BCOR 103 1st Edition Lecture 26 Outline of Last Lecture I. CancerII. Tumor Suppressors Outline of Current Lecture I. Cancer CellsII. Oncogene MutationsIII. Heterotypic SignalingCurrent Lecture- Hallmarks of cancer cells: normal somatic cells do not possess these characteristics.o no obligatory order of acquisitiono multiple ways to acquire a specific trait (different combinations of mutations in different genes)- Key concept: Tumor is seen as a complex tissue/organ that is composed of both cancer cells and normal cells. - Key: cancer cells and normal cells interact.- Oncogene mutations (dominant, gain of function): not inherited- Tumor suppressor gene mutations (recessive, loss of function): may be inherited (basis for predisposition to specific cancers, such as some breast cancers)- Oncogenic mutations in cell signaling proteins: result in constitutive mitotic signaling - Targeted cancer therapies: designed to block the activity of a specific oncogene.- Herceptin use: need to know if the breast tumor over-expresses HER2.- Perjeta and Herceptin are monoclonal antibodies aimed at different regions of the HER2receptor. The sticker price on Perjeta is $5,900 a month, or about $71,000 a year, and Herceptin's price tag is $4,500 a month, or $54,000 a year. That's $115,000 for a year's worth of treatment.- Progression-free survival (PFS) is the length of time during and after medication or treatment during which the disease being treated does not get worse. However, PFS improvements do not always result in corresponding improvements in overall survival, These notes represent a detailed interpretation of the professor’s lecture. GradeBuddy is best used as a supplement to your own notes, not as a substitute.and the control of the disease may come at the biological expense of side effects from the treatment itself.- Traditional anti-cancer therapies and targeted therapies both encounter the problem of resistance. In principle, all anti-cancer therapies represent a new selective pressure thatcancer cells may evolve to overcome. - Key concept: somatic cell evolution- In principle, mutation of nearly any component of these signaling pathways may lead constitutive mitotic signaling.- Given the complexity of cell signaling networks, it is unlikely that any single component is essential for the development of cancer.- Heterotypic signaling: cancer cells may induce normal cells to provide essential growth factors. - Tamoxifen: estrogen receptor antagonist, must be metabolized to the active compound endoxifen by a cytochrome P450 family enzyme (deficient in 6 – 10% of Europeans)- P53 is inactivated in ~50% of all human tumors.- Telomerase is not expressed in most human somatic cells.- Telomerase is activated in ~90% of all human tumors.- The angiogenesis inhibitor Avastin targets VEGF that is produced by normal cells. Initially assumed that a cancer therapy that targets normal cells would not be subject to the development of resistance. A naïve assumption.- Avastin increased colon cancer survival by 4.7 months.- Avastin was initially approved for treatment of breast cancer, but approval was later withdrawn when evidence showed that although it slowed progression of metastatic breast cancer, it did not extend or improve the quality of life. It also caused adverse effects including severe high blood pressure and hemorrhaging.- Cancer cells are under stringent environmental selective pressure.- Cancer cells exhibit a generalized loss of DNA methylation (hypomethylation) along withspecific methylation (hypermethylation) of tumor suppressor