Impact of TGF-ß1 -509C/T and 869T/C polymorphisms on glioma risk and patient prognosis

Transforming growth factor beta (TGF-ß) plays an important role in carcinogenesis. Two polymorphisms in the TGF-ß1 gene (-509C/T and 869T/C) were described to influence susceptibility to gastric and breast cancers. The 869T/C polymorphism was also associated with overall survival in breast cancer patients. In the present study, we investigated the relevance of these TGF-ß1 polymorphism in glioma risk and prognosis. A case-control study that included 114 glioma patients and 138 cancer-free controls was performed. Single nucleotide polymorphisms (SNPs) were evaluated by polymerase chain reaction followed by restriction fragment length polymorphism (PCR-RFLP). Univariate and multivariate logistic regression analyses were used to calculate odds ratio (OR) and 95 % confidence intervals (95 % CI). The influence of TGF-ß1 -509C/T and 869T/C polymorphisms on glioma patient survival was evaluated by a Cox regression model adjusted for patients' age and sex and represented in Kaplan-Meier curves. Our results demonstrated that TGF-ß1 gene polymorphisms -509C/T and 869T/C are not significantly associated with glioma risk. Survival analyses showed that the homozygous -509TT genotype associates with longer overall survival of glioblastoma (GBM) patients when compared with patients carrying CC + CT genotypes (OR, 2.41; 95 % CI, 1.06-5.50; p = 0.036). In addition, the homozygous 869CC genotype is associated with increased overall survival of GBM patients when compared with 869TT + TC genotypes (OR, 2.62; 95 % CI, 1.11-6.17; p = 0.027). In conclusion, this study suggests that TGF-ß1 -509C/T and 869T/C polymorphisms are not significantly associated with risk for developing gliomas but may be relevant prognostic biomarkers in GBM patients.This work was supported by Fundação para a Ciência e Tecnologia, Portugal (PTDC/SAU-GMG/113795/2009 and SFRH/BPD/33612/2009 to B.M.C.; SFRH/BD/88121/2012 to J.V.C.; SFRH/BD/92786/2013 to C.S.G.; PTDC/SAU-ONC/115513/2009 to R.R.)

Inhibition of colony stimulating factor-1 receptor abrogates microenvironment-mediated therapeutic resistance in gliomas.

Glioblastomas represent the most aggressive glioma grade and are associated with a poor patient prognosis. The current standard of care, consisting of surgery, radiation and chemotherapy, only results in a median survival of 14 months, underscoring the importance of developing effective new therapeutic strategies. Among the challenges in treating glioblastomas are primary resistance and the rapid emergence of recurrent disease, which can result from tumor cell-intrinsic mechanisms in addition to tumor microenvironment (TME)-mediated extrinsic resistance. Using a PDGF-B-driven proneural glioma mouse model, we assessed a panel of tyrosine kinase inhibitors with different selectivity profiles. We found that PLX3397, an inhibitor of colony stimulating factor-1 receptor (CSF-1R), blocks glioma progression, markedly suppresses tumor cell proliferation and reduces tumor grade. By contrast, the multi-targeted tyrosine kinase inhibitors dovitinib and vatalanib, which directly target tumor cells, exert minimal anti-tumoral effects in vivo, despite killing glioma cells in vitro, suggesting a TME-mediated resistance mechanism may be involved. Interestingly, PLX3397 interferes with tumor-mediated education of macrophages and consequently restores the sensitivity of glioma cells to tyrosine kinase inhibitors in vivo in preclinical combination trials. Our findings thus demonstrate that microenvironmental alteration by CSF-1R blockade renders tumor cells more susceptible to receptor tyrosine kinase inhibition in a preclinical glioblastoma model, which may have important translational relevance

P09.59 Phase 2 trial of palbociclib in adult patients with recurrent Rb positive glioblastoma

Abstract Alterations in the CDK4/6 – RB signaling pathway are common causes of dysregulation of the cell cycle in many cancers, including glioblastoma. Palbociclib is an oral, highly selective, reversible inhibitor of CDK4/6, which leads to phosphorylation of RB and cell-cycle arrest. In a two-arm study, we evaluated the efficacy and safety of palbociclib in patients with recurrent glioblastoma. Notable eligibility criteria included confirmation of RB proficiency by IHC; ≤ 3 relapses; KPS ≥ 60; secondary glioblastomas were included; there were no limitation on prior treatments including bevacizumab. Patients were administered oral palbociclib 125 mg daily for 21 consecutive days followed by a 7 day break. Arm 1 planned for 15 patients to receive palbociclib for 7 days prior to indicated surgical resection for progression, followed by palbociclib. Arm 2 planned for 15 patients to receive palbociclib without additional resection. The primary objective was PFS-6, which was hypothesized to be 30% in this heavily pretreated population, and null hypothesis of 10%. Secondary objectives of toxicity, OS, and ORR. Exploratory results included biomarker assessment and pharmacodynamic effects for the surgical Arm 1 patients. A total of 22 patients were enrolled; 6 on Arm 1 and 16 on Arm 2. Median age for all arms was 47.5 years old (range 23 – 78 years old); 54% (12 patients) were male; and the median KPS was 90 (range 60 – 100). Palbociclib was started at first recurrence in 50% (11 patients – 3 in Arm 1 and 8 in Arm 2) of patients; at second recurrence in 36% (8 patients – 3 in Arm 1 and 5 in Arm 2); and at third recurrence in 14% (3 patients, all in Arm 2). Bevacizumab had previously been used in 77% (17 patients – 4 in Arm 1 and 13 in Arm 2) of cases. The trial was stopped early secondary to futility, with 95% (18 of 19) evaluable patients progressing within 6 months of intiating treatment. Four samples were available for immunohistochemistry for Rb and Ki67. There were no consistent changes in Rb expression or cell proliferation when compared to samples from diagnosis. Median progression free survival for all patients was 5.14 weeks (range 5 days – 142 weeks) and median overall survival was 15.4 weeks (range 2 – 274 weeks). Two patients (10%) had treatment related AEs that were grade ≥3. In this trial, palbociclib did not appear to have been an effective treatment for recurrent glioblastoma. However, this was a heavily pretreated patient population and targeting the CDK4/6 pathway may deserve further exploration