Targeted Therapy: Cancer Therapies Targeting the Tumor Microenvironment

What is targeted therapy for cancer?

Some targeted cancer therapies aim at the pro-survival factors in the tumor microenvironment. The tumor microenvironment is the surrounding tissue, known as stroma, which provides the support for cancer's growth and survival.

Targeted cancer therapy is a specialized cancer treatment with medications which target specific cellular mechanisms that give rise to cancer and help its growth and spread. Unlike traditional treatments such as chemotherapy and radiation, targeted therapy does not kill the cancer cells directly, but interferes with the proteins and cell-signaling pathways to prevent their growth.

Targeted cancer therapy medications come in two forms:

Small molecule drugs: Microscopic particles that interact with proteins inside the cell or on the cell membrane to suppress cancer growth.
Monoclonal antibodies: Lab-produced cancer-specific antibodies that bind to proteins on the cell membrane and invite immune activity.

Does ‘tumor’ mean cancer?

Tumors are abnormal tissue growths which can remain benign and localized where they originated. When tumors invade and spread to other parts of the body (metastasis), they are termed to be malignant or cancerous. Certain cancers such as leukemia do not have tumor growths, but all cancers result from uncontrolled proliferation of a single type of cell.

Cancers arise from genetic mutations in some cells, which make them impervious to rules that govern normal cell cycle of growth, division, differentiation into cells with specific functions, and programmed cell death (apoptosis) at the appropriate time. Genetic mutations may be caused by hereditary or environmental factors, certain viral infections, or just by an unfortunate chance combination of cellular events.

How do tumors survive?

Tumors grow and evade death by flouting regulatory mechanisms that normal cells follow, but their continued survival and proliferation depend on several additional factors. To survive, tumors must escape attack from the immune system, continue to receive blood supply and transform into cells that can migrate and grow elsewhere.

Tumors survive by enlisting other elements in their immediate environment. Tumors develop the ability to recruit unsuspecting normal cells, and subvert normal pro-survival cell mechanisms in the tumor microenvironment to help them survive, grow and eventually migrate and metastasize in other parts of the body.

What is the tumor microenvironment?

The tumor microenvironment is the environment around the tumor, known as stroma, which provides the support for its growth and survival. Stroma includes immune cells, connective tissue, cell-signaling molecules, blood vessels and extracellular matrix, a supportive structure to which all cells adhere to form tissue.

Tumors manipulate the following mechanisms in the microenvironment to abet their growth:

Immune surveillance: The immune system initially detects tumor antigens and develops antibodies, but tumor cells rapidly mutate to grow without these antigens and escape detection. Uncontrolled tumor growth outpaces the oxygen and nutrient supply, resulting in an acidic microenvironment, which suppresses antitumor response and enhances wound healing response from the immune system.
Stress response: Reduced oxygen (hypoxia) and nutrient supply causes stress to the tumor cells leading to further DNA damage. Stress signals from the tumor cells elicit a protective response from the body which stabilizes the tumor cell.
Tumor-stroma interactions: Tumor cells interact with the stroma to generate new blood vessel growth (neo-angiogenesis), transform into tissue stem cells known as mesenchymal cells, and break off from the extracellular matrix to invade nearby tissue and metastasize.
Cytokine pro-survival factors: The tumor microenvironment is full of immune cells which release inflammatory signals in the form of proteins known as cytokines. The resulting inflammation induces the immune cells to release pro-survival cytokines which promote angiogenesis and directly assist tumor growth.

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What therapies target tumor microenvironment?

Several therapies targeting the pro-survival factors in the tumor microenvironment are in different stages of development. Some have been approved by the FDA.

Immune surveillance

Two types of immunity are active in the tumor microenvironment:

Innate immunity: Natural immunity that recognizes common pathogens and destroys them. Innate immune cells also suppress acquired immune activity and promote angiogenesis to assist the healing process.
Acquired immunity: Immunity that develops with antibody production after exposure to specific antigens.

Therapies that target immune surveillance include:

Immunomodulatory drugs: Suppress innate immunity and enhance acquired immunity, and also prevent angiogenesis.
Monoclonal antibodies: Bind to the tumor cells and enable killer T cells to destroy them. Monoclonal antibody therapies are still in the early phase of clinical trials.

The FDA-approved immunomodulatory drugs include:

Thalidomide: Approved for newly diagnosed multiple myeloma
Lenalidomide: Approved for
- Multiple myeloma
- Myelodysplastic syndrome with 5q deletion abnormality
- Refractory mantle cell lymphoma
- Previously treated follicular lymphoma
- Previously treated marginal zone lymphoma
Pomalidomide: Approved for
- Kaposi sarcoma
- Advanced multiple myeloma

Stress response

The continuous DNA repair and metabolism required by tumor cells to sustain growth and replication creates stress which elicits a protective response from the body, a protective response the tumor uses to shield itself from immune attack. Targeted therapies to overwhelm protective stress responses include three types:

Heat-shock response: Maintaining protein stability (homeostasis) is important for a cell’s survival. Misfolding of proteins in tumor cells evokes a heat-shock response, which activates heat-shock protein-90 (HSP90) known as a chaperone protein that helps refold the proteins and stabilize the tumor cells.
- Therapies targeting HSP90 activity in tumor cells are in clinical trials.
Ubiquitin-proteasome response: Unfolded or misfolded proteins in a cell are degraded by an intracellular process known as ubiquitin-proteasome pathway (UPP). An intact UPP is essential for cellular functions such as regulation of cell cycle, DNA repair, differentiation and angiogenesis.
- Inhibiting the UPP can halt the progression of cancers.Therapies targeting UPP are in clinical trials and FDA has approved one small molecule UPP inhibitor:
  - Bortezomib: Approved for
    - Multiple myeloma
    - Mantle cell lymphoma
Hypoxic and metabolic stress response: Rapid growth causes tumors to outstrip oxygen and other nutrient supply, and tumors are in constant stress to develop new blood vessels for sustenance. Hypoxia in the tumor cells induces the release of a protein complex known as hypoxia-inducible factor-1 (HIF-1) which stimulates angiogenesis.

Some therapies targeting HIF-1 are in clinical trials and FDA has approved two medications:

Temsirolimus: Approved for advanced renal cell carcinoma
Everolimus: Approved for
- Advanced renal cell carcinoma
- Metastatic neuroendocrine tumors of pancreatic, gastrointestinal or lung origin
- Hormone-receptor positive, HER2-negative breast cancer
- Tuberous sclerosis complex-associated renal angiomyolipoma
- Tuberous sclerosis complex-associated subependymal giant cell astrocytoma

Tumor-stroma interactions

Tumor cells proliferate, migrate and metastasize by complex interactions with the stroma using intracellular (autocrine) and cell-cell (paracrine) signals. One of the signaling pathways tumors employ is sonic hedgehog (SHH) pathway, named after the popular video game character. SSH normally regulates embryogenesis, but is activated in tumor cells. Therapies to inhibit the sonic hedgehog pathway are in early stages of development.

Cytokine pro-survival factors

Pro-survival cytokines, chemokines (small cytokines) and other proteins are abundant in the tumor microenvironment due to chronic inflammation. Monoclonal antibodies (MABs) targeting cytokines to inhibit the growth-stimulating and healing properties, and enhance antitumor response, are in development.

Anti-TNF MABs: Tumor necrosis factor-alpha (TNF-A) is a cytokine that activates TNF-A receptors in stromal and other tissue cells and promotes survival and proliferation of malignant cells. TNF-A was the first targeted cytokine in cancer therapy, but there are no successful anti-TNF MABs so far.
Anti-IL-6 chimeric MABs: IL-6 is a cytokine that induces innate immune response and promotes tumor growth. Anti-IL-6 MABs are in different stages of clinical trials.
Anti-RANK ligand MABs: Receptor activator of NF-kb ligand (RANKL) is a molecule that activates receptors in bone tissue causing bone resorption. Bone resorption is the process by which a type of bone cell known as osteoclast degrades bone tissue and releases the calcium into the blood.
- Inhibition of RANKL leads to osteoclast apoptosis and prevents bone loss. There is one FDA-approved anti-RANK ligand MAB:
- Denosumab: Approved for metastatic lytic bone lesions from
  - Multiple myeloma
  - Breast cancer
  - Prostate cancer
CXCR4 antagonists: Chemokine receptor CXCR4 plays a role in tumor cell migration and invasion, and is required for tumor cells to maintain contact with the stroma. CXCR4 antagonists inhibit CXCR4 activity.
- Three CXCR4 antagonists are in clinical trials and one, which has the ability to release white cell progenitors from the bone marrow, has been approved by the FDA:
  - Plerixafor: Approved for stem cell mobilization before auto-stem cell transplantation in
    - Multiple myeloma
    - Non-Hodgkin lymphoma
Anti-CCL2 MAB: CCL2 is a chemokine that attracts monocytes to the tumor microenvironment, which promotes angiogenesis, immune suppression and metastasis. Anti-CCL2 MABs are in clinical trials.
Anti-CCR4 MAB: Cytokines released by a type of skin cell known as keratinocyte activate CC chemokine receptor 4 (CCR4) found on cutaneous T cells in certain skin cancers. CCR4 facilitates migration of T-cells to the skin leading to accumulation of T-cells under the skin in these skin cancers.
- In 2018, the FDA approved an anti-CCR4 Mab:
  - Mogamulizumab: Approved for two types of relapsed or refractory cutaneous T-cell lymphoma, after at least one prior systemic therapy:
    - Mycosis fungoides
    - Sezary syndrome