Background Although safety and prognostic factors for overall survival (OS) have been extensively studied in Phase I clinical trials on patients with solid tumours, data on lymphoma trials are scarce. Here, we investigated safety, outcomes and prognostic factors in relapsed or refractory lymphoma patients included in a series of Phase I trials. Method and patients All consecutive adult patients with recurrent/refractory lymphoma enrolled in 26 Phase I trials at a single cancer centre in France between January 2008 and June 2016 were retrospectively assessed. Results 133 patients (males: 65%) were included in the analysis. The median (range) age was 65 (23-86). Aggressive non-Hodgkin, indolent non-Hodgkin and Hodgkin types accounted for 64%, 25% and 11% of the patients, respectively. The patients had received a median (range) of 3 (1-13) lines of treatment prior to trial entry. The median [95% confidence interval] progression-free survival and OS times were 3.0 [1.8-3.6] and 17.8 [12.7-30.4] months, respectively. High-grade toxicity (grade 3 or higher, according to the National Cancer Institute's Common Terminology Criteria for Adverse Events classification) was experienced by 56 of the 133 patients (42%) and was related to the investigational drug in 44 of these cases (79%). No toxicity-related deaths occurred. Dose-limiting toxicity (DLT) was encountered in 11 (9%) of the 116 evaluable patients. High-grade toxicity occurred during the DLT period for 34 of the 56 patients (61%) and after the DLT period in the remaining 22 (39%). The main prognostic factors for poor OS were the histological type (i.e. tumour aggressiveness), an elevated serum LDH level, and a low serum albumin level. Early withdrawal from a trial was correlated with the performance status score, the histological type and the serum LDH level. The overall objective response and disease control rates were 24% and 57%, respectively. Conclusion Performance status, LDH, albumin and histological type (tumour aggressiveness) appear to be the most relevant prognostic factors for enrolling Phase I participants with relapsed or refractory lymphoma. 39% of the patients experienced a first high-grade toxic event after the dose-limiting toxicity period, suggesting that the conventional concept of dose-limiting toxicity (designed for chemotherapy) should be redefined in the era of modern cancer therapies.
Metastatic progression of cancer, which is responsible for 90% of patients death, results from tumor cells dissemination out of the primary tumor throughout the body. During the first step of this process -that consists in invasion of the peritumoral stroma- cancer cells can adopt 1) a single cell mode of invasion, in which cell have lost cell-cell junctions to move individually, 2) or a collective mode of invasion where cells maintain their cell-cell junctions to move as a cohort in which Leader cells at the front drag the follower cells at the rear. Although tumour histology data from cancer patients show that invasion occurs predominantly in a collective manner, this mode of cell invasion remains underinvestigated. My work aims at identifying the molecular and cellular mechanisms underlying colorectal carcinoma (CRC) collective invasion. I use 3D organotypic models of CRC: Caco-2 cell lines or organoids generated from CRC patients derived xenografts (PDX) and assess invasion in collagen-I based gels using microscopy approaches on fixed or live samples. Knowing its central role in the cytoskeleton dynamics which is the motor of cell motility, we hypothesize that RhoGTPases signaling pathways could control the collective mode of invasion. We therefore performed a siRNA based screen targeting the 98 effectors of the pathway and found ROCK to be an anti-invasive protein. Although it had been described as a proinvasive protein in the single cell mode of invasion, we confirmed using pharmacological inhibitors (Y27632 and H1152), that ROCK activity inhibition triggered collective invasion. Using a ROCK2 dominant negative mutant specifically targeting ROCK2 isoform but not ROCK1, I demonstrated that ROCK2 inhibition was sufficient to induce leader cell formation leading to collective invasion. In contrast, depletion of MyosinII -ROCK’s most common effector- was not sufficient to induce efficient protusive leader cells. However I found RAC1 to be necessary and in a 2nd siRNA based screen targeting GEFs, we identified FARP2, a GEF for Rac1, as the mediator of ROCK-RAC1 crosstalk in collective invasion. Even though the activation of FARP2 alone or RAC1 alone were not sufficient to induce leader cell formation, the concomitant inhibition of MyosinII recapitulated the collective invasion induced by ROCK inhibition. Altogether these results show a new anti-invasive role of ROCK2 kinase in collective invasion as it controls the formation of leader cells, through 1) the negative regulation of RAC1 and its GEF FARP2, and 2) the positive regulation of MyosinII. Citation Format: Fotine Libanje, Joel Raingeaud, Zoé ap Thomas, Fatiha Sangar-Mavouna, Anne Chauchereau Chauchereau, Fanny Jaulin. ROCK dependent signalling pathways contribution to collective invasion of colorectal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 892. doi:10.1158/1538-7445.AM2017-892
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