82 research outputs found
Genetic Mouse Models as In Vivo Tools for Cholangiocarcinoma Research
Cholangiocarcinoma (CCA) is a genetically and histologically complex disease with a highly dismal prognosis. A deeper understanding of the underlying cellular and molecular mechanisms of human CCA will increase our current knowledge of the disease and expedite the eventual development of novel therapeutic strategies for this fatal cancer. This endeavor is effectively supported by genetic mouse models, which serve as sophisticated tools to systematically investigate CCA pathobiology and treatment response. These in vivo models feature many of the genetic alterations found in humans, recapitulate multiple hallmarks of cholangiocarcinogenesis (encompassing cell transformation, preneoplastic lesions, established tumors and metastatic disease) and provide an ideal experimental setting to study the interplay between tumor cells and the surrounding stroma. This review is intended to serve as a compendium of CCA mouse models, including traditional transgenic models but also genetically flexible approaches based on either the direct introduction of DNA into liver cells or transplantation of pre-malignant cells, and is meant as a resource for CCA researchers to aid in the selection of the most appropriate in vivo model system
Single-institution experience in clinical trials during the COVID-19 pandemic in Spain: Not so bad after all?
The impact of the COVID-19 outbreak in Spain during
March-April 2020 has been unbalanced throughout
the different regions of the country. The alarm status
defined by the government on March 14, and still in
place at the time of this writing, has transformed the
country in different perspectives, including care of
patients with cancer.1 In many centers, clinical trial
activity was suspended, because it was not considered
a priority under the health care challenge of the
COVID-19 pandemic.2 Nevertheless, experimental
therapy is the only and/or best therapeutic option for
many patients with cancer
Genetic mouse models as in vivo tools for cholangiocarcinoma research
Cholangiocarcinoma (CCA) is a genetically and histologically complex disease with
a highly dismal prognosis. A deeper understanding of the underlying cellular and molecular
mechanisms of human CCA will increase our current knowledge of the disease and expedite
the eventual development of novel therapeutic strategies for this fatal cancer. This endeavor is
effectively supported by genetic mouse models, which serve as sophisticated tools to systematically
investigate CCA pathobiology and treatment response. These in vivo models feature many of the
genetic alterations found in humans, recapitulate multiple hallmarks of cholangiocarcinogenesis
(encompassing cell transformation, preneoplastic lesions, established tumors and metastatic disease)
and provide an ideal experimental setting to study the interplay between tumor cells and the
surrounding stroma. This review is intended to serve as a compendium of CCA mouse models,
including traditional transgenic models but also genetically flexible approaches based on either the
direct introduction of DNA into liver cells or transplantation of pre-malignant cells, and is meant as a
resource for CCA researchers to aid in the selection of the most appropriate in vivo model system
Endoscopical and pathological dissociation in severe colitis induced by immune-checkpoint inhibitors
Checkpoint inhibitors have improved the survival of patients with advanced tumors and show
a manageable toxicity profile. However, auto-immune colitis remains a relevant side effect, and combinations of anti-PD1/PDL1 and anti-CTLA-4 increase its incidence and severity. Here, we report the case of
a 50-year-old patient diagnosed with stage IV cervical cancer that relapsed following radical surgery,
external radiation/brachytherapy and standard chemotherapy. She was subsequently treated with
Nivolumab and Ipilimumab combination and developed grade 2 colitis presenting a dissociation
between endoscopic and pathological findings. At cycle 10 the patient reported grade 3 diarrhea and
abdominal discomfort, without blood or mucus in the stools. Immunotherapy was withheld and
a colonoscopy was performed, showing normal mucosa in the entire colon. Puzzlingly, histologic
evaluation of randomly sampled mucosal biopsy of the distal colon showed an intense intraepithelial
lymphocyte infiltration with crypt loss and some regenerating crypts with a few apoptotic bodies set in
a chronically inflamed lamina propria, consistent with the microscopic diagnosis of colitis. Treatment
with methylprednisolone 2 mg/kg was initiated which led to a decrease in the number of stools to grade
1. Additional investigations to exclude other causes of diarrhea rendered negative results. The patient
experienced a major partial response and, following the resolution of diarrhea, she was re-challenged
again with immunotherapy, with the reappearance of grade 2 diarrhea, leading to permanent immunotherapy interruption. We conclude and propose that performing random colonic biopsies should be
considered in cases of immune checkpoint-associated unexplained diarrhea, even when colonoscopy
shows macroscopically normal colonic mucosa inflammatory lesions
An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer
KRAS mutated tumours represent a large fraction of human cancers, but the vast majority remains refractory to current clinical therapies. Thus, a deeper understanding of the molecular mechanisms triggered by KRAS oncogene may yield alternative therapeutic strategies. Here we report the identification of a common transcriptional signature across mutant KRAS cancers of distinct tissue origin that includes the transcription factor FOSL1. High FOSL1 expression identifies mutant KRAS lung and pancreatic cancer patients with the worst survival outcome. Furthermore, FOSL1 genetic inhibition is detrimental to both KRAS-driven tumour types. Mechanistically, FOSL1 links the KRAS oncogene to components of the mitotic machinery, a pathway previously postulated to function orthogonally to oncogenic KRAS. FOSL1 targets include AURKA, whose inhibition impairs viability of mutant KRAS cells. Lastly, combination of AURKA and MEK inhibitors induces a deleterious effect on mutant KRAS cells. Our findings unveil KRAS downstream effectors that provide opportunities to treat KRAS-driven cancers
Cytokines in clinical cancer immunotherapy
Cytokines are soluble proteins that mediate cell-to-cell communication. Based on the discovery of the potent anti-tumour activities of several pro-inflammatory cytokines in animal models, clinical research led to the approval of recombinant interferon-alpha and interleukin-2 for the treatment of several malignancies, even if efficacy was only modest. These early milestones in immunotherapy have been followed by the recent addition to clinical practice of antibodies that inhibit immune checkpoints, as well as chimeric antigen receptor T cells. A renewed interest in the anti-tumour properties of cytokines has led to an exponential increase in the number of clinical trials that explore the safety and efficacy of cytokine-based drugs, not only as single agents, but also in combination with other immunomodulatory drugs. These second-generation drugs under clinical development include known molecules with novel mechanisms of action, new targets, and fusion proteins that increase half-life and target cytokine activity to the tumour microenvironment or to the desired effector immune cells. In addition, the detrimental activity of immunosuppressive cytokines can be blocked by antagonistic antibodies, small molecules, cytokine traps or siRNAs. In this review, we provide an overview of the novel trends in the cytokine immunotherapy field that are yielding therapeutic agents for clinical trials
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