PMCOL 344 Winter 2024 Cancer Introduction PDF

1/26/2024 PMCOL 344 Winter Term 2024 Anticancer Drugs Dr. James Hammond [email protected] 9-55 MSB http://www.cancer.ca/ Canadian Cancer Statistics...

1/26/2024 PMCOL 344 Winter Term 2024 Anticancer Drugs Dr. James Hammond [email protected] 9-55 MSB http://www.cancer.ca/ Canadian Cancer Statistics 1  1/26/2024 Cancer in Males 2  1/26/2024 Cancer in Females Cancer Cancer is a group of more than 100 diseases that develop across time. Cancer can develop in virtually any of the body's tissues Both hereditary and environmental factors contribute to its development. 3  1/26/2024 Cancer Solid tumours versus hematological cancers (e.g. leukemia). Metastasis: (Note: a cancer is always named for the place it began). Benign versus malignant. Different types of cancer can behave very differently, and respond to treatment very differently. Cancer Cancer develops due to the loss of growth control in cells. Loss of control occurs as a result of mutations in genes that are involved in cell cycle control – point mutations – gene amplification – chromosomal translocation http://www.biology-pages.info/M/Mutations.html 4  1/26/2024 Mutations Hereditary (Inherited) mutations – Gene changes (mutations) that come from a parent and therefore exist in all cells of the body - also called germ-line mutations. – 5% to 10% of cancers Acquired mutations – environmental influences such as exposure to radiation or toxins - not passed on to offspring - also called sporadic or somatic mutations. Multiple-Hit Hypothesis (Knudson Hypothesis) Non-Hereditary Hereditary Knudson's work led to the identification of cancer-related genes - won the 1998 Albert Lasker Clinical Medical Research Award for this work. 5  1/26/2024 Oncogenes Mutated forms of genes (proto-oncogenes) that cause normal cells to grow out of control and become cancer cells. Proto-oncogenes are the genes that normally control how often a cell divides and the degree to which it differentiates (or specializes). When a proto-oncogene mutates into an oncogene, it becomes permanently "turned on" or activated when it is not supposed to be. Major Classes of Oncogenes Growth factors (e.g. sis. - overproduction platelet- derived growth factor) Growth factor receptors (e.g. HER2/neu amplification in breast cancer - herceptin) Signal transducers (e.g. abl in chronic myelocytic leukemia) Transcription factors / nuclear transducers (e.g. myc) Programmed cell death regulators (e.g. bcl-2 – inhibits apoptosis) 6  1/26/2024 Tumor Suppressor Genes Normal genes that slow down cell division, repair DNA mistakes, and tell cells when to die. When tumor suppressor genes don’t work properly, cells can grow out of control, which can lead to cancer. About 30 tumor suppressor genes have been identified, including p53, BRCA1, BRCA2, APC, and RB1. Tumor Suppressor Genes Genes that control cell division (e.g. RB1 - retinoblastoma gene) Genes that repair DNA (HNPCC -hereditary nonpolyposis colon cancer) Cell "suicide" genes (p53 gene) 7  1/26/2024 Cancer Development 1 – uncontrolled proliferation 2 – dedifferentiation and loss of function 3 – invasiveness 4 – metastasis Invasive Cancer The mutations leading to invasive cancer include all of those possibilities mentioned earlier as well as… – Production of metalloproteinases to break down extracellular matrix – Telomerase expression – an enzyme that maintains and stabilizes telomeres – Factors leading to growth of local blood vessels (tumour-directed angiogenesis) 8  1/26/2024 Angiogenesis and Cancer Solid tumors < 2 mm3 are not vascularized. Solid tumors > 2 mm3 become hypoxic which triggers the onset of tumoral angiogenesis. New blood vessel development favors the transition from hyperplasia to neoplasia CHEMOTHERAPY The Basics 9  1/26/2024 Classification of Cytotoxic Anticancer Drugs Alkylating agents Platinum complexes Antimetabolites Topoisomerase inhibitors Microtubule disruptors (Mitotic inhibitors) Hormonal therapies Molecularly-targeted agents Cancer Chemotherapy Fundamental Issues Cancer is often far advanced by the time of detection ~30 cell doublings = cell mass with a diameter of 2 cm -~109 cells – within the limits of diagnostic procedures, though it might be unnoticed in many organs. Another 10 doublings would produce ~1012 cells - ~20 cm in diameter if it were all in one clump – a tumour mass that is likely to be lethal. The neoplasm would, therefore, be silent for the first three quarters or more of its existence 10  1/26/2024 Cancer Chemotherapy Fundamental Issues They are your own cells! There can be little reliance on the host immunological defense mechanisms in ridding the body of the cancer cells Any thing that kills cancer cells is likely to also affect normal cells Cancer Chemotherapy Fundamental Issues Cannot leave any cancer cells behind after treatment ends a given therapeutic dose of a cytotoxic drug destroys a constant fraction of the malignant cells. Thus a dose which kills 99.99% of cells, if used to treat a tumour with 1011 cells, will still leave 10 million (107) viable malignant cells! 11  1/26/2024 Cancer Chemotherapy Fundamental Issues Most cancer chemotherapy drugs target proliferating cells G0; resting - nothing is happening G1 (or gap 1; a growth phase), S (synthesis; the replication of DNA occurs) G2 (gap 2; another growth phase) M (mitosis; the actual division from 1 cell into 2) Anticancer Drugs and the Cell Cycle 12  1/26/2024 Cancer Chemotherapy Fundamental Issues Chemotherapeutic drugs target rapidly dividing cells preferentially, thus any rapidly dividing cell in the body will be impacted by the agents bone marrow toxicity (myelosuppression) with decreased leukocyte production and thus decreased resistance to infection impaired wound healing loss of hair (alopecia) damage to gastrointestinal epithelium depression of growth in children sterility teratogenicity. Cancer Chemotherapy Fundamental Issues Solid Tumour Heterogeneity Compartment A - dividing cells, A possibly being continuously in cell B cycle C Compartment B -resting cells (G0) Compartment C - cells that are no longer able to divide but which contribute to the tumour volume. 13  1/26/2024 Cancer Chemotherapy Fundamental Issues Development of drug resistance Primary - present when the drug is first given Acquired - result from either adaptation of the tumour cells or mutation Differing biological modes of acquired drug resistance volume 22 | number 3 | March 2016 nature medicine 14  1/26/2024 Drug Resistance Mechanisms 15