Novel targets and therapeutic strategies for the treatment of hepatocellular carcinoma (HCC)

Liver cancer is a leading cause of cancer-related mortality worldwide and accounts for more than 800.000 deaths per year. Hepatocellular carcinoma (HCC) is a common cancer with high lethality, which is diagnosed most often at advanced stages when surgical or local treatment options are not possible. For the treatment of advanced HCC, sorafenib has been the only approved systemic treatment for nearly 10 years. Lately however, a number of additional compounds targeting tumour-specific signalling pathways, such as regorafenib, lenvatinib, and cabozantinib, and most recently, ramucirumab, provided positive results in phase-3 clinical trials. In addition, the approval of nivolumab as second-line treatment revealed the importance of the immune response in determining the development in HCC and set the stage for extensive clinical research with these agents. These new therapeutic options for HCC have significantly prolonged the life expectancy in patients with advanced-stage disease and collectively provided evidence that targeted therapy in different lines of treatment is a feasible strategy also for HCC. Nevertheless, a great individual variability in clinical benefits in response to these agents can be observed, and prognosis remains extremely poor in the majority of patients not responding to the treatments. By the two presented research projects, we aimed at assessing new therapeutic targets and possible therapeutic strategies for the treatment of HCC. In the first project, which was previously published in the form of an abstract, we explored the possibility of enhancing the therapeutic potential of sorafenib by its combination with the novel and clinically viable PI3K-Akt-Tor inhibitor copanlisib. To this regard, we found that copanlisib possesses potent anticancer activity as single agent and acts synergistically in combination with sorafenib in human HCC, hereby representing a rational potential therapeutic option for advanced HCC. In the second project, which was also presented and published as an abstract, we investigated the role of olfactomedin 4 (OLFM4), a glycoprotein predominantly expressed in bone marrow and gastrointestinal tract, in the pathogenesis of HCC. By performing immunohistochemical staining in human HCC tissues and functional in vitro assays of Huh7 and HepG2 cell lines, we provided the first report on a possible role of this molecule in determining the development of HCC by showing that increased expression of OLFM4 is a common event in the pathogenesis of this tumor with independent prognostic significance. Our preclinical results from these two studies, which are presented in the form of the two different manuscripts about to be submitted or published, warrant further investigation of PI3K-Akt-Tor signalling as a mechanism of cancer development and chemoresistance during HCC treatment, as well as of the role played by OLFM4 in determining invasion and metastasis in this tumor

Concomitant Irradiation to Checkpoint Inhibitor Therapy of Hepatocellular Carcinoma Patients: A Systematic Retrospective, Single-Center Analysis

Introduction: Immunotherapy has been established as the standard treatment option for patients with advanced hepatocellular carcinoma (aHCC). Despite the increased efficacy, disease progression occurs in a relevant proportion of patients even after an objective response. Combination concepts with locoregional therapy are currently under investigation for hepatic disease but are also in discussion for the control of distant metastasis. Radiotherapy is a highly effective treatment modality for local tumor control. It is also thought to increase the efficacy of checkpoint inhibition and sensitize distant lesions to the effects of immunotherapy, but may potentially increase adverse effects. In our center, few patients with aHCC treated with immune checkpoint inhibitors (ICIs) received concomitant radiotherapy for symptom or disease control. The aim of this study was to retrospectively analyze adverse effects and efficacy of concomitant radiotherapy in patients with aHCC treated with checkpoint inhibition. Methods: To this aim, patients who received a combination of ICI and radiotherapy in our institution were retrospectively considered for analysis. The predefined inclusion criterion was radiotherapy after initiated checkpoint inhibition and continuation of ICI therapy for at least 8 weeks. Adverse effects and efficacy measurements were performed according to local standards. Results: The database search of 2016–2021 revealed six consecutive patients fulfilling the predefined criteria for concomitant ICI and radiotherapy. Three patients received high-dose-rate brachytherapy (15 Gy) to treat progredient hepatic lesions. Two patients received stereotactic body radiotherapy (SBRT) (25–30 Gy) for symptom control, and 1 patient received brachytherapy and SBRT to treat metastases. No severe adverse events were reported in the period (<6 months) after concomitant radiotherapy. In 5 out of 6 cases, long-term tumor control could be achieved by this therapeutic combination. Conclusion: A good efficacy of concomitant radiotherapy and checkpoint inhibition has been achieved with no safety concerns. Further investigations should evaluate the safety, appropriate clinical context, and efficacy of this promising approach

Whole exome sequencing identifies frequent somatic mutations in cell-cell adhesion genes in chinese patients with lung squamous cell carcinoma

Lung squamous cell carcinoma (SQCC) accounts for about 30% of all lung cancer cases. Understanding of mutational landscape for this subtype of lung cancer in Chinese patients is currently limited. We performed whole exome sequencing in samples from 100 patients with lung SQCCs to search for somatic mutations and the subsequent target capture sequencing in another 98 samples for validation. We identified 20 significantly mutated genes, including TP53, CDH10, NFE2L2 and PTEN. Pathways with frequently mutated genes included those of cell-cell adhesion/Wnt/Hippo in 76%, oxidative stress response in 21%, and phosphatidylinositol-3-OH kinase in 36% of the tested tumor samples. Mutations of Chromatin regulatory factor genes were identified at a lower frequency. In functional assays, we observed that knockdown of CDH10 promoted cell proliferation, soft-agar colony formation, cell migration and cell invasion, and overexpression of CDH10 inhibited cell proliferation. This mutational landscape of lung SQCC in Chinese patients improves our current understanding of lung carcinogenesis, early diagnosis and personalized therapy

Sex differences in oncogenic mutational processes.

Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Interpreting the lake-status record of the East Asian monsoon using a hydrological model

AbstractThe East Asian monsoon (EAM) has experienced significant changes over the past 10,000 years that influenced East Asian agricultural development. However, the magnitude and extent of the EAM precipitation fluctuations at 6 ka remain unresolved, owing to uncertainty in individual lake records and substantial variations in the expansion limits in simulations of the mid-Holocene EAM precipitation. Here we present an approach based on multiple lake-level records using the “1D lake level—2D lake area—3D catchment hydrology” model to reconstruct the precipitation patterns in northern China, and to further quantify the extent of the EAM precipitation expansion in the mid-Holocene relative to today. The precipitation reconstructions suggest an ~550–1100 km northward expansion and an ~530–840 km westward migration of the EAM at 6 ka. At that time, the EAM precipitation domain covered over 6 million square kilometers. Thus, this approach mitigates the uncertainty and arbitrariness of reconstructions of the limit of the EAM precipitation fields and provides a benchmark for future climate modeling studies.</jats:p