Lecture+6_Hallmarks+of+Cancer.pptx

Required accompanying reading Pharmacology 4001: Mechanisms of Drug Action Review Article #1 Lecture 6: Hallmarks of Cancer Optional Review Article Feb 1, 2024 Cheuk Leung, PhD Assistant Professor Director of Undergraduate Studies Department of Pharmacology Masonic Cancer Center University of Minnes...

Required accompanying reading Pharmacology 4001: Mechanisms of Drug Action Review Article #1 Lecture 6: Hallmarks of Cancer Optional Review Article Feb 1, 2024 Cheuk Leung, PhD Assistant Professor Director of Undergraduate Studies Department of Pharmacology Masonic Cancer Center University of Minnesota Medical School Cancer A collection of diseases characterized by abnormal growth and spread of mutant cells >100 distinct types of cancer, and subtypes of tumors can be found within specific organs Cancer cells have defects in regulatory circuits that govern normal cell proliferation and homeostasis. Mutations that produce oncogenes with dominant gain of function Loss of tumor suppressor genes A multistep process that reflects genetic alterations driving the progressive transformation Hallmarks of Cancer Capabilities of Cancer … that are distinct from normal cells Target Selectivity Figure 1 Kill cancer cells Stop cancer cell growth Stop cancer cell spreading …Without affecting the normal cells Figure 1 Growth Signals Growth Factor Signaling Anti-growth signals Cell cycle checkpoints Apoptosis Programmed cell death Limitless replication Hayflick's limit Telomerase Non-apoptosis programmed cell death Necroptosis, Paraptosis, Pyroptosis, Ferroptosis, Figure 1 Angiogenesis Supply nutrients for continual growth in size for solid tumors Signals the migration, growth, and differentiation of endothelial cells to form new blood vessels into the tumors Tissue invasion & Metastasis Spread to secondary organs Cell migration, invasion, extravasation, intravasation, colonization, metastasis Figure 2 Invasion & Metastasis Anti-growth Growth Apoptosis Figure 3 Figure 4 Approximately what percentage of cancer cells are in S phase? A. 1-5% B. 5-25% C. 25-50% D. 50-75% E. >75% Mitchison TJ. The proliferation rate paradox in antimitotic chemotherapy. Mol Biol Cell. 2012 Jan;23(1):1-6. doi: 10.1091/mbc.E10-04-0335. PMID: 22210845 Targets for Anti-cancer Drugs Crucial drivers of the cancer Selectivity Target e.g. Cisplatin e.g. Herceptin All dividing cells Cancer and normal cells that rely on that growth signal Selectivity DNA replication Drug Example: Growth Growth factor signal Specific oncogene signal e.g. Imatinib Cancer cells harboring the specific chromosomal fusion Cancer drugs come in many forms Small Molecules cisplatin Antibodies Antibody derivatives Imatinib Engineered Immune cells (Antibody conjugates, cell engagers) Cancer Vaccine (in clinical trial) CAR-T Nano-formulated chemo Nucleotide-based (in clinical trial) Cancer Immunotherapy Harnessing the patients’ immune system to target their own cancer T cells, NK cells Immune checkpoint inhibitors e.g. Anti PD-1 Immune cell engagers e.g. T cell engager Engineered immune cells e.g.CAR-T Figure 4 Heterogeneity Genetic Non-genetic Tumor Microenvironment Immune cells, fibroblasts, extracellular matrix, bacteria, etc Plasticity Drug response & resistance Pharmacokinetics Pharmogenomics Personalized Medicine https://www.mdpi.com/2072-6694/15/2/376 https://doi.org/10.1002/adfm.201807553