Targeting Cancer Pathways: The Epigenetics Question

Описание: Participating Experts: Stephen B. Baylin, MD (Johns Hopkins), Charles Roberts, MD PhD, (Dana Farber), Ali Shilatifard, PhD (Northwestern)
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Tumors are complex tissues in which the cancer cells evolve traits that promote their own survival and progression of the disease. Some of these traits involve epigenetic mechanisms to drive oncogenesis, stimulate tumor cell proliferation, and evasion of the immune system. This webinar explores how aberrant changes in epigenetic modification can affect the expression of key genes and contribute to the pathological progression of cancer. Topics include:
• The major epigenetic changes seen in tumor tissue
• How specific epigenetic pathways can be targeted for therapeutic intervention
• The role of histone modifications (methylation, acetylation, ubiquitylation, phosphorylation, and others) in tumor survival and progression.

Table of Contents
0:00 Welcome and overview
2:32 Stephen Baylin speaker profile
3:18 Epigenetics – classical and modern
4:52 Epigenomics hard drive and software
5:53 Cancer and the Epigenome
7:39 The position of mutations and the abnormal epigenome in tumor progression
8:51 The hallmarks of cancer and therapy targets
10:29 A trial of low dose epigenetic therapy for advanced NSCLC – what have we learned?
11:32 Images of patient with partial response: hepatic metastases
12:59 Potential for epigenetic Rx priming to immune tolerance therapy
14:11 Immune tolerance
14:54 Study design
16:19 Viral defense – nucleotide sensing
18:15 Hypothesis – epigenetic therapy sensitizing to immune checkpoint therapy
19:35 Charles Roberts speaker profile
20:27 SWI/SNF (BAF) chromatin remodeling complexes in cancer
21:34 Rhabdoid tumors
22:01 The SWI/SNF complex mobilizes nucleosomes
22:53 Snf5 targeted mice develop aggressive cancers
22:43 Frequent inactivating mutations of SWI/SNF complex subunitsd in a variety of cancers
24:54 Rhabdoid tumors have the lowest somatic mutation rate across cancers analyzed so far at the Broad (~3000 exomes)
25:51 Swi/Snf and polycomb: epigenetic antagonism?
26:36 Ezh2 is essential for in vivo tumor formation after Snf5 inactivation
27:33 Phase I trial: Complete response in a malignant rhabdoid tumor patient treated with and EZH2 inhibitor
29:02 Project Achilles: ARID1B is the #1 dependency in ARID1A mutant cancer cells
29:47 Residual SWI/SNF complexes can be a vulnerability in cancers containing a SWI/SNF subunit mutation
31:14 Conclusions
32:04 Ali Shilatifard speaker profile
33:31 Cancer prevalence with age
34:39 Enhancer malfunction in cancer
35:43 Stem cells and epigenetic processes in cancer pathogenesis
37:44 Chromosomal translocations in MLL and leukemogenesis?
40:13 Examples of acute leukemia
41:06 Model systems for study of MLL
42:23 Purification of yeast Set1/COMPASS family of H3K4 methylases
45:13 Cancer genes identified
46:38 Enhancer/promoter looping in transcriptional activation
47:39 Enhancer malfunction in upregulated activation of oncogene expression
48:49 Question and answer

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