Progression-free survival | EPFL Graph Search

Progression-free survival (PFS) is "the length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse". In oncology, PFS usually refers to situations in which a tumor is present, as demonstrated by laboratory testing, radiologic testing, or clinically. Similarly, "disease-free survival" is the length of time after patients have received treatment and have no detectable disease. Time to progression (TTP) does not count patients who die from other causes but is otherwise a close equivalent to PFS (unless there are many such events). The FDA gives separate definitions and prefers PFS. Background PFS is widely used as a surrogate endpoint in oncology. The definition of "progression" generally involves imaging techniques (plain radiograms, CT scans, MRI, PET scans, ultrasounds) or other aspects: biochemical progression may be defined on the basis of an increase in a tumor marker (such as CA125 for epith

Combinatorial targeting of angiogenesis with inducers of autophagy in the treatment of glioblastoma multiforme

Julie Laetitia Scotton

Malignant gliomas represent 80% of tumors developing in the central nervous system, with 50% being glioblastomas (GBM), the most aggressive form of the disease. The benefit from current therapies is very limited, the overall 5-year survival rate of patients with GBM being less than 5%. Thus, there is an urgent need for better therapies. It has been reported that the use of tricyclic antidepressants (TCAs) is linked with reduced incidence of gliomas. In line with these observations, our lab previously demonstrated that combining imipramine (IM), a TCA that activates adenylate cyclase and elevates production of cAMP, with ticlopidine (TIC), an inhibitor of the purinergic receptor P2Y12 that otherwise suppresses cAMP, results in a concerted increase in the levels of intracellular cAMP, which consequently stimulates increased autophagy in glioma cells, leading to autophagy-associated cell death (AACD) in culture and during orthotopic tumor growth. In several mouse models of glioma, the combination improved survival and reduced malignant grade. Seeking to assess the therapeutic translational potential of these repurposed drugs, particularly IM, we performed pre-clinical trials combining IM+/-TIC with anti-VEGF therapy, which is commonly used in patients with GBM; such anti-angiogenic therapy is associated with a transitory improvement in progression-free survival and quality of life, but does not translate into an overall survival benefit. Using genetic mouse models with enabling bioluminescent monitoring of the cancer cells, we treated established GBMs with imipramine, ticlopidine, and B20S, an anti-mouse VEGF monoclonal antibody. We observed transient stabilization of tumor growth, and the overall survival was significantly extended in the regimens combining B20S with IM +/- TIC compared to control and single treatments. Similar to clinical observations in GBM patients treated with anti-angiogenic therapy, mice treated with B20S alone had no survival benefit, implicating a synergetic effect for the combination of anti-VEGF treatment with imipramine and ticlopidine. We found that the combinatorial therapy elicited further increases in autophagy and displayed some indication of blood vessel normalization, concomitant with an elevation of CD8+T lymphocyte infiltration into the orthotopic tumors. Notably, we could partially reverse the beneficial effect of the combinations using a CD8+T cell-depleting antibody, revealing the involvement of the recruited CD8+T cells in the efficacy of the combinatorial treatment, in addition to the cell-intrinsic autophagy-associated death that is demonstrable in culture and in tumors. Together, these results suggest a strategy to improve anti-angiogenic therapy in patients with glioblastoma, by using repurposed FDA-approved drugs that markedly elevate autophagy in concert with anti-VEGF therapy. The recruitment of CD8+ T cells into the treated tumors and their evident contribution to therapeutic efficacy motivates ongoing experiments aimed to heighten and sustain the induced anti-tumor immune response.

EPFL2018

CL9/9L-beta-catenin Signaling is Associated With Poor Outcome in Colorectal Cancer

Michel Aguet, Pascale Anderle Pedone, Sylvie André Baflast, Frédérique Baruthio, Mauro Delorenzi, Andreas Eduard Moor, Patrick Rodriguez, Norbert Wiedemann

BCL9/9L proteins enhance the transcriptional output of the beta-catenin/TCF transcriptional complex and contribute critically to upholding the high WNT signaling level required for stemness maintenance in the intestinal epithelium. Here we show that a BCL9/9L-dependent gene signature derived from independent mouse colorectal cancer (CRC) models unprecedentedly separates patient subgroups with regard to progression free and overall survival. We found that this effect was by and large attributable to stemness related gene sets. Remarkably, this signature proved associated with recently described poor prognosis CRC subtypes exhibiting high stemness and/or epithelial-to-mesenchymal transition (EMT) traits. Consistentwith the notion that high WNT signaling is required for stemnessmaintenance, ablating Bcl9/9l-beta-catenin inmurine oncogenic intestinal organoids provoked their differentiation and completely abrogated their tumorigenicity, while not affecting their proliferation. Therapeutic strategies aimed at targetingWNT responses may be limited by intestinal toxicity. Our findings suggest that attenuating WNT signaling to an extent that affects stemness maintenance without disturbing intestinal renewal might be well tolerated and prove sufficient to reduce CRC recurrence and dramatically improve disease outcome. (C) 2015 The Authors. Published by Elsevier B.V.

Elsevier Science Bv2015

The miR-96 and RAR gamma signaling axis governs androgen signaling and prostate cancer progression

Gerard Llimos Aubach

Expression levels of retinoic acid receptor gamma (NR1B3/RARG, encodes RAR gamma) are commonly reduced in prostate cancer (PCa). Therefore, we sought to establish the cellular and gene regulatory consequences of reduced RAR gamma expression, and determine RAR gamma regulatory mechanisms. RARG shRNA approaches in non-malignant (RWPE-1 and HPr1-AR) and malignant (LNCaP) prostate models revealed that reducing RAR gamma levels, rather than adding exogenous retinoid ligand, had the greatest impact on prostate cell viability and gene expression. ChIP-Seq defined the RAR gamma cistrome, which was significantly enriched at active enhancers associated with AR binding sites. Reflecting a significant genomic role for RAR gamma to regulate androgen signaling, RAR gamma knockdown in HPr1-AR cells significantly regulated the magnitude of the AR transcriptome. RAR gamma downregulation was explained by increased miR-96 in PCa cell and mouse models, and TCGA PCa cohorts. Biochemical approaches confirmed that miR-96 directly regulated RAR gamma expression and function. Capture of the miR-96 targetome by biotin-miR-96 identified that RAR gamma and a number of RAR gamma interacting co-factors including TACC1 were all targeted by miR-96, and expression of these genes were prominently altered, positively and negatively, in the TCGA-PRAD cohort. Differential gene expression analyses between tumors in the TCGA-PRAD cohort with lower quartile expression levels of RARG and TACC1 and upper quartile miR-96, compared to the reverse, identified a gene network including several RAR gamma target genes (e.g., SOX15) that significantly associated with worse disease-free survival (hazard ratio 2.23, 95% CI 1.58 to 2.88, p = 0.015). In summary, miR-96 targets a RAR gamma network to govern AR signaling, PCa progression and disease outcome.

Springer2019

Combinatorial targeting of angiogenesis with inducers of autophagy in the treatment of glioblastoma multiforme

Julie Laetitia Scotton

EPFL2018