Therapeutic options in cancer

Question 1

Illustrate the importance of cell turnover and kinetics on actions of anti-cancer therapies.

Answer 1

1. Cell Turnover in Normal and Cancerous Tissues
   Cell Turnover: This refers to the process of cell division (proliferation) and cell death (apoptosis). Normal tissues have a controlled turnover, where cell division balances with cell death, ensuring tissue homeostasis. However, in cancer, this balance is disrupted, leading to uncontrolled proliferation and evasion of apoptosis.
   Cancer Cells: Cancerous tissues exhibit rapid and often uncontrolled cell division (proliferation), accompanied by abnormal cell cycle regulation. This results in hyperplasia, where cells divide much faster than normal, contributing to tumor growth.
   Normal vs. Tumor Cells: Tumor cells typically have an increased rate of cell turnover compared to normal tissues. This makes them more susceptible to therapies that target cell division. However, the extent of this susceptibility can vary depending on the tumor’s characteristics.
2. Cell Kinetics and the Action of Anti-Cancer Therapies
   The effectiveness of most anti-cancer therapies depends on the cell cycle kinetics of the tumor. Anti-cancer therapies are typically most effective against cells that are actively dividing. These therapies often exploit specific points in the cell cycle to induce damage or prevent the cell from continuing its division process.

Proliferation and the Cell Cycle: Cancer cells typically exhibit rapid and uncontrolled progression through the cell cycle. The cell cycle consists of phases (G1, S, G2, and M) during which cells grow, replicate their DNA, and divide.
S-phase: Where DNA replication occurs.
M-phase: Where cell division (mitosis) occurs.
G1 and G2 phases: Periods of growth and preparation for DNA replication and mitosis.
Anti-cancer treatments often target cells during specific phases of the cell cycle:

Chemotherapy: Many chemotherapy drugs target cells during active phases of the cell cycle (typically the S-phase or M-phase) where DNA replication and cell division occur. These drugs are most effective against rapidly proliferating cancer cells.
Radiation Therapy: Radiation also targets rapidly dividing cells, inducing DNA damage that the cell cannot repair, leading to cell death. However, cells in the G0 phase (resting phase) are less sensitive to radiation because they are not actively dividing.
3. The Role of Cell Turnover in Chemotherapy and Radiation Response
Chemotherapy: Chemotherapy drugs, such as alkylating agents, antimetabolites, taxanes, and topoisomerase inhibitors, work by interfering with DNA replication and cell division. Since cancer cells are dividing more rapidly than normal cells, they are more likely to be affected by these drugs.
Cell-cycle specificity: Some chemotherapy agents are cell-cycle phase-specific, meaning they are more effective at certain stages of the cell cycle. For example, methotrexate and fluorouracil (5-FU) are most effective during the S-phase, while vincristine and taxanes are more effective in the M-phase of the cell cycle.
Cell-cycle non-specific agents: Other drugs, such as cisplatin, can act on DNA in a way that doesn’t depend on the phase of the cell cycle, making them effective against both proliferating and non-proliferating cells.
Radiation Therapy: Radiation is more effective against cells that are actively dividing because they are more vulnerable to DNA damage during mitosis. However, radiation can also induce mutations and damage in cells that are not in active division (i.e., G0 phase). Cells in the G1, S, and G2 phases are more sensitive to radiation than those in G0.
Fractionation: Radiation therapy is often delivered in fractions, allowing normal cells in the surrounding tissues to recover while cancer cells, which may not recover as effectively, are destroyed over time.
4. Impact of Cell Turnover on Resistance to Therapy
Tumors that exhibit slow turnover (e.g., low proliferation rates or a high proportion of cells in the G0 phase) may be less responsive to therapies targeting rapidly dividing cells. Such tumors might be less sensitive to chemotherapy and radiation, which primarily affect proliferating cells. For example:

Tumors with a low growth fraction (i.e., low cell turnover) have a higher proportion of cells in the G0 phase, making them less sensitive to therapies targeting the cell cycle.
Tumor heterogeneity: Different regions of the tumor may have varying rates of cell turnover. Some tumor cells might be actively proliferating, while others are in a dormant phase (G0), making the tumor more difficult to treat effectively with a single modality.
5. Cell Turnover and Tumor Microenvironment
Hypoxia: Tumor cells often exist in areas with low oxygen levels (hypoxia) due to rapid cell proliferation and insufficient blood supply. Hypoxic cells may have altered cell kinetics, and the lack of oxygen can impair the effectiveness of certain therapies, particularly radiation therapy. Oxygen is crucial for the formation of free radicals in radiation therapy, and a hypoxic tumor environment may lead to radiation resistance.
Tumor dormancy: Some cancer cells enter a state of dormancy (a non-proliferative state) and may not respond to therapies targeting rapidly dividing cells. These dormant cells can be present in metastases and may lead to cancer recurrence once they “reactivate” and begin proliferating again.
6. Cell Turnover and the Development of Therapy Resistance
The rapid turnover of cancer cells can contribute to genetic instability and the accumulation of mutations, which may allow cancer cells to develop resistance to therapies over time.

Chemotherapy resistance: As tumor cells divide, they may acquire genetic mutations that confer resistance to chemotherapy agents. For example, mutations in the p53 gene (which regulates the cell cycle and apoptosis) can lead to defective DNA repair and impaired apoptosis, allowing cancer cells to survive chemotherapy.
Radiation resistance: Similar mutations, as well as tumor hypoxia, can contribute to radiation resistance. Cells that are in the G0 phase may be more resistant to radiation, and tumors with high heterogeneity may have subpopulations of resistant cells.
7. Cell Kinetics in Targeted and Immunotherapies
Targeted therapies: Many targeted therapies, such as EGFR inhibitors, HER2 inhibitors, and PARP inhibitors, work by inhibiting specific molecules or signaling pathways that regulate tumor cell growth and survival. These therapies are not necessarily dependent on cell cycle kinetics, as they target molecular pathways rather than directly interfering with cell division. However, they may still be more effective against tumors with higher cell turnover, as the targeted pathways are more active in rapidly dividing cells.
Immunotherapy: Immunotherapy, such as checkpoint inhibitors (e.g., pembrolizumab), works by enhancing the body’s immune response to cancer cells. While not directly related to cell cycle kinetics, tumors with high cell turnover may be more easily recognized by the immune system because they often present more tumor-specific antigens. Additionally, immunotherapies are often more effective in hot tumors—those with a high level of immune cell infiltration—while cold tumors (with lower immune cell presence) may require combination approaches to enhance efficacy.

Conclusion
Cell turnover and kinetics are central to the effectiveness of most cancer therapies. Therapies such as chemotherapy, radiation, and targeted treatments are designed to exploit the rapid division and abnormal regulation of cancer cells, making tumors with high cell turnover more susceptible to these therapies. However, slow-growing tumors or those with a large fraction of cells in a non-dividing state (G0 phase) may be less responsive. Additionally, therapy resistance can emerge as tumors evolve through rapid cell turnover and genetic instability. Understanding these dynamics is essential for improving therapeutic strategies and tailoring treatments to individual patient needs.

Question 2

Describe modalities of therapy currently available.

Answer 2

1. Surgery
   Description: Surgery is one of the oldest and most effective cancer treatments, particularly for tumors that are localized and accessible. It involves the physical removal of cancerous tissue, and it can be curative in early-stage cancers.
   Purpose: The goal is to remove the tumor entirely, reduce tumor burden, and, in some cases, alleviate symptoms like obstruction or bleeding.
   Types of Surgery:
   Curative surgery: Removes all of the cancerous tumor (e.g., tumor resection).
   Debulking surgery: Reduces the size of the tumor, typically when it can’t be fully removed, to make other treatments more effective.
   Palliative surgery: Performed to relieve symptoms (e.g., pain, obstruction) in advanced cancers but not to cure the disease.
   Example: Removal of a breast tumor (lumpectomy) for breast cancer, or resection of a colon tumor in colorectal cancer.
2. Radiation Therapy
   Description: Radiation therapy uses high-energy rays or particles (such as X-rays or protons) to destroy cancer cells or shrink tumors. It can be used to treat both primary and metastatic tumors.
   Purpose: To kill or damage cancer cells’ DNA, preventing them from growing or dividing. It’s often used for localized tumors and to alleviate symptoms in advanced cancer.
   Types of Radiation:
   External beam radiation: Radiation is delivered from outside the body and directed at the tumor.
   Internal radiation (Brachytherapy): Radioactive material is placed inside or near the tumor.
   Systemic radiation: Radioactive substances are administered intravenously or orally and travel through the body to target cancer cells.
   Example: Radiation to treat prostate cancer, brain tumors, or to shrink a tumor before surgery.
3. Chemotherapy
   Description: Chemotherapy uses powerful cytotoxic drugs to kill rapidly dividing cancer cells. It can be used alone or in combination with other treatments such as surgery and radiation.
   Purpose: To destroy cancer cells, prevent the spread of the disease, shrink tumors before surgery, or eliminate microscopic disease (micrometastases).
   Mechanism: Chemotherapy targets fast-growing cells, which includes both cancerous and some healthy cells (e.g., hair, bone marrow). It works by disrupting cell division and DNA replication.
   Administration: Chemotherapy can be given orally, intravenously, or directly into a body cavity (e.g., intrathecal for brain tumors).
   Example: Drugs like cisplatin, paclitaxel, and methotrexate are used for cancers such as breast cancer, colon cancer, leukemia, and lung cancer.
4. Targeted Therapy
   Description: Targeted therapies are drugs designed to specifically target and block the molecular abnormalities driving cancer cell growth. Unlike chemotherapy, which kills all rapidly dividing cells, targeted therapies are designed to interfere with specific cancer-related molecules, reducing damage to normal cells.
   Purpose: To interfere with specific genes or proteins that promote cancer cell growth, survival, and spread.
   Mechanism: Targeted therapies can block the action of mutated proteins or prevent the cancer from making new blood vessels (angiogenesis).
   Types:
   Monoclonal antibodies: Lab-made antibodies that specifically target proteins on the surface of cancer cells or tumor blood vessels (e.g., trastuzumab (Herceptin) for HER2-positive breast cancer).
   Small molecule inhibitors: Target specific signaling pathways or enzymes (e.g., imatinib (Gleevec) for chronic myelogenous leukemia).
   Example: Imatinib (Gleevec) for chronic myelogenous leukemia, bevacizumab (Avastin) for colorectal cancer.
5. Immunotherapy
   Description: Immunotherapy uses the body’s own immune system to recognize and destroy cancer cells. It aims to boost the immune response or block immune checkpoints that prevent immune cells from attacking cancer.
   Purpose: To stimulate or enhance the immune system’s natural ability to fight cancer.
   Types:
   Checkpoint inhibitors: Block immune checkpoints like PD-1/PD-L1 and CTLA-4, which prevent T-cells from attacking cancer cells (e.g., pembrolizumab (Keytruda) and nivolumab (Opdivo)).
   Monoclonal antibodies: Can be used to trigger the immune system or directly mark cancer cells for destruction.
   Cytokine therapy: Uses proteins such as interleukins and interferons to boost immune activity.
   CAR T-cell therapy: Involves modifying a patient’s T-cells to make them better at targeting and killing cancer cells.
   Example: Pembrolizumab (Keytruda) for melanoma, CAR T-cell therapy (Kymriah) for leukemia and lymphoma.
6. Hormone Therapy
   Description: Hormone therapy works by blocking or lowering the levels of hormones that fuel certain cancers (such as estrogen or testosterone).
   Purpose: To treat cancers that rely on hormones for growth, such as breast cancer and prostate cancer.
   Types:
   Anti-estrogens: Block estrogen receptors or lower estrogen levels (e.g., tamoxifen for estrogen receptor-positive breast cancer).
   Aromatase inhibitors: Block the conversion of androgens to estrogens (e.g., letrozole).
   Androgen deprivation therapy (ADT): Lowers testosterone in prostate cancer (e.g., leuprolide).
   Example: Tamoxifen for breast cancer, leuprolide for prostate cancer.
7. Stem Cell Transplantation (Bone Marrow Transplant)
   Description: Stem cell or bone marrow transplantation involves replacing diseased or damaged bone marrow with healthy stem cells. It is often used after high-dose chemotherapy or radiation to restore the body’s ability to produce blood cells.
   Purpose: To treat cancers that affect the blood or bone marrow, such as leukemia, lymphoma, and multiple myeloma.
   Types:
   Autologous transplant: The patient’s own stem cells are used.
   Allogeneic transplant: Stem cells from a donor (usually a sibling or unrelated donor).
   Example: Used for leukemias, lymphomas, and myeloma.
8. Precision Medicine and Genomic Therapy
   Description: Precision medicine tailors cancer treatment based on the genetic profile of the patient’s tumor. By identifying specific genetic mutations and molecular characteristics of cancer, doctors can choose therapies that are more likely to be effective for that individual.
   Purpose: To select the most effective treatment based on the genetic and molecular makeup of the cancer, enhancing the chance of success and minimizing unnecessary side effects.
   Example: EGFR inhibitors for lung cancer, BRAF inhibitors for melanoma, and PARP inhibitors for BRCA-mutant cancers.
9. Palliative Care
   Description: Palliative care focuses on improving the quality of life for patients with advanced cancer by managing symptoms, providing psychological support, and helping with end-of-life decisions.
   Purpose: To control pain, nausea, fatigue, and other distressing symptoms, and provide emotional, spiritual, and practical support to patients and their families.
   Types of Palliative Interventions: Pain management (opioids, nerve blocks), anti-nausea medications, psychological counseling, and hospice care for terminal cancer.
   Example: Pain management in advanced pancreatic cancer or end-of-life care for metastatic cancer.