The opening lecture “Inflammation, Metabolism, Aging and Cancer: Dangerous Liaisons” at the IDIBELL Cancer Conference (ICC) on Personalized Cancer Medicine, that took place in Hesperia Convention Hotel, was given by Michael Karin, from the University of California San Diego (UCSD).
Obesity, related with hypernutrition, is related with the formation of lipids droplets that can lead to a Hepatosteatosis. The downregulation of IKKalpha and upregulation of p62 is also seen in human pancreatic cancer.
Colitis is associated with spontaneous colorectal cancer
There are four stages in the colorectal cancer: spontaneous colon cancer, ACF, Adenoma and, then, Carcinoma (CRC). The elevated expression of IL17-T(h)17 signature genes correlates with poor prognostic and decreased survival in human CRC. IL-23 is upregulated in spontaneous colorectal cancer. “We see a similar situation in human and in mice model. The role of IL-23 signalling promotes colorectal cancer”, said Karin. The IL-23R signalling promotes colorectal cancer and it is required for CRC tumorigenesis. IL-23/ IL-23R signalling in hematopoietic cells controls spontaneous colorectal tumour growth, related with tumour size, and also the expression of inflammatory cytokines and IL-17 producing cells. IL-17 is required for CRC development and progression. MyD88/TLR signalling in hematopoietic cells is important for tumour growth.
The antibiotics reduce tumour load in CPC-APC mice, after a study developed during 4 months. “We saw in mice model that the development of colorectal tumours is associated with a localized increase in permeability to microbes and their products” said Michael Karin and continued “we have also demonstrated that colorectal adenomas exhibit specific loss of barrier proteins. The early human adenomas display loss of Mucin expression”. “We can determine the basis of the variation in human population, the genetic factors dictate a higher Th17 response in these patients”, concluded the researcher.
Manel Esteller: PharmacoEpigenetic and Cancer
After the opening conference, took place the talk of Manel Esteller, about the important marks in epigenetics. The epigenetic differences arise during life. “We have found discordant twins for breast cancer. The epigenetics can be a predictor about the illness”, said the IDIBELL researcher. “More and more we see more epigenetic targets”, said Esteller. “Now, we analyse the same question with –omics”. MGMT Hypermethylation predicts good clinical response of Dacarbazine in colorectal cancer patients.
Another example provided is the BRCA1. Breast cancer is one of the most common cancers. Exploring the BRCA1 and BRCA2 defects in therapy we can see that BRCA1 epigenetic inactivation predicts sensitivity to platinum—based Chemotherapy
There are some drugs, like EZH2, that are genes suppressors that give new opportunities for cancer treatment and therapy. “For example, Enoxacin is a small drug to enhance miRNA production”, said the IDIBELL researcher. “The future? We have a complex scenario”, concluded Esteller who briefly showed the results about centenary and baby epigenome.
Nick La Thangue: “HR23B is a predictive biomarker for HDAC inhibitor”
Nick La Thangue, from the Department of Oncology at the University of Oxford, talked about HDAC inhibitors and cancer, in the conference “The HDAC inhibitors from bench to clinic, and back again”. The HDAC inhibitors can influence in the protease activity. HR23B regulates the proteasome activity. HR23B sensitises cells by influencing protein turnover – high levels choke proteasome activity. The HDAC inhibitors cause apoptosis, in part through the proteasome. We find a biomarker expression in HDAC inhibitor treated tumours. The HDAC6 is involved in the protein quality control and regulates HR23B and sensitivity to apoptosis. HR23B is a predictive biomarker for HDAC inhibitor response.
Christopher Vakoc: “BRD4 maintains MYC transcription in leukemia”
The 70% of Acute Myeloid Leukemia (AML) patients obtain initial remission with treatment. AML is caused by aberrant chromatin regulation. “Our hypothesis was that targeting of chromatin regulators in leukaemia will be an effective treatment strategy. There are few unique requirements in non-leukemia cancer lines”, said the researcher. The BRD4 is a “reader” of acetylated histones and it maintains Myc transcription in leukemia. Its pharmacological inhibition extinguishes Myc expression. “What explains the hypersensitivity of Myc expression to JQ1 in leukemia?”, asked Vakoc. The role of BRD4 in maintaining Myc expression is unique to haematological cancer and it occupies all active promoters in the leukaemia genome.