Targeted Therapy

Targeted Therapy

Targeted therapy stops the action of molecules that are key to the growth of cancer cells. Thus, it affects cancer cells more so than normal cells. Targeted therapy's specific action differs from traditional chemotherapy, which affects all fast growing cells.

There are two main types of targeted therapy. The first type is small molecule drugs, which are small enough to enter cells. The second type is monoclonal antibodies, which are too large to enter cells. Instead, monoclonal antibodies affect targets outside of cells or targets on cells' surface.

The types of targeted therapy are discussed next. They are grouped by their target. Some targeted therapies are now being used to deliver toxic substances to cancer cells. These drugs are called antibody loaded therapies. These drugs are also described below.

Signaling targets

Signal transduction is a pathway of chemical signals that starts cell action. Signal transduction inhibitors block these pathways to stop cell action, including cell growth. Signal transduction inhibitors are the largest type of targeted therapy in use today.

Monoclonal antibodies

Within cells, there are molecules called receptors. Receptors are able to attach (bind) to other molecules. When binding occurs, the receptor is “turned on” and can alter the action of other molecules.

Many receptors are found within the outer membrane that surrounds the cell. These receptors are called cell surface receptors. They are often the starting point of the signal transduction pathway. Some monoclonal antibodies attach to cell surface receptors to stop the pathway from being triggered.

EGFR inhibitors

EGFR—also called HER1—is one type of cell surface receptor. It is a transmembrane receptor. It expands from the outside of the cell through the membrane to the inside of the cell. It is turned on by a molecule outside of the cell called epidermal growth factor. Once turned on, EGFR stimulates the cell to divide. In many cancers, too many signals for the cell to divide are sent by EGFRs causing the cancer to grow uncontrollably.  EGFR inhibitors help stop the cancer from growing.

  • Cetuximab (Erbitux®) attaches to the end of EGFR that is outside the cell to block epidermal growth factor. It is used for colon, rectal, head & neck cancers, non-small lung cancers, and non-melanoma skin cancers.
  • Panitumumab (Vectibix®) also attaches to end of EGFR that is outside the cell to block epidermal growth factor. It is used for colon, penile, and rectal cancers.

HER2 inhibitors and conjugates

Like EGFR, HER2 is a transmembrane receptor. It is also called ErbB2 or HER2/neu. HER2 receptors are not turned on by binding with a molecule from outside the cell. Instead, they are turned on when it attaches to other cell surface receptors. HER2 receptors turn a gene for the cell to divide on and off. In some cancers, this gene is always on, causing the cancer to grow. HER2 inhibitors bind to HER2 and turn the gene off to slow cancer growth.

  • Trastuzumab (Herceptin®) attaches to the end of HER2 that is outside the cell to stop HER2 from attaching to other receptors. It is used for breast, gastric, and esophageal cancers.
  • Pertuzumab (Perjeta™) also attaches to the end of HER2 that is outside the cell to stop HER2 from attaching to other receptors. It is used for breast cancers.
  • Ado-trastuzumab emtansine (Kadcyla™) is a combination of trastuzumab and the chemotherapy drug emtansine. If emtansine is given alone, it can affect any cell. However, ado-trastuzumab emtansine affects mostly cancer cells with too many HERs since trastuzumab attaches to HER2 receptors. It is used for breast cancers.

Kinase inhibitors

Kinases are molecules that move chemicals, called phosphates, from one molecule to another. The former molecule is called the “donor” and the latter is called the “substrate.” The phosphate creates a chemical reaction within the substrate, changing its course of action.

There are several hundred types of kinases. They are named after the substrate they affect. Many kinases affect proteins. This large group of kinases is called protein kinases.
Protein kinases are grouped by the part of the substrate that accepts the phosphate. This part of the substrate is called the residue. Residues include tyrosine, serine, threonine, or histidine. Some protein kinases act on tyrosine only, histidine only, or both serine and threonine. Other protein kinases act on serine, threonine, and tyrosine.

Kinases are often found within the signal transduction pathway. Some kinases are part of transmembrane receptors and are located at the end of the receptor that is inside the cell. Other kinases are found within the fluid that fills the cell. This fluid is called cytoplasm.
Kinase inhibitors stop phosphates from being transferred by a kinase from the donor to the substrate molecule. They are small molecule drugs that work inside of cancer cells. Kinase inhibitors may affect one or more types of kinase. Those that target multiple kinases are called multikinase inhibitors.

To date, most kinase inhibitors target tyrosine kinases. There are about 20 “families” of receptor tyrosine kinases. EGFR and HER2 belong to one family of receptor tyrosine kinases. There are about 11 “families” of cytoplasmic tyrosine receptors.

  • Axitinib (Inlyta) blocks the action of VEGF1/2/3 receptor tyrosine kinase. It is used for kidney cancer.
  • Bosutinib (Bosulif®) blocks the action of BCR-Abl, Src, Lyn, and Hck cytocplasmic tyrosine kinases. It is used for acute lymphoblastic leukemias and chronic myelogenous leukemias.
  • Cabozantinib (Cometriq™) blocks the action of RET, Met, VEGF1/2/3, Kit, TrkB, Flt3, Axl, and Tie2 receptor tyrosine kinases. It is used for thyroid cancer.
  • Crizotinib (Xalkori®) blocks the action of ALK, ROS1, and c-Met receptor tyrosine kinases. It is used for non-small lung cancers and sarcomas.
  • Dabrafenib (Tafinlarâ) blocks the action of B-Raf cytoplastic serine/threonine kinase. It is used for melanoma cells that have an abnormal BRAF gene.
  • Dasatinib (Sprycel®) blocks the action of Kit, EphA2, and PDGFRβ receptor tyrosine kinases as well as BCR-Abl, Src, Lck, Yes, and Fyn cytocplasmic tyrosine kinases. It is used for acute lymphoblastic leukemias, chronic myelogenous leukemias, and soft tissue sarcomas.
  • Erlotinib (Tarceva®) blocks the action of EGFR tyrosine kinase. It is used for bone, esophageal, kidney, pancreatic and non-small lung cancers.
  • Ibrutinib (Imbruvica™) blocks the action of BTK (Bruton's tyrosine kinase). This is a cytoplasmic kinase. It is used to treat some leukemias and lymphomas.
  • Imatinib (Gleevec®) blocks the action of BCR-Abl cytocplasmic tyrosine kinases as well as Kit and PDGFR receptor tyrosine kinases. It is used for bone cancers, non-melanoma skin cancers, acute lymphoblastic leukemias, chronic myelogenous leukemias, melanomas, non-hodgkin's lymphomas, and soft tissue sarcomas.
  • Lapatinib (Tykerb®) blocks the action of EGFR and HER2 tyrosine kinases. It is used for some bone, breast, and central nervous system cancers.
  • Nilotinib (Tasigna®) blocks the action of PDGFR receptor tyrosine kinase and BCR-Abl cytoplasmic tyrosine kinase. It is used for acute lymphoblastic leukemias, chronic myelogenous leukemias, and soft tissue sarcomas.
  • Pazopanib (Votrient®) blocks the action of VEGF1/2/3, FGFR1/3, Kit, Fms, and PDGFRα/β receptor tyrosine kinases as well as Lck and Itk cytoplasmic tyrosine kinases. It is used for kidney, thyroid, and uterine cancers and soft tissue sarcomas.
  • Ponatinib (Iclusig®) blocks the action of Flt3, Kit, RET, Tie2, Eph, VEGF, PDGFR, and FGFR receptor tyrosine kinases and Src and BCR-Abl cytoplasmic tyrosine kinases. It is used for acute lymphoblastic leukemia and chronic myelogenous leukemias.
  • Regorafenib (Stivarga®) blocks the action of VEGF1/2/3, Kit, PDGFRα/β, RET, FGFR1/2, Tie2, and Eph2A receptor tyrosine kinases, BCR-Abl cytoplasmic tyrosine kinase, and B-Raf and B-Raf (V600E) cytoplastic serine/threonine kinases. It is used for colon and rectal cancers and soft tissue sarcomas.
  • Sorafenib (Nexavar®) blocks the action of Kit, Flt3, RET, VEGF1/2/3, and PDGFRα/β receptor tyrosine kinases as well as C-Raf, B-Raf, and B-Raf (V600E) cytoplastic serine/threonine kinases. It is used for bone, hepatobiliary, kidney, and thyroid cancers and sarcomas.
  • Sunitinib (Sutent®) blocks the action of PDGFRα/β, VEGF1/2/3, Kit, Flt3, CSF-1R, and RET receptor tyrosine kinases. It is used for bone, kidney, neuroendocrine, and thyroid cancers and sarcomas.
  • Trametinib (Mekinist™) blocks the action of MEK1/2 cytoplastic serine/threonine kinase. It is used for melanoma cells that have an abnormal BRAF gene.
  • Vandetanib (Caprelsa®) blocks the action of EGFRs, VEGFs, RET, Tie2, and EphRs receptor tyrosine kinases as well as Brk and Src cytoplastic tyrosine kinases. It is used for thyroid cancers.
  • Vemurafenib (Zelboraf™) blocks the action of A/B/C-Raf and B-Raf cytoplastic serine/threonine kinase. It is used for melanoma cells that have an abnormal BRAF gene.

mTOR inhibitors

mTor is a protein kinase within the cell. In some cancers, mTORs are active when they shouldn't be. mTor activity causes the cell to grow. mTor inhibitors enter the cell and block mTORs activity.

  • Sirolimus (Rapamune®) is used for bone cancers and soft tissue sarcomas.
  • Everolimus (Afinitor®) is used for breast, kidney, and neuroendocrine cancers, soft tissue sarcomas, and Waldenström's Macroglobulinemia.
  • Temsirolimus (Toricel®) is used for kidney and uterine cancers.

Hedgehog pathway inhibitor

The Hedgehog pathway is a very important signal transduction pathway when a baby is in the womb. This pathway controls a baby's growth. One of the key proteins in the Hedgehog pathway is SMO (Smoothened). In adults, the Hedgehog pathway is mostly not active. However, many people with non-melanoma skin cancers have abnormal Hedgehog signaling. Hedgehog pathway inhibitors block the proteins in the pathway.

  • Vismodegib (Erivedge®) blocks SMO and shrinks non-melanoma skin cancers.

Immune system targets

Some monoclonal antibodies act on targets within the immune system. The immune system is your body's natural defense against illness. The largest group of such drugs is the anti-CD20 antibodies. CD20 is a cell surface antigen on B cells. B cells are a type of white blood cells, called lymphocytes, which are part of the immune system. Anti-CD20 antibodies attach to CD20 causing the immune system to attack B cells. Anti-CD52 antibodies work in the same fashion on lymphocytes.

Monoclonal antibodies are also used to deliver toxic drugs to lymphocytes. Such currently used  drugs can attach to CD20 or CD30. CD30 is a cell surface receptor on B and T cells.
A third immune target of monoclonal antibodies is CTLA-4. CTLA-4 is a cell surface receptor on T-cells. CTLA-4-blocking antibodies attach to CTLA-4, which blocks signals that “turn off” the T-cell.

  • Alemtuzumab (Campath®) is an anti-CD52 antibody. It is used for some non-Hodgkin lymphomas and Waldenström's Macroglobulinemia.
  • Brentuximab vedotin (Adcetris®) attaches to CD30 and releases into the cell a chemotherapy drug called MMAE (monomethyl auristatin E). Brentuximab vedotin is used for peripheral T-cell lymphomas and Hodgkin lymphomas.
  • Ipilimumab (Yervoy®) is a CTLA-4-blocking antibody. It is used is used for melanomas.
  • Ibritumomab tiuxetan (Zevalin®) attaches to CD20 and releases radioactive substances into the cell to kill it. Ibritumomab tiuxetan is used for some non-Hodgkin lymphomas.
  • Obinutuzumab (Gazyva™) is an anti-CD20 antibody. It is used for some non-Hodgkin lymphomas.
  • Ofatumumab (Azerra®) is an anti-CD20 antibody. It is used for some non-Hodgkin lymphomas and Waldenström's Macroglobulinemia.
  • Rituximab (Rituxan®) is an anti-CD20 antibody. It is used for acute lymphoblastic leukemia, central nervous system cancers, Hodgkin lymphomas, some non-Hodgkin lymphomas, and Waldenström's Macroglobulinemia.

Angiogenesis targets

Angiogenesis is the process by which new blood vessels are formed. Cancer cells need blood to grow so cancer cells release VEGF to start angiogenesis. VEGF is a molecule that attaches to VEGF receptors, which are found on cells that form blood vessels. When VEGF attaches to the receptors, it causes the cells to grow.

There are multiple types of drugs that can stop the action of VEGF. Some kinase inhibitors described above, such as sunitinib and sorafenib, block the action of VEGF receptor kinases. Other drugs used are VEGF receptor inhibitors. These drugs attach to VEGF which stops VEGF from attaching to its receptors.

VEGF receptor inhibitors

  • Bevacizumab (Avastin®) is used for breast, central nervous system, cervical, colon, kidney, ovarian, rectal, and uterine cancers as well as sarcomas and non-small cell lung cancers.
  • Ziv-aflibercept (Zaltrap®) is used for colon and rectal cancers.

Hormonal targets

Hormones are chemical messengers that can travel anywhere in the body. Hormone therapy stops the action of or reduces the amount of hormones in the body. It is used to reduce the risk of or to treat certain cancers. Some hormone therapy drugs are targeted therapies and some are not. Current targeted therapies affect estrogen or androgen. Estrogen is one of the main hormones in women. Androgen is one of the main hormones in men.

Estrogen Targets

Within cells are receptors for estrogen. When estrogen attaches to these receptors, changes within the cell are started that cause the cell to grow. The growth of some cancers is fueled by estrogen. Blocking estrogen from receptors helps stop the growth of the cancer. SERMS (selective estrogen receptor modulators) are drugs that attach to estrogen receptors and block estrogen. SERDs (selective estrogen receptor downregulators) are drugs that block and reduce the number of estrogen receptors.

Substances involved in the making of estrogen are other targets. Aromatase inhibitors block a protein involved in the making of estrogen. However, they do not stop the ovaries from making estrogen in women who still have menstrual periods (premenopausal). Thus, the aromatase inhibitors are only used among postmenopausal women.

  • Anastrozole (Arimidex®) is an aromatase inhibitor. It is used for breast, ovarian, and uterine cancers.
  • Exemestane (Aromasin®) is an aromatase inhibitor. It is used for breast and uterine cancers.
  • Fulvestrant (Faslodex®) is a SERD. It is used for breast cancer.
  • Letrozole (Femara®) is an aromatase inhibitor. It is used for breast, ovarian, and uterine cancers.
  • Raloxifene (Evista®) is a SERM. It is used to reduce the risk of breast cancer.
  • Tamoxifen citrate is a SERM. It is used to reduce the risk of breast cancer. It is also used to treat breast, ovarian, and uterine cancers as well as soft tissue sarcoma.
  • Toremifene citrate (Fareston®) is a SERM. It is used for breast cancer and soft tissue sarcoma.

Androgen targets

Androgen targets are much like those for estrogen. Antiandrogens block testosterone from attaching to hormone receptors in cells. They help stop certain types of cancer cells from growing. Androgen biosynthesis inhibitors impede a protein involved in the making of testosterone. These inhibitors can block all sources of testosterone in the body. All drugs targeting androgens are used for prostate cancer.

  • Abiraterone acetate (Zytiga®) is an androgen biosynthesis inhibitor.
  • Bicalutamide (Casodex®) is a nonsteroidal antiandrogen.
  • Enzalutamide (Xtandi®) is a nonsteroidal antiandrogen.
  • Flutamide is a nonsteroidal antiandrogen.
  • Nilutamide (Nilandron®) is a nonsteroidal antiandrogen.

Proteasome targets

Inside of cells are proteasomes. Proteasomes are rings of proteins that break down other proteins. Some of these proteins need to be broken down in order for the cell to grow. Proteasome inhibitors block the action of proteasomes, which leads to cell death.

  • Bortezomib (Velcade®) is a proteasome inhibitor used for multiple myelomas, non-Hodgkin lymphomas, and Waldenström's Macroglobulinemia.
  • Carfilzomib (Kyprolis™) is a proteasome inhibitor used for multiple myelomas.

Histone deacetylase targets

Histones are proteins that DNA (deoxyribonucleic acid) wraps tightly around to form chromosomes. Histone deacetylase is a class of proteins that removes a chemical group from histones so that DNA can wrap more tightly. There are four classes of histone deacetylase. Histone deacetylase inhibitors block the action of histone deacetylase which can lead to cell death.

  • Romidepsin (Istodax®) is a histone deacetylase inhibitor used for non-Hodgkin lymphomas. 
  • Vorinostat (Zolinza®) is a histone deacetylase inhibitor used for multiple myelomas and a rare form of non-Hodgkin lymphomas

Folate targets

Folate is needed for the replication of cells. Cancer cells especially need folate because they replicate quickly. As a result, it appears that some cancer cells make too much RFC-1. RFC-1 is a protein in cells that helps maintain levels of folate.

Since folate is needed for cell growth, antifolates can be used as cancer drugs. Dihydrofolate reductase inhibitors are one type of antifolates. These drugs enter cells and attach to dihydrofolate reductase. As a result, folate is not reduced into smaller parts that are needed for cell growth.

  • Pralatrexate (Folotyn®) is a dihydrofolate reductase inhibitor. It is used for some types of non-Hodgkin lymphoma.

Retinoic acid receptor targets

Retinoids are small molecule drugs. They enter cells and bind to retinoic receptors, which help to manage the life cycle of cells. Retinoids are mostly known as treatments for acne. They cause new growth of skin. They are also used as treatments for some cancers. Retinoids can foster the growth of an immature cell into a mature cell, which is helpful for APL (acute promyelocytic leukemia). Retinoids can also help stop the growth of some types of cancer cells.

  • Isotretinoin is used for a rare type of non-Hodgkin lymphomas and non-melanoma skin cancers.
  • Tretinoin is used for APL and rare type of non-Hodgkin lymphomas.
  • Acitretin (Soriatane®) is used for rare type of non-Hodgkin lymphomas and non-melanoma skin cancers.
  • Bexarotene (Targretin®) is used for rare type of non-Hodgkin lymphomas.