MODULE 47 Cancer Therapies PDF
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Geisinger Commonwealth School of Medicine
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This document provides a detailed overview of various cancer therapies, including conventional, targeted, and immunotherapy approaches. It explores different mechanisms of action and limitations of each strategy.
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MODULE 47 The Conventional Cancer Therapies: - Radiation (X-ray): Kills cancer cells by damaging their DNA but also damages normal cells. It has limited success against systemic disease and may induce second malignancies. - Chemotherapy: Utilizes antimetabolites, spindle poisons, alkylating agents...
MODULE 47 The Conventional Cancer Therapies: - Radiation (X-ray): Kills cancer cells by damaging their DNA but also damages normal cells. It has limited success against systemic disease and may induce second malignancies. - Chemotherapy: Utilizes antimetabolites, spindle poisons, alkylating agents, and topoisomerase inhibitors. Some chemicals are derived from chemical warfare agents (e.g., nitrogen mustards), causing damage in both cancer and normal cells. - Surgery: Highly successful for localized neoplasms but typically not applicable for metastatic stage cancer. Targeted Cancer Therapies: - Based on drugs that interfere with cancer cell growth signaling or angiogenesis, stimulate the immune system to destroy cancer cells, and deliver toxic drugs to cancer cells. - Includes Immunotherapy, therapy targeting cancer-promoting proteins, and antiangiogenic therapy. Immunotherapy: William Coley met a sarcoma patient whose tumor disappeared following infection by Streptococcus pyogenes (erysipelas). Other doctors had recorded similar observations. Coley used bacteria to treat cancer and created a mixture of bacterial infusions known as Coley's Toxins or Coley's vaccine. The infusion was injected in increasing doses to induce fever. Compared to normal cells, neoplastic cells are more sensitive to high temperatures, and their death releases mutant proteins that stimulate the immune system to attack cancer cells. Passive Immunotherapy: It does not stimulate the patient’s immune system to respond to the disease antibodies or other immune system components are made outside the body and administered to patients monoclonal antibodies are generated usually in mice and these antibodies are directed against cancer cell-surface antigens the antibodies are “humanized” by replacing some portion of the antibody with a human portion limitations: - many antibodies are not administered as first-line therapy but are offered late in treatment when the immune system is weakened by chemotherapy, etc.; this limits the effect - not all cancers “of the same type” express the same antigens: in general, response rates to these therapies is ~20- 30% - tumor cells mutate, if the target changes due to additional mutations, then the antibody becomes ineffective - toxicity could be significant Examples: cetuximab for head/neck squamous cell carcinoma, colorectal cancer, binds to EGFR, panitumumab for metastatic colon cancer, targets EGFR; trastuzumab for breast cancer, gastric or gastroesophageal junction adenocarcinoma, binds to the tyrosine kinase receptor HER-2 MODULE 47 Active Immunotherapy It triggers the patient's immune system to respond to the disease vaccines are created with co-cultured patient's cancer and immune cells; the activated immune cells are delivered back to the same patient with other proteins (e.g., IL-2) to facilitate the immune response vector-based cancer vaccines, in which an engineered virus, or another vector, introduces cancer-specific molecules to the patient; the goal is to stimulate the patient's immune system to recognize the tumor cells limitations: tumor cells and their antigens mutate not all patients' cancers express the targeted antigen; response rates are around 20-30% autologous vaccine therapy presents manufacturing challenges, and it is costly many cancer vaccines are poorly immunogenic and require the use of adjuvants, which may increase toxicity the therapy may cause auto-reactivity and the development of an autoimmune disease One example of a transfer of chimeric antigen receptor-modified cells as a cancer therapy. Preventive Cancer Vaccines: The FDA has approved vaccines to prevent cancer: vaccines against the hepatitis B virus, which can cause liver cancer vaccines against some human papillomavirus types, which are responsible for most cervical cancer cases, as well as for some other types of cancer Targeting the Immune Response Checkpoints: PD-1 is a cell-surface receptor on T cells and pro-B cells and the binding of tumor cells’ PD-L1 ligands to PD1 prevents the activation of the immune cells; antibodies to the receptor/ligands prevent this interaction and allow for immune response to cancer; anti-PD1 is administered for melanoma, renal-cell cancer, and non-small cell lung cancer ipilimumab for melanoma targets CTLA-4, a receptor that suppresses immune responses MODULE 47 Therapies Targeting Oncogenes and Deregulated Pathways: oncogene proteins are the products of oncogenes; they support unrestrained cell growth and proliferation; act in an abnormal way due to their overexpression or mutation oncogene addiction: when the survival of the cancer cells is dependent upon the activity of a protein with abnormal function the premise of the therapy: blocking the activity of an oncogenic protein will kill the cancer cells Kinase Inhibitors - Examples Drugs ending in -tinib (tyrosine and threonine) Antiangiogenic Therapies: All cells in tissues need to reside within 100 micrometers of a capillary blood vessel to obtain oxygen and nutrients. Without angiogenesis, the tumor is arrested at a microscopic state of 1-2 mm3 or less. Molecularly Targeted Therapies: these therapies extend the life of a patient by weeks to months; the main reason for the short-lived benefit is the cancer heterogeneity and the dynamic evolution of the cancer cells detection of mutations that contribute to acquired resistance requires biopsy/re-biopsy and sequencing of the cancer genome before and after treatment; there are no consistently common mutations for drug resistance even if resistance-associated mutations are discovered, the protein products may not be “druggable” Gene Therapy: in the future, gene therapy approaches can be utilized against cancer, including hereditary cancer syndromes, by repairing gene mutations that cause cancer (e.g., with CRISPR), by knocking down genes with aberrant expression, and/or by restoring expression of anti-oncogenic genes an effective and safe gene therapy delivery system will be required Putting It Together: standard therapies for cancer include radiation, chemotherapy, and surgery, each with its advantages and disadvantages more targeted cancer therapeutics are required advances, current or future, include molecularly targeted therapy, passive or active immunotherapy, and gene therapy