 patients who received an ADC diagnosis following the onset of systemic therapy, 40 (85.1%) received chemotherapy (n=20 as monotherapy), 20 (42.6%) received immunotherapy (n=4 as monotherapy) and 12 (25.5%) received hormone therapy (n=2 as monotherapy). Only 54% of patients experiencing an ADC after cancer diagnosis had a history of diabetes prior to cancer, and on average their first diabetes diagnosis was 5.4 ± 4.4 years prior to their cancer diagnosis. Discussion: ADCs may be common following a cancer diagnosis, however a substantial number occurred prior to the onset of systemic cancer therapy and in patients with no prior history of diabetes. Disclosure R. Viskochil: None. S. Hardikar: None. S. Pauleck: None. M. Winn: None. K. Funai: None. M. L. Litchman: Research Support; Self; Abbott Diabetes. W. Akerley: None. H. Colman: Advisory Panel; Self; Adastra Pharmaceuticals, Orbus Therapeutics, Consultant; Self; Best Doctors/Teladoc. C. M. Ulrich: None. M. C. Playdon: None. Funding University of Utah Health/Larry H. Miller Family Wellness Initiative

Abstract New approaches are needed to overcome intrinsic therapy resistance in glioblastoma (GBM). Because GBMs exhibit sexual dimorphism and are reported to express steroid hormone receptors, we reasoned that signaling through the androgen receptor (AR) could mediate therapy resistance in GBM, as it does in AR-positive prostate and breast cancers. Using RNAseq, immunoblot and immunohistochemistry, we found that nearly half of GBM cell lines, patient-derived xenografts and human tumors express AR transcript and protein with levels that overlap those of primary prostate cancer. AR expression in GBM did not vary by sex, age or common molecular alterations. We identified two cell line models of GBM that expressed AR protein (LN18 and T98G: termed “AR positive”) and two that did not (8MGBA and AM38: termed “AR negative”). Seviteronel, a blood-brain barrier permeable CYP17 lyase inhibitor and antiandrogen slowed growth in AR positive GBM cell lines (GI50 3-4 µM) but not AR negative lines (GI50 > 500 µM) as measured by the colony formation assay. The antiandrogen enzalutamide, which also penetrates the blood brain barrier, similarly preferentially slowed growth in AR positive GBM cell lines. Seviteronel and enzalutamide sensitized AR positive GBM cell lines to radiation with enhancement ratios of 1.3-1.6 as measured by the clonogenic survival assay. Antiandrogens had no effect on the radiosensitivity of AR negative GBM cell lines. Seviteronel treatment did not affect the growth of AR positive T98G xenografts grown in vivo, but did sensitize these tumors to radiation (median time to tripling: 15 d with radiation alone and not reached with radiation combined with seviteronel). Enzalutamide similarly had modest single agent effects on an AR positive GBM patient-derived xenograft (GBM26 from the Mayo Clinic GBM PDX national resource) grown in vivo but sensitized these tumors to radiation (median time to tripling: 25.5 d with radiation alone and 39 d with radiation combined with enzalutamide). RNAseq performed on GBM26 tumors grown in vivo revealed that enzalutamide treatment caused minimal transcriptional changes when given as monotherapy but, when given in combination with radiation, blocked the ability of AR-positive GBMs to engage adaptive transcriptional programs related to multiple DNA repair pathways. We confirmed these mechanistic findings in vitro, as antiandrogens selectively impaired the repair of radiation-induced double strand DNA breaks in AR positive GBM cell lines. These results suggest that AR signaling may mediate therapy resistance in AR positive GBMs, and patients with these tumors could derive clinical benefit from combination therapies involving radiation and blood-brain-barrier permeable antiandrogens. Citation Format: Christian K. Werner, Uchechi Nna, Hanshi Sun, Kari Wilder-Romans, Joseph Dresser, Ayesha Kothari, Weihua Zhou, Yangyang Yao, Arvind Rao, Stefanie Stallard, Carl Koschmann, Tarik Bor, Waldemar Debinski, Alexander Hegedus, Meredith Morgan, Sriram Venneti, Edwina Baskin-Bey, Daniel Spratt, Howard Colman, Jann Sarkaria, Arul Chinnayain, Joel Eisner, Corey Speers, Theodore S. Lawrence, Roy Strowd, Daniel R. Wahl. Repurposing antiandrogens to overcome therapy resistance in androgen receptor-positive glioblastoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6267.