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What is targeted cancer therapy?
Cancer cells grow and proliferate endlessly. Targeted therapy to stimulate cell death or “apoptosis” can help keep tumors in check.
Targeted cancer therapy is a focused treatment for certain cancers in which the specific cancer-causing factors can be identified and targeted with drugs. Targeted therapy involves administration of medications that alter the way cancer cells function at the cellular level and stop their spread.
Traditional therapies such as chemotherapy and radiation kill cancer cells because they are toxic to cells (cytotoxic), healthy and cancerous alike. Targeted therapy’s goal is to induce a programmed death (apoptosis) of cancer cells alone and preserve the healthy cells as much as possible.
Two types of drug formulations are used in targeted cancer therapies:
- Small molecule drugs: Minute particles that attach to proteins on the cell surface or get right inside the cell and modify its activity.
- Monoclonal antibodies: Larger molecules that cannot get inside the cell, but attach to the cell surface and activate immune activity.
How does cancer start?
Cancer is a unique group of diseases resulting from certain mutations in genes that regulate growth and development, which enable uncontrolled cell growth and proliferation. Cancers most often start in a cell during cell division due to DNA damage or errors while copying (transcription) DNA.
Genetic mutations are most often caused by hereditary factors, environmental factors and certain viral infections, but can sometimes happen for no fathomable reason. Cancer can develop in any part of the body and spread to other parts in a process known as invasion and metastasis. Cancer cells can also develop resistance to medications.
What is apoptosis and its purpose?
Normal cells have a finite cell cycle of growth, division into two daughter cells, and differentiation into specialized cells with specific functions. The final stage in the cell cycle is apoptosis, or programmed cell death, when they are infected, old, damaged or simply no longer needed. This promotes continued regeneration of healthy new cells.
Apoptosis is a programmed death that individual cells undergo to benefit the health and survival of the whole organism. An apoptotic cell withdraws from the neighboring cells, shrinks and disintegrates into a neat packet, which immune cells called phagocytes engulf and digest such apoptotic cells.
Apoptosis is strictly regulated by enzymes known as caspases which cleave the proteins in the cells when activated. Caspases are present in an inactive form in all cells, and when a caspase is activated, it triggers a cascade of downstream activity in all the caspases present in the cell. The caspases cleave all the proteins in the cell, which results in apoptosis.
The caspases may be activated in two ways:
- Extracellular signals: Cell surfaces have proteins known as death receptors which can be activated by proteins on the surface of killer immune cells such as lymphocytes. Lymphocytes usually activate apoptosis when they recognize signs of infection in a cell.
- Intracellular signals: During cell division, DNA damage or errors during transcription of DNA cause release of certain proteins which activate caspase activity. Stress signals from the cell due to insufficient oxygen (hypoxia) or certain nutrients also can initiate apoptosis.
Why is apoptosis important in cancer?
Cancer cells breach several cellular mechanisms that regulate the cell cycle, to grow and proliferate endlessly. Such unregulated growth can be maintained only by also evading apoptosis, which is one of cancer’s most important survival strategies.
Genetic mutations in the cancer cells lead to defects in cell-signaling systems that initiate apoptosis. The cancer cells hijack the family of proteins that regulate apoptosis, silence the pro-apoptosis proteins and overproduce the anti-apoptosis proteins.
What are the targeted cancer therapies for promoting apoptosis?
Therapies targeting apoptosis activate the proteins that promote apoptosis and block the activity of anti-apoptotic proteins. Targeted therapy for promoting apoptosis includes both small molecule drugs that can activate caspases inside the cell and monoclonal antibodies that activate receptors on the cell surface.
Bcl-2 inhibitors
Bcl-2 are a family of apoptotic proteins that regulate the intracell apoptosis signaling. To activate the caspases and initiate apoptosis, the mitochondria (a cellular organelle that helps burn calories and other functions) releases a protein known as cytochrome c. Different proteins in the Bcl-2 family either suppress or promote the release of cytochrome c by altering the permeability of the mitochondrial membrane.
Cancer cells have excessive presence of the type of Bcl-2 proteins that block the mitochondria from releasing cytochrome c. Bcl-2 inhibitors are therapies that are targeted to overcome the activity of anti-apoptotic Bcl-2 proteins, enable the release of cytochrome c from the mitochondria, and initiate apoptosis.
Many Bcl-2 inhibitors are in various stages of clinical trials, but only one is FDA-approved:
- Venetoclax (Venclexta)
Approved for adult patients with:
- Chronic lymphocytic leukemia (CLL)
- Small lymphocytic lymphoma (SLL)
- Newly diagnosed acute myeloid leukemia (AML) in adults 75 years or older, who cannot have other therapy
Antisense therapy for IAPs
The inhibitor of apoptosis (IAP) family of genes encode proteins that suppress extracellular and intracellular signals and protect the cancer cell from apoptosis. A particular gene in the IAP family known as X-linked inhibitor of apoptosis (XIAP) is extremely potent in preventing apoptosis.
Many cancers have a high presence of the XIAP proteins encoded by the XIAP gene. Small molecule antisense medications attach to the XIAP gene in the messenger RNA (mRNA), a tiny molecule that is involved in the transcription of DNA, and arrest the transcription process and activation of the XIAP gene.
Antisense is the non-coding strand of the DNA which the mRNA uses as a template for copying. Antisense therapy makes the cancer cells more sensitive to apoptotic signals and chemotherapy. Currently antisense therapies are in the early phases of trials.
Death receptors
Death receptors are proteins on the cell surface which activate caspases when stimulated by extracellular signals. Tumor necrosis factors (TNF) and TNF-related apoptosis inducing ligands (TRAIL or Apo2L) are cytokines (proteins secreted by immune cells) which bind to death factors and directly activate apoptosis. A ligand is an ion or molecule that can bind to another compound and form a complex molecule.
Several therapies including purified formulations of TRAIL cytokines and monoclonal antibodies that stimulate death receptors are in early phase of clinical trials.