Patient-customized Drug Combination Prediction and Testing for T-cell Prolymphocytic Leukemia Patients

The molecular pathways that drive cancer progression and treatment resistance are highly redundant and variable between individual patients with the same cancer type. To tackle this complex rewiring of pathway crosstalk, personalized combination treatments targeting multiple cancer growth and survival pathways are required. Here we implemented a computational-experimental drug combination prediction and testing (DCPT) platform for efficient in silico prioritization and ex vivo testing in patient-derived samples to identify customized synergistic combinations for individual cancer patients. DCPT used drug-target interaction networks to traverse the massive combinatorial search spaces among 218 compounds (a total of 23,653 pairwise combinations) and identified cancer-selective synergies by using differential single-compound sensitivity profiles between patient cells and healthy controls, hence reducing the likelihood of toxic combination effects. A polypharmacology-based machine learning modeling and network visualization made use of baseline genomic and molecular profiles to guide patient-specific combination testing and clinical translation phases. Using T cell prolymphocytic leukemia (T-PLL) as a first case study, we show how the DCPT platform successfully predicted distinct synergistic combinations for each of the three T-PLL patients, each presenting with different resistance patterns and synergy mechanisms. In total, 10/24 (42%) of selective combination predictions were experimentally confirmed to show synergy in patient-derived samples ex vivo. The identified selective synergies among approved drugs, including tacrolimus and temsirolimus combined with BCL-2 inhibitor venetoclax, may offer novel drug repurposing opportunities for treating T-PLL.

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hPCL3s promotes hepatocellular carcinoma metastasis by activating {beta}-catenin signaling

Two isoforms of human Polycomb-like protein 3 (hPCL3) have been reported as components of the nuclear Polycomb repressive complex 2 (PRC2) with the short isoform (hPCL3s) showing a dominant cytoplasmic localization. The function of cytoplasmic hPCL3s has however not been addressed. In this study, we report that hPCL3s is upregulated in clinical hepatocellular carcinoma (HCC) samples and its expression correlated with HCC clinical features. hPCL3s positively regulated the migration, invasion, and metastasis of HCC cells. hPCL3s interacted with components of the cytoplasmic beta-catenin destruction complex, inhibited beta-catenin degradation, and activated beta-catenin/T-cell factor (TCF) signaling. Downstream of the beta-catenin cascade, interleukin 6 (IL-6) mediated the motility-promoting functions of hPCL3s. Forced expression of hPCL3s in the liver of a HCC mouse model promoted tumorigenesis and metastasis. Taken together, these data show that hPCL3s promotes the metastasis of HCC by activating the beta-catenin/IL-6 pathway.

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A soft microenvironment protects from failure of midbody abscission and multinucleation downstream of the EMT-promoting transcription factor Snail

Multinucleation is found in more than one third of tumors and is linked to increased tolerance for mutation, resistance to chemotherapy, and invasive potential. The integrity of the genome depends on proper execution of the cell cycle, which can be altered through mechanotransduction pathways as the tumor microenvironment stiffens during tumorigenesis. Here we show that signaling downstream of matrix metalloproteinase-3 (MMP3) or transforming growth factor-beta (TGFbeta), known inducers of epithelial-mesenchymal transition (EMT), also promotes multinucleation in stiff microenvironments through Snail-dependent expression of the filament-forming protein septin-6, resulting in midbody persistence, abscission failure, and multinucleation. Consistently, we observed elevated expression of Snail and septin-6 as well as multinucleation in a human patient sample of metaplastic carcinoma of the breast, a rare classification characterized by deposition of collagen fibers and active EMT. In contrast, a soft microenvironment protected mammary epithelial cells from becoming multinucleated by preventing Snail-induced upregulation of septin-6. Our data suggest that tissue stiffening during tumorigenesis synergizes with oncogenic signaling to promote genomic abnormalities that drive cancer progression.

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IRAK1 augments cancer stemness and drug resistance via the AP-1/AKR1B10 signaling cascade in hepatocellular carcinoma

Frequent relapse and drug resistance in patients with hepatocellular carcinoma (HCC) can be attributed to the existence of tumor-initiating cells (T-IC) within the tumor bulk. Therefore, targeting liver T-IC may improve the prognosis of these patients. From transcriptome sequencing of 16 pairs of clinical HCC samples, we report that interleukin-1 receptor-associated kinase 1 (IRAK1) in the TLR/IRAK pathway is significantly upregulated in HCC. IRAK1 overexpression in HCC was further confirmed at the mRNA and protein levels and correlated with advanced tumor stages and poor patient survival. Interestingly, IRAK4, an upstream regulator of IRAK1, was also consistently upregulated. IRAK1 regulated liver T-IC properties including self-renewal, tumorigenicity, and liver T-IC marker expression. IRAK1 inhibition sensitized HCC cells to doxorubicin and sorafenib treatment in vitro via suppression of the apoptotic cascade. Pharmacological inhibition of IRAK1 with a specific IRAK1/4 kinase inhibitor consistently suppressed liver T-IC populations. We identified aldo-keto reductase family 1 member 10 (AKR1B10) as a novel downstream target of IRAK1, which was found to be overexpressed in HCC and significantly correlated with IRAK1 expression. Knockdown of AKR1B10 negated IRAK1-induced T-IC functions via modulation of the AP-1 complex. Inhibition of IRAK1/4 inhibitor in combination with sorafenib synergistically suppressed tumor growth in an HCC xenograft model. In conclusion, targeting the IRAK4/IRAK1/AP-1/AKR1B10 signaling pathway may be a potential therapeutic strategy against HCC.

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A randomized phase 3 trial comparing paclitaxel plus 5-fluorouracil versus cisplatin plus 5-fluorouracil in Chemoradiotherapy for locally advanced esophageal carcinoma—the ESO-shanghai 1 trial protocol

Abstract

Background

Concurrent chemoradiotherapy is a standard modality for locally advanced esophageal squamous cell carcinoma (ESCC) patients. Cisplatin combined with 5-fluorouracil continuous infusion (PF) remains the standard concurrent chemotherapy regimen. However, radiotherapy concurrent with PF showed a high incidence of severe side effects. Paclitaxel showed a promising radiosensitivity enhancement in the treatment of esophageal carcinoma in both vitro and vivo studies. The ESO-Shanghai 1 trial examines the hypothesis that paclitaxel plus 5-fluorouracil (TF) concurrent with radiotherapy has better overall survival and lower toxicity for patients with local advanced ESCC.

Method

Four hundred thirty-six ESCC patients presenting with stage IIa to IVa will be enrolled in a prospective multicenter randomized phase 3 study. Patients will be randomized to either concurrent chemoradiotherapy with PF (cisplatin 25 mg/m²/d, d1–3, plus 5-fluorouracil 1800 mg/m², continuous infusion for 72 h) once every 4 weeks for 2 cycles followed by consolidation chemotherapy for 2 cycles or concurrent chemoradiotherapy with weekly TF (5-fluorouracil 300 mg/m², continuous infusion for 96 h plus paclitaxel 50 mg/m², d1) for 5 weeks followed by consolidation chemotherapy (5-fluorouracil 1800 mg/m², continuous infusion for 72 h, plus paclitaxel 175 mg/m² d1) once every 4 weeks for 2 cycles. The radiotherapy dose is 61.2 Gy delivered in 34 fractions to the primary tumor including lymph nodes. The primary end-point is the 3-yr overall survival analyzed by intention to treat. The secondary endpoints are disease progression-free survival, local progression-free survival, and number and grade of participants with adverse events.

Discussion

The aim of this phase 3 study is to determine whether the TF regimen could replace the standard PF regimen for inoperable ESCC patients. An overall survival benefit of 12% at 3 years should be expected in the TF group to achieve this goal.

Trial registration

ClinicalTrials.gov Identifier: NCT01591135. Registered 18 April 2012.

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A new tissue segmentation method to calculate 3D dose in small animal radiation therapy

Abstract

Background

In pre-clinical animal experiments, radiation delivery is usually delivered with kV photon beams, in contrast to the MV beams used in clinical irradiation, because of the small size of the animals. At this medium energy range, however, the contribution of the photoelectric effect to absorbed dose is significant. Accurate dose calculation therefore requires a more detailed tissue definition because both density (ρ) and elemental composition (Z_eff) affect the dose distribution. Moreover, when applied to cone beam CT (CBCT) acquisitions, the stoichiometric calibration of HU becomes inefficient as it is designed for highly collimated fan beam CT acquisitions. In this study, we propose an automatic tissue segmentation method of CBCT imaging that assigns both density (ρ) and elemental composition (Z_eff) in small animal dose calculation.

Methods

The method is based on the relationship found between CBCT number and ρ*Z_eff product computed from known materials. Monte Carlo calculations were performed to evaluate the impact of ρZ_eff variation on the absorbed dose in tissues. These results led to the creation of a tissue database composed of artificial tissues interpolated from tissue values published by the ICRU. The ρZ_eff method was validated by measuring transmitted doses through tissue substitute cylinders and a mouse with EBT3 film. Measurements were compared to the results of the Monte Carlo calculations.

Results

The study of the impact of ρZ_eff variation over the range of materials, from ρZ_eff = 2 g.cm^− 3 (lung) to 27 g.cm^− 3 (cortical bone) led to the creation of 125 artificial tissues. For tissue substitute cylinders, the use of ρZ_eff method led to maximal and average relative differences between the Monte Carlo results and the EBT3 measurements of 3.6% and 1.6%. Equivalent comparison for the mouse gave maximal and average relative differences of 4.4% and 1.2%, inside the 80% isodose area. Gamma analysis led to a 94.9% success rate in the 10% isodose area with 4% and 0.3 mm criteria in dose and distance.

Conclusions

Our new tissue segmentation method was developed for 40kVp CBCT images. Both density and elemental composition are assigned to each voxel by using a relationship between HU and the product ρZ_eff. The method, validated by comparing measurements and calculations, enables more accurate small animal dose distribution calculated on low energy CBCT images.

http://ift.tt/2Cn7t7N

A randomized phase 3 trial comparing paclitaxel plus 5-fluorouracil versus cisplatin plus 5-fluorouracil in Chemoradiotherapy for locally advanced esophageal carcinoma—the ESO-shanghai 1 trial protocol

Abstract

Background

Concurrent chemoradiotherapy is a standard modality for locally advanced esophageal squamous cell carcinoma (ESCC) patients. Cisplatin combined with 5-fluorouracil continuous infusion (PF) remains the standard concurrent chemotherapy regimen. However, radiotherapy concurrent with PF showed a high incidence of severe side effects. Paclitaxel showed a promising radiosensitivity enhancement in the treatment of esophageal carcinoma in both vitro and vivo studies. The ESO-Shanghai 1 trial examines the hypothesis that paclitaxel plus 5-fluorouracil (TF) concurrent with radiotherapy has better overall survival and lower toxicity for patients with local advanced ESCC.

Method

Four hundred thirty-six ESCC patients presenting with stage IIa to IVa will be enrolled in a prospective multicenter randomized phase 3 study. Patients will be randomized to either concurrent chemoradiotherapy with PF (cisplatin 25 mg/m²/d, d1–3, plus 5-fluorouracil 1800 mg/m², continuous infusion for 72 h) once every 4 weeks for 2 cycles followed by consolidation chemotherapy for 2 cycles or concurrent chemoradiotherapy with weekly TF (5-fluorouracil 300 mg/m², continuous infusion for 96 h plus paclitaxel 50 mg/m², d1) for 5 weeks followed by consolidation chemotherapy (5-fluorouracil 1800 mg/m², continuous infusion for 72 h, plus paclitaxel 175 mg/m² d1) once every 4 weeks for 2 cycles. The radiotherapy dose is 61.2 Gy delivered in 34 fractions to the primary tumor including lymph nodes. The primary end-point is the 3-yr overall survival analyzed by intention to treat. The secondary endpoints are disease progression-free survival, local progression-free survival, and number and grade of participants with adverse events.

Discussion

The aim of this phase 3 study is to determine whether the TF regimen could replace the standard PF regimen for inoperable ESCC patients. An overall survival benefit of 12% at 3 years should be expected in the TF group to achieve this goal.

Trial registration

ClinicalTrials.gov Identifier: NCT01591135. Registered 18 April 2012.

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