PHAR3251_L5_Cancer Chemotherapy

Course Information

  • Title: PHAR3251 Clinical and Experimental Pharmacology

  • Focus: Cancer chemotherapy

  • Professor: Jeff Holst

  • Contact: j.holst@unsw.edu.au

  • University: University of New South Wales, Sydney

  • Copyright Notice: Material reproduced under Copyright Act 1968

Key Learning Objectives

  • Understand the distinct hallmarks of cancer and their implications for developing effective therapies.

  • Comprehend the complex processes involved in the development, testing, and regulatory approval of new cancer drugs, including the significance of clinical trial phases.

  • Describe various types of chemotherapies, their specific mechanisms of action, potential side effects, and the criteria for their use in different scenarios.

  • Apply pharmacological knowledge to critically evaluate real-world use cases for various chemotherapies across different cancer subtypes, considering factors such as patient demographics and cancer staging.

Epidemiology of Cancer in Australia

  • Prevalence: Cancer is the leading burden of disease in Australia, accounting for 16.6% of total disease burden according to 2023 data.

  • Statistics:

    • 2nd most common cause of death, with approximately 3 out of 10 deaths due to cancer.

    • Most common cancers diagnosed in 2023 include Prostate, Breast, Melanoma, Colorectal, and Lung cancers.

    • Leading causes of cancer deaths are Lung, Colorectal, Prostate, Pancreatic, and Breast cancers.

    • Estimated new cases in 2023 are 164,694 with a distribution of 73,806 females and 90,888 males.

    • Estimated cancer deaths in 2023 are 48,591.

    • The 5-year survival rate for cancer patients from 2012-2016 was 71%, indicating improvements in early detection and treatment.

  • Data Sources: Information is derived from the Australian Institute of Health and Welfare (AIHW).

Risk Factors for Developing Cancer

  • Intrinsic Risk Factors: non-modifiable

    • Random errors in DNA replication

  • Extrinsic Risk Factors:

    • Endogenous (partially modifiable): biological aging, genetic susceptibility, DNA repair machinery, hormones, growth factors, inflammation ect.

    • Genetic susceptibility, such as inherited mutations (e.g., BRCA1/2).

    • Biologic aging, which affects cellular repair processes.

    • DNA repair capacity, where defects can lead to increased mutation rates.

    • Random errors during DNA replication that may contribute to oncogenesis

    • Exogenous (modifiable): radiation, lifestyle (smoking), chemical carcinogens, tumour causing viruses,

    • Factors such as exposure to certain types of radiation, specific chemicals known to be carcinogenic, and persistent viral infections (e.g., HPV, Hepatitis B/C).

What is Cancer?

  • Definition: Cancer is a term that describes a group of diseases characterized by uncontrolled cell division driven by genetic mutations—

  • Two main types of genetic change:

    • activation of proto-oncogenes, which promote cell growth

    • inactivation of tumor suppressor genes, which normally inhibit cell division.

  • In Situ vs. Invasive Cancer:

    • In Situ: Tumor cells are localized and have not invaded surrounding tissues. This stage is often associated with a better prognosis and treatment outcomes.

    • Invasive: Tumor invades surrounding tissues and has the potential to shed cells into blood/lymph, leading to metastasis, thus posing a greater challenge for treatment.

Standard Treatment Options

  • Neoadjuvant Therapy: Administered prior to surgery aimed at shrinking primary tumours and increasing the chance of successful surgical removal.

    • Chemotherapy: Utilizes cytotoxic drugs to kill rapidly dividing cells.

    • Hormone Therapy: Utilizes hormones or hormone-blocking drugs for cancers that are hormone-sensitive.

    • Targeted Therapy: Involves drugs that specifically target cancer cell pathways responsible for growth and survival.

    • Radiation Therapy: Targets and destroys cancer cells using high doses of radiation

  • Primary therapy: eliminate tumour

    • Surgery: Physical removal of tumors.

    • Radiation Therapy

  • Adjuvant Therapy: Given post-surgery to eradicate any residual cancer cells and reduce recurrence risk.

    • Chemotherapy

    • Hormone therapy

    • Targeted therapy

    • Radiation therapy

Hallmarks of Cancer (Hanahan & Weinberg)

  • The hallmark traits of cancer include:

    • sustained proliferative signalling : activation of oncogenes that drive the growth of the cancer cells

    • inactivation of growth suppressors genes

    • avoidance of immune destruction

    • enabling replicative immortality

    • tumor-promoting inflammation

    • activation of invasion and metastasis

    • genome instability and mutation,

    • inducing angiogenesis,

    • resisting cell death,

    • deregulating cellular energetics.

    • Emerging hallmarks include: nonmutational epigenetic reprogramming, highlighting the evolving understanding of tumor biology.

Development and Testing of Therapeutic Agents

  • Initial Testing: Testing therapeutic agents through in-vitro studies either in suspension or attached to plastic, using cell lines to assess drug efficacy and toxicity. Common assays include MTT and colony-forming assays with either 96 or 386 well plates ( so we can test lots of different drugs and/or doses at once) to evaluate cell viability and proliferation following treatment.

How are new drugs developed:

  • accidental discovery

  • bioactive molecules found in nature

  • screening synthetic chemical libraries or natural product libraries

finding cancer-specific proteins/ mutations

  • using structure-based drug design to develop new inhibitors

  • using ligand-based drug design to develop new inhibitors/ activators

  • making biologicals (e.g. antibodies/ antibody-drug conjugates/ CAR-T cells)

Animal Models: Follow-up testing is performed using tumor models like immunocompromised mice to observe drug behaviors in a living organism.

  • Clinical Phases:

    • Phase 1: Focuses on safety by administering drugs to small patient groups to assess side effects.

    • Phase 2: Determines maximum tolerated dose in a larger cohort, collecting preliminary data on efficacy.

    • Phase 3: Efficacy trials conducted in large populations comparing the new treatment to standard therapies to establish its relative effectiveness.

Side Effects / Adverse Events

  • Grading System: Utilized for consistent reporting of adverse events using the CTCAE (Common Terminology Criteria for Adverse Events).

    • Grade 1: Mild symptoms that usually do not require intervention.

    • Grade 2: Moderate symptoms, requiring some medical intervention.

    • Grade 3: Severe symptoms, not immediately life-threatening, may require hospitalization.

    • Grade 4: Life-threatening consequences demanding immediate medical attention.

    • Grade 5: Death resulting from the adverse event.

Types of Chemotherapy and Mechanisms

  • Alkylating Agents:

    • Examples: Chlorambucil, Cyclophosphamide.

    • Mechanism: Work by cross-linking DNA strands, preventing cell division and leading to apoptosis.

  • Platinum-Based Drugs:

    • Example: Cisplatin.

    • Mechanism: Induces DNA cross-linking, leading to disruption of DNA synthesis and ultimately cell death.

  • Anti-Metabolites:

    • Examples: Methotrexate, 5-Fluorouracil.

    • Mechanism: Inhibit DNA/RNA synthesis through mimicking normal cellular substrates preventing cell proliferation.

  • Microtubule Inhibitors:

    • Example: Paclitaxel.

    • Mechanism: Prevents mitosis by stabilizing microtubules and inhibiting the normal breakdown of the mitotic spindle.

Conclusion

  • Cancer chemotherapy involves various approaches that target specific mechanisms of cancer progression, from cellular proliferation to immune evasion. Understanding the underlying biology of cancer and treatment modalities is crucial for developing effective therapeutic strategies while also considering the patient's overall health and treatment tolerability.