Every part of the human body must have a constant supply of blood to survive. Blood carries vital substances to different part of body. Blood vessels are the "pipelines" that carry blood throughout the body. Normal cells are supplied with blood by vessels that develop as your body develops. A tumor develops from a single normal cell that has turned cancerous and then continues to divide, creating more cancer cells. At first these cells can use the nearby blood vessels, but as the tumor grows, some of these cells get further away from a blood supply. For the tumor to continue growing, it must have new blood vessel formation or angiogenesis. Antiangiogenesis treatment is the use of drugs or other substances to stop tumors from developing new blood vessels. Without a blood supply, tumors can't grow freely.
| Product | Target | Indication | Clinical Status | Manufacturer |
|---|---|---|---|---|
| 2-methoxyestradiol (Panzem) |
Microtubule | Breast, prostate cancer, and multiple myeloma | Phase II | EntreMed |
| ABT-510 | Pro-angiogenic growth factors | Breast, colorectal , lung cancer, and sarcoma | Phase I | Abbott |
| ABT-627 (Xinlay, Atransentan) |
Endothelin-A | Prostate cancer | Phase III | Abbott |
| Volocimab (Anti-a5ß1 Integrin) |
Integrin | Various tumors | Phase I | Protein Design Lab |
| AVE8062 | Vascular targeting (Combretastatin A4 derivative) | Various tumors | Phase I/II | Aventis |
| BMS-275291 | Metalloprotein-ase | Lung cancer | Phase II | Celltech |
| Combretastatin A4 prodrug (CA4P) (Zybrestat) | Vascular targeting | Various tumors | Phase I-III | Oxigene |
| Neovastat (AE-941) |
VEGF | Non-small cell lung cancer | Phase III | Aeterna Zentaris |
| VEGF Trap | VEGF | Various tumors | Phase I | Regenron |
| Zactima | VEGF and EGFR | Various tumors | Phase III | AstraZeneca |
| ZD4054 | Endothelin-A antagonist | Various tumors | Phase II | AstraZeneca |
| ZD6126 | Cytoskeleton of endothelial cells | Various tumors | Phase II | AstraZeneca |
The growth of the endothelial cells that form the inner lining of the blood vessels is one of the most important step in establishing new blood vessels. Various angiogenesis inhibitors have been developed to target vascular endothelial cells and block tumor angiogenesis. Vascular endothelial growth factor (VEGF) Trap is a blocker of VEGF. It traps the VEGF being made by the tumor, stopping it from stimulating the VEGF receptor, and thus preventing the tumor from promoting blood vessel growth. A number of antibodies and small molecules target VEGF.
Vascular targeting agent (VTA) attacks the blood vessels of solid tumors and may have applications in diseases characterized by neo-vasculature. It attacks the vasculature within the tumor itself, reducing blood flow to deprive the tumor of oxygen and nutrients, causing tumor cell death. Unlike anti-angiogenesis drugs, which attempt to prevent the formation of new tumor blood vessels from developing, the VTA starves existing solid tumors by depriving them of the blood flow that feeds the tumor, causing tumor cell death. Combretastatin A4 Prodrug is a synthetic compound and acts as a VTA. AVE8062 (AC-7700) is a water-soluble derivative of combretastatin A4, which has strong suppressive effects on tumor blood flow. ZD6126 is a small molecule VTA.
Endothelin (ET), a protein normally produced in the body that can stimulate the growth and spread of cancer cells. Both endothelin and its receptor are found in various cancers including prostate, non-small cell lung, colorectal, breast and kidney cancers. There are two endothelin receptors, ET-A and ET-B. Atrasentan and ZD4054 selectively target this ET-A receptor.
Type XVIII collagen is a component of the matrix in endothelial and epithelial basement membranes. It possesses a unique carboxyl-terminal domain, a 182 amino acid polypeptide termed endostatin, which acts as an endogenous angiogenesis inhibitor when proteolytically cleaved from the native protein.
Panzem, 2-methoxyestradiol or 2ME2, has multiple mechanisms of action, including inhibiting angiogenesis, disrupting microtubule (cell structure) formation, down regulating hypoxia inducible factor-one alpha (HIF-1a, a survival protein), and inducing apoptosis (cell death). The mechanisms of Panzem are particularly relevant to the treatment of cancer involve inhibiting endothelial cell growth (anti-angiogenic activity) and killing tumor cells directly (pro-apoptotic activity). Panzem has activity in cell lines that are resistant to various chemotherapy agents including taxanes (microtubule stabilizing agents), etoposide, adriamycin and methotrexate (DNA synthesis interfering agents), and tamoxifen (anti-estrogen agent).
BMS 275291 is a second-generation selective matrix metalloproteinase (MMP) inhibitor as an anti-angiogenic drug for cancer.
Volocixmab (Anti-a5ß1 Integrin) is a chimeric antibody that inhibits angiogenesis, including vessel formation induced by VEGF, basic fibroblast growth factor (bFGF), as well as other pro-angiogenic growth factors. The antibody binds to a5ß1 integrin receptors that are present on activated endothelial cells and inhibits the formation of new blood vessels to the tumor, a process that is required for tumors to grow and metastasize.
ABT-510 is a synthetic peptide that mimics the antiangiogenic activity of the naturally occurring protein, thrombospondin-1 (TSP-1). ABT-510 blocks the actions of multiple pro-angiogenic growth factors known play a role in cancer related blood vessel growth, such as VEGF, bFGF, hepatocyte growth factor (HGF), and IL-8.
Neovastat is a naturally occuring antiangiogenic compound, extracted from cartilage, with multiple antiangiogenic mechanisms of action that provide broad therapeutic potential for a number of diseases. While most antiangiogenic agents target only one mechanism of the complicated angiogenic process, Neovastat acts on multiple fronts: blocking VEGF binding, inhibiting MMP (strong inhibition of gelatinolytic and elastinolytic activities for MMP-2, MMP-9, and MMP-12), induction of endothelial cell specific apoptosis, and increase in the level of angiostatin.
Zactima (ZD6474) is a novel, orally active, anti-cancer agent that selectively inhibits two key cancer pathways: tumor blood vessel development through VEGF receptor inhibition and tumor cell growth and survival through epidermal growth factor receptor inhibition.
The immune system in human body consists of cells that generate effective factors defending the body against pathogens (antigens). Antibody produced by B lymphocyte is an important arm of the defense mechanism. Cancer cells have cancer-associated antigens on the surface. The antibody attaches to the antigens on the surface of cancer cells. The cancer cells can thus be identified and destroyed by antibodies or other cells in the immune system.
Hybridoma technology makes mass-production of antibody possible. It is achieved by fusing a myeloma (a type of bone marrow cancer) with B cell that produces a specific antibody. Thus, the combination of a B cell that can recognize a particular antigen and a myeloma cell that lives indefinitely makes the hybridoma cell a kind of perpetual antibody-generating machine. Since the antibodies are all identical clones produced from a single (mono) hybridoma cell, they are called monoclonal antibodies (Mabs).
Antibody-based cancer therapy have enjoyed a renaissance. Since the first Mab, Rituxan, was approved for patients with non-Hodgkin's lymphoma in November 1997, there are currently eight Mabs available for treatment of different kind of cancers (Table). The applications of these Mab for treatment of cancer patient will likely generate significant excitement and growing acceptance by the medical community, which led to a high level of regulatory comfort. In future, the number of Mabs that will be approved is likely going to be much higher taking into account that there are huge numbers of antibodies in clinical development (Table).
| Product | Target | Indication | Clinical status | Manufacturer |
|---|---|---|---|---|
| Avastin (Bevacizumab) |
Vascular endothelial growth factor | Colorectal cancer | Market | Genentech |
| Bexxar (Iodine 131 Tositumomab) |
CD20 | B-cell non-Hodgkin's lymphoma | Market | GlaxoSmithKline (Corixa) |
| Campath (Alemtuzumab) |
CD52 | B cell chronic lymphocytic leukemia | Market | Genzyme and Millennium |
| Erbitux (Cetuximab) |
Epidermal growth factor receptor | Colorectal cancer | Market | Bristol-Myers Squibb and ImClone |
| Herceptin (Trastuzumab) | HER2 | Breast cancer | Market | Genentech |
| Mylotarg (Gemtuzumab ozogamicin) | CD33 | Acute myeloid leukemia | Market | UCB (Celltech) and Wyeth |
| Rituxan (Rituximab) |
CD20 | B-cell non-Hodgkin's lymphoma | Market | BiogenIdec and Genentech |
| Vectibix (ABX-EGF, ?(Panitumumab) |
Epidermal growth factor receptor | Metastatic Colorectal cancer |
Market | Amgen (Abgenix) |
| Zevalin (Yttrium-90, Ibritumomab tiuxetan) |
CD20 | B-cell non-Hodgkin's lymphomas | Market | BiogenIdec |
| Vectibix (ABX-EGF, ?(Panitumumab) |
Epidermal growth factor receptor | ?Esophageal, kidney, lung, and pancreatic cancers | Phase III | Amgen (Abgenix) |
| ABX-MA1 | MUC18 | Melanoma | Phase I | Amgen (Abgenix) |
| Avastin alone or + Tarceva | Liver cancer | Phase II | Genentech | |
| CDP791 | Vascular endothelial growth factor | Non-small cell lung cancer | Phase II | UCB (Celltech) |
| CDP860 | Beta receptor of platelet growth factor | Various tumors | Phase II | UCB (Celltech) |
| CMC544 | Antibdoy-cytotoxic conjugate | Non-Hodgkin's Lymphoma | Phase I | UCB (Celltech) |
| Cotara | Tumor necrosis factor | Brain tumor | Phase II | Peregrine |
| DenosuMab (AMG162) |
Receptor activator of nuclear factor kappa B ligand | Advanced breast cancer with bone metastasis | Phase II | Amgen |
| HuC242-DM4 | CanAg | Various tumor | Phase I | ImmunoGen |
| HuN901-DM1 | CD56 | Small cell lung cancer and multiple myeloma | Phase I/II | ImmunoGen |
| IMC-BEC2 | GD3 | Lung cancer | Phase III | ImClone |
| IMC-1121b | Vascular endothelial growth factor | Colorectal cancer | Phase I | ImClone |
| IMC-11F8 | Epidermal growth factor receptor | Solid and liquid tumors | Phase I | ImClone |
| Lymphocide (Eparatuzumab, Immu103) |
CD22 in B cells | Non-Hodgkin's lymphoma | Phase II | Immunomedics |
| MDX-010 (Ipilimumab) |
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) | Breast cancer, melanoma, and prostate cancer | Phase II/III | Medarex |
| MDX-060 | CD30 | Hodgkin's disease and anaplastic large cell lymphoma | Phase II | Medarex |
| MDX-070 | Prostate-specific membrane antigen (PSMA) | Prostate cancer | Phase II | Medarex |
| MDX-214 | Epidermal growth factor receptor | EGFR-positive cancers | Phase I | Medarex |
| MLN2704 | PSMA targeting Mab with a chemothera-peutic agent | Prostate cancer | Phase 1 | Millennium |
| Omnitarg | HER | Breast, lung, prostate, and ovarian cancers | Phase II | Genentech |
| SGN-30 | CD30 | Hodgkin's disease | Phase II | Seattle Genetics |
| SGN-40 | CD40 | Multiple myeloma | Phase I | Seattle Genetics |
| Vitaxin | Integrins | Melanoma and prostate cancer | Phase II | MedImmune |
| Ticilimumab (CP-675206) |
CTLA-4 | Melanoma | Phasee III | Pfizer (Abgenix) |
There are two major types of Mabs used in cancer therapy. One is Mab alone. Mabs attach themselves to specific antigens on cancer cells. The interaction between Mab and cell surface molecules results in anti-cancer effects. The other is conjugated Mab. This is to connect radioactive moieties, toxins, enzymes, or prodrugs to a Mab. The conjugated Mab has the capacity to recognize and attach to cancer cells, which bring the attached drugs to kill the targeted cancer cells.
CD20 is a B-cell-specific protein. Rituxan is used for treatment of B-cell non-Hodgkin's lymphoma. This drug binds to CD20 on the surface of lymphoma cells, targeting them for destruction through several possible mechanisms, including antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis. CD52 is an important marker for B cell chronic lymphocytic leukemia on cell surface. Campath binds to CD52 and from there, it recruits the body's immune system to attack and kill the marked leukemia cells.
Epidermal growth factor receptor (EGFR) normally helps regulate the growth of many different cells in the body. EGFR also can stimulate cancer cells to grow. Many cancer cells require signals mediated by EGFR for their survival. Residing on the surface of these tumor cells, EGFR is activated when naturally occurring proteins in the body, such as epidermal growth factor (EGF) or transforming growth factor alpha (TGF-a), bind to it. This binding changes the shape of EGFR, which, in turn, triggers internal cellular signals that stimulate tumor cell growth. Erbitux and Panitumumab binds to EGFR, preventing the natural ligands such as EGF and TGF-a from binding to the receptor and interfering with the signals that would otherwise stimulate growth of the cancer cells. This blockade also interferes with tumor invasion and metastases, cell division, and angiogenesis. IMC-11F8 is a fully human monoclonal antibody that is designed to bind to the EGFR, thereby inhibiting certain ligands known as growth factors from binding to and activating the receptor. This action blocks a signal pathway key to tumor growth and repair and has also been shown to induce cell death, or apoptosis, in human tumors.
Heceptin attaches to human epidermal growth factor receptor 2 (HER2) and blocks the other molecules from binding there. This Mab thus prevents the cancer cells from growing rapidly. Omnitarg is a humanized antibody and the first in a new class of agents known as HER dimerization inhibitors (HDIs). HDIs block the ability of the HER2 receptor to collaborate with other HER receptor family members (HER1/EGFR, HER3, and HER4). In cancer cells, interfering with HER2's ability to collaborate with other HER family receptors blocks cell signaling and may ultimately lead to cancer cell growth inhibition and death of the cancer cell. HDIs, because of their unique mode of action, have the potential to work in a wide variety of tumors, including those that do not overexpress HER2.
Formation of new blood vessels is critical for tumor growth. The growth of the endothelial cells that form the inner lining of the blood vessels is one of the most important step in establishing new blood vessels. Vascular endothelial growth factor (VEGF) makes a significant contribution to this process.Avastin binds to VEGF, inhibits VEGF, and prevents tumor angiogenesis (the formation of new blood vessels). CDP791 was also designed to target vascular endothelial growth factor to interrupt the growth of the blood vessels. IMC-1121B is a fully human monoclonal antibody that is designed to bind to the VEGFR-2 found on tumor vasculature, thereby inhibiting vascular endothelial growth factors from binding to and activating the receptor.
During angiogenesis, proteins called integrins are expressed on the surface of these new vessels, which enable the integrins to adhere to the surrounding tissue, allowing them to continue their extension toward and into the tumor. Vitaxin has been shown to bind and block alpha-v beta-3, an integrin which is specifically found on these newly sprouting blood vessels, and to stop the growth of these vessels through an apoptotic (programmed cell death) signaling mechanism.
Denosumab is a fully human monoclonal antibody that specifically targets the receptor activator of nuclear factor kappa B ligand (RANKL), a key mediator of the resorptive phase of bone remodeling. Denosumab is being studied across a range of conditions, including cancer bone metastases and multiple myeloma.
The conjugated-antibody delivers radioactive moieties, toxins, enzymes, or prodrugs directly to the cancer cells. The conjugated Mab circulates in the body and attach to a cancer cell with a matching antigen. It directs the therapeutic agents to the targeted cells and minimizes damage to the normal cells.
Zevalin is the first radiolabeled Mab approved for treatment of cancer. It delivers radioactivity to cancerous B lymphocytes and is used to treat B cell non-Hodgkin's lymphoma. Another radiolabeled Mab, Bexxar, is also used to treat B cell non-Hodgkin's lymphoma.
Mylotarg is a Mab conjugated with a toxin called calicheamicin. The antibody targets the CD33 antigen, which is present on most leukemia cells. It is used to treat acute myelogenous leukemia.
MLN2704 consists of a targeting monoclonal antibody vehicle designed to deliver a lethal payload specifically to tumor cells that express prostate-specific membrane antigen (PSMA) on their surfaces. The lethal payload consists of the chemotherapeutic agent maytansinoid (DM1). PSMA is expressed on virtually all prostate cancer cells, both primary and metastatic, and its abundance on the cell surface increases as the cancer progresses. Thus MLN2704 recognizes, attaches, and delivers drug to kill tumor cells.
HuN901-DM1 comprises huN901 antibody, which targets CD56, and DM1 cell-killing agent, a tumor activated prodrug (TAP). A TAP compound consists of: a monoclonal antibody that binds specifically to a target ? its antigen ? found on cancer cells with a potent cell-killing agent attached. The antibody serves to target the compound specifically to cancer cells and the cell-killing agent serves to kill the cancer cells. HuC242-DM4 comprises huC242 CanAg-targeting antibody and DM4 cell-killing agent
Cotara is an antibody conjugated to Iodine 131, a therapeutic radioisotope. The antibody is specific for tumor necrosis factor, which is concentrated in the core of the tumor. Thus it is attracted to necrotic regions throughout the tumor, the radioisotope can be delivered to neighboring viable cancer cells, resulting in their death.
ABX-MA1 targets a protein called MUC18, a cell surface adhesion molecule that is highly expressed on metastatic melanoma cells but not on normal skin cells. MUC18 has been demonstrated to play a critical rolel in melanoma growth and metastasis by regulating the adhesion and interaction between melanoma cells and surrounding skin cells and new blood vessel cells. Binding of the MUC18 antigen by ABX-MA1 inhibited primary melanoma tumor growth and the formation of tumor metastases.
Anti-idiotype antibody technology can be used to generate anti-tumor activities. The variable regions in the antibody bear unique antigenic determinants called idiotopes. Anti-idiotypic (anti-id) antibodies can potentially induce a human anti-anti-idiotypic response. The anti-anti-idiotypic antibodies mimic the original antigen. Because of this mimicry, vaccination with anti-id has induced protective immunity. However, very limited success was achieved in this field. IMC-BEC2 is an investigational anti-idiotypic monoclonal antibody that mimics GD3, a ganglioside expressed on the cell membrane of most small cell lung cancer tumors. It failed in Phase III clinical trial.
Humanized antibodies represent an enormous leap forward among potentially effective anticancer treatments. It is feasible for the antibody to maintain the capacity of recognizing the antigen and to have structure like a human antibody. This is done by the transfer of the murine CDRs (complementary determining regions) to a human framework. Most of the antibodies listed in the Tables 1 are humanized antibodies.
The genomics/proteomics revolution that is currently taking place will provide an exploding number of genetic and biological targets over the next several years. Antibodies are becoming a very important and attractive class of drugs and cheapest way to transfer discoveries in genomics/proteomics into globally marketable novel drugs. The preclinical development pathways for antibodies are now well-known, and antibodies can typically be developed in a much shorter length time than small molecules. This ability to shorten the time to market and thus, development costs, will make antibodies increasing valuable as new disease targets proliferate over the next decades to come.
Antimetabolites are structurally related to normal cellular components. They generally interfere with the availability of normal purine or pyrimidine nucleotide precursors by inhibiting their synthesis or by competing with them in DNA or RNA synthesis. The antimetabolites are a clinically important group of cancer drugs used in the treatment of a variety of solid tumors and hematologic malignancies. The widely used compounds include the antifolate, methotrexate (MTX), the pyrimidine analogues, 5-fluorouracil (5-FU) and cytosine arabinoside (ara-C, 1-ß-D-arabinofuranosylcytosine, cytarabine).
| Product | Target | Indication | Clinical Status | Manufacturer |
|---|---|---|---|---|
| Alimta | Dihydrofolate reductase | Mesothelioma and lung cancer | Market | Eli Lilly |
| Clolar (Clofarabine) | Mitochondria | Various tumors | Phase I/II | Genzyme |
| Cloretazine | DNA | Various tumors | Phase I | Vion |
| Decitabine (Dacogen) |
Methylation | Various tumors | Phase II | SuperGen and MGI Pharma |
| Gemzar | Nucleoside analogue | Pancreatic and non-small cell lung cancers | Market | Eli Lilly |
| Nelarabine | Nucleoside analogue | Lung cancer | Phase III | GlaxoSmithKline |
| Tezacitabine | Nucleoside analogue | Colorectal and gastric-esophageal cancers | Phase II | Chiron |
| Triapine | Ribonucleotide reductase | Various tumors | Phase II | Vion |
| Xeloda (Capecitabine) |
Nucleoside analogue | Breast and colorectal cancers | Market | Roche |
Alimta (Pemetrexed) is a novel antifolate, a class of drugs that targets the folic acid metabolic pathway, which effects availability of certain B complex vitamins.
Nelarabine is a novel water soluble prodrug of ara-G with T- cell selectivity. It is a nucleoside analogue that is rapidly converted to its corresponding arabinosylguanine nucleotide triphosphate (araGTP), resulting in inhibition of DNA synthesis and cytotoxity.
Tezacitabine (FMdC) interrupts DNA replication and is a next-generation nucleoside analogue, to treat cancer. Nucleoside analogues are a class of drugs that affect DNA synthesis.
Gemzar is a nucleoside analogue. It is a novel chemotherapeutic agent that mimics a natural building block of DNA. It disrupts the process of cell replication and works by interfering with the process by which cells divide and repair themselves, thus preventing the further growth of cancer cells and leading to cell death.
Clofarabine, purine nucleoside antimetablolite, is a nucleoside analog from the family of compounds which include the marketed drugs fludarabine, cladribine and gemcitabine and targets DNA and mitochondria. Clofarabine (a second generation, synthetic nucleoside) was designed to be potent, resistant to cellular inactivation, stable chemically and better tolerated than other nucleoside analogs. Clofarabine appears to have multiple mechanisms of action, including inhibition of both DNA polymerases and ribonucleotide reductase and the induction of apoptosis. Clofarabine has shown clinical activity in leukemias, and pharmacological activity in solid tumors.
Triapine is a small molecule that inhibits an enzyme, ribonucleotide reductase, necessary for the synthesis of DNA. Synthesis of DNA is necessary for cancer cells to replicate; therefore, inhibition of the ribonucleotide reductase enzyme prevents cancer cells from dividing in the body. Disruption of DNA synthesis in some cancer cells will also cause their death. DNA synthesis is involved in repairing damage to cancer cells that have been treated with many of the standard cancer chemotherapy agents, which work by damaging DNA. The ability of cancer cells to rapidly repair DNA damage is one reason that cancer cells become resistant to standard chemotherapy agents. Because Triapine inhibits DNA synthesis, it can inhibit DNA repair, and therefore it can be predicted to increase the anti-tumor effects of many of the common anti-cancer drugs, such as cisplatin, cyclophosphamide, and etoposide.
Decitabine is a chemotherapeutic agent that has been shown to have a broad spectrum of activity in several hematological malignancies as well as solid tumors. Decitabine belongs to a new class of drugs called hypomethylating agents, with a unique mechanism of action. Methylation is a process in which methyl (CH3) groups are added to DNA to inactivate or "silence" genes. Recent research demonstrates tumor suppressor genes and DNA repair genes are hypermethylated and silenced in a majority of cancers, typically at an early stage of the disease. Hypermethylation, then, is an early warning sign that may prove useful for early cancer detection and screening of cancer patients. Therapy that removes the methyl groups (by hypomethylation) may "switch on" natural defense mechanisms against cancerDecitabine is the most specific and potent hypomethylating agent so far tested in clinical trials.
Strictly speaking, alkylating agents and platinum-based cancer drug are not antimetabolite cancer drugs. They are described here, since their actions are closely related to antimetabolite agents. Alkylating agents, such as Carmustine, Cyclophosphamide, Ifosfamide, Iomustine, Mechlorethamine, and Streptozotocin, leads to cross-linkages among nucleotides in the DNA chains and facilitates DNA strand breakage. Compared to the standard available alkylating agents, Cloretazine has unique and advantageous features, which could lead to an enhanced spectrum, or improved antitumor activity.? For example, in addition to damaging DNA, Cloretazine also inhibits a key enzyme O6-alkylguanine-DNA alkyltransferase(AGT) involved in the repair of the DNA damage. Thus, it blocks a major mechanism of drug resistance common to several of the standard alkylating agents. Cloretazine also exhibited excellent penetration across the blood brain barrier, and a high degree of antitumor activity against intra-cranially implanted leukemia cells. The latter distinguishes Cloretazine from many anticancer agents that have difficulty penetrating into the brain, a site where primary tumors can occur and a common site of metastases for several other solid tumors. Oxaliplatin (Eloxatin) and Satraplatin is new generation of platinum-based cancer drug.
Proteins are the molecular machines of life. They are responsible for most of the cells functions, including maintenance of structure, signaling processes and metabolism. The blueprints for all proteins are carried in DNA (deoxyribonucleic acid). In order for the DNA to become a protein an intermediate step is required, whereby the DNA is transcribed into the message RNA (ribonucleic acid) or mRNA.
Antisense drugs are small, chemically modified strands of DNA. These oligonucleotides are engineered in a sequence that is exactly opposite to the coding (sense) sequence of mRNA for the purpose of binding to that mRNA. Upon binding to the mRNA a duplex is formed. This duplex recruits an enzyme that degrades the mRNA portion of the duplex, thereby inhibiting the production of the intended protein. When these compounds bind tightly to the disease-causing sequence, the genetic process is inhibited, thus disabling the pathogenic process. This is called antisense technology because the strands of genetic material that get translated into a protein are called "sense" strands, and so "antisense" drugs are meant to stop that translation process.
| Product | Target | Indication | Clinical Status | Manufacturer |
|---|---|---|---|---|
| AVI-4126 | c-MYC | Various tumors | Phase II | AVI Biopharma |
| Genasense (Oblimersen sodium) | Bcl-2 | Variuos tumors | Phase II/III | Genta |
| ISIS112989 (OGX-011) | Secretory protein clusterin | Pancreatic cancer | Phase II | Isis Pharmaceuticals |
| LY2181308 (ISIS23722) | Survivin | Various tumors | Phase I | Isis Pharmaceuticals and Eli Lilly |
| LY2275796 | eIF-4E | Various tumors | Phase I | Isis Pharmaceuticals and Eli Lilly |
| MG98 | DNA methyltransferase | Acute myeloid leukemia and myelodysplasia | Phase I | MGI Pharma |
ISIS112989 (OGX-011) is an inhibitor of the secretory protein clusterin (sCLU), which is in the CLU family of proteins. sCLU acts as a cell-survival protein and is over-expressed in response to tumor killing strategies, such as chemotherapy, hormone ablation and radiation therapy. sCLU has been associated with preventing cell death in tumors, a function that may be related to its ability to clear cell debris after damage from tumor killing strategies. Inhibiting sCLU is intended to enhance the effects of traditional therapies in cancer treatment.
LY2181308 targets survivin, a molecule that allows the survival of cells that would normally undergo programmed cell death or apoptosis. When cancer cells grow, they appear to need the help of survivin. The molecule is abundant in many types of cancers, including colon, brain, lung, skin and others, but nearly nonexistent in normal cells.
LY2275796 targets eukaryotic initiation factor-4E (eIF-4E), a protein that is upregulated or overexpressed in a variety of cancers, including breast, head and neck, prostate, lung, bladder, colon, thyroid and non-Hodgkin's lymphomas. The molecule facilitates the synthesis of tumor angiogenic factors (factors that facilitate the growth of new blood vessels to support the development and progression of tumors), growth factors and survival factors by selectively enhancing their translation.
Genasense inhibits production of Bcl-2, a protein that is highly expressed in malignant cell from patients with cancers. Bcl-2 regulates a critical pathway in the body known as programmed cell death (or apoptosis). Cancer cells frequently develop multiple defects in this pathway that can delay or completely prevent cell death, even after treatment with high doses of chemotherapy. High levels of Bcl-2 are believed to be a fundamental cause of the inherent resistance of cancer cells to being killed by contemporary forms of anticancer therapy. Bcl-2 expression has been linked to lower response, faster time to cancer progression, and markedly decreased survival. By reducing the amount of Bcl-2 in cancer cells, Genesense may enhance the effectiveness of current anticancer treatments.
MG98 is an antisense compound and an inhibitor of DNA methyltransferase. Methyltransferase is associated with silencing tumor suppressor genes via hypermethylation. MG98 is used to enhance tumor suppressor genes by inhibiting DNA methyltransferase.
Gene therapy is the insertion of a functional gene into the cells of a patient to correct an inborn error of metabolism or function, to alter or repair an acquired genetic abnormality, and to provide a new function to a cell. Cancer gene therapy employs gene delivery technologies to express desired proteins for combating the tumor cells.
| Product | Target | Indication | Clinical Status | Manufacturer |
|---|---|---|---|---|
| Advexin | P53 | Various tumors | Phase I-III | Introgen |
| Gendicine | P53 | Nasopharyngeal carcinoma | Market in China | Sibiono GeneTech |
| INGN241 | MDA-7 | Melanoma | Phase II | Introgen |
P53 is a normal constituent of cells and is known as a tumor suppressor because it provides a powerful halt signal on cell growth. However, the P53 gene mutation in tumor cells results in the loss of tumor suppressor function and uncontrolled tumor cell growth. Advexin, adenoviral p53 gene therapy, supplies p53 protein in very high concentration in cancer tissue and restore p53 function, which selectively kills cancer cells while not harming the surrounding normal cells. Advexin combines the p53 tumor suppressor with a nonreplicating and nonintegrating adenoviral delivery system. Gendicine employed modified adenovirus serotype 5 expressing human normal p53 tumor suppressor gene. It was approved by the China State Food & Drug Administration (SFDA) and is the first commercialized gene therapy product ever approved in the world.
Melanoma differentiation associated gene-7 (MDA-7) functions not only as a tumor suppressor, but also as an immune enhancing cytokine. INGN241, adenovial MDA-7 protein gene therapy, expresses MDA-7 protein. The expressed MDA-7 protein is active and has a wide area of biological effect on cancers.
Many other gene therapy approaches are pursued for cancer treatments, inserting a "sensitivity" or suicide' gene into the tumor, for example by introducing the gene that encodes HSVtk; blocking the expression of oncogenes, for example by introducing the gene that encodes antisense K-RAS message; protecting stem cells from the toxic effects of chemotherapy, for example by introducing the gene that confers multiple drug resistance gene (MDR-1); blocking the mechanisms by which tumors evade immunological destruction, for example by introducing the gene that encodes antisense insulin-like growth factor-1 (IGF-1) message; killing tumor cells by inserting toxin genes under the control of a tumor-specific promoter, for example the gene that encodes diphtheria A chain.
Vaccines have been exceptionally effective against a number of diseases and have become one of the safest and most cost-effective weapons in medicine's arsenal against communicable disease. Vaccines generally induce both T cell and B cell responses.
Like vaccines that prevent infectious diseases, cancer vaccines work by stimulating the immune system to build an army of cells that recognize, attack, and kill the cancer cells. Differing from the vaccines for infectious diseases, most of the investigational cancer vaccines are designed for therapeutic purposes. It is very important to use tumor-specific or tumor associated antigens (proteins) displayed on tumor cells but not normal cells so that the induced immunity is directed against tumor cells.
| Product | Target | Indication | Clinical Status | Manufacturer |
|---|---|---|---|---|
| Allovectin-7 | HLA-B7 and ? microglobulin | Melanoma | Phase II | Vical |
| Avicine | hCG | Colorectal and pancreatic cancer | Phase III | SuperGen |
| BLP25 | MUC1 Peptide | Non-small cell lung cancer | Phase II | Biomira |
| Canvaxin | Multiple tumor associated antigens | Melanoma | Phase III | MITI (CancerVax) |
| Cervarix | Human papillomavirus (HPV) | Cervical cancer | Market | GlaxoSmithKline |
| GVAX | Multiple tumor associated antigens and GM-CSF | Prostate cancer, pancreatic cancer, acute and chronic myelogenous leukemia. | Phase II/III | Cell Genesys |
| Gardasil | HPV | Cervical cancer | Market | Merck |
| GMK | GM2 ganglioside | Melanoma | Phase III | Perogenics |
| MyVax Personalized Immunotherapy (GTOP99) |
Immune system | Non-Hodgkin's lymphoma | Phase III | Genitope |
| Melannoma antigen family A, 3 (MAGEA3) + QS-21 | MAGEA3 | Non-small cell lung cancer | Phase III | GlaxoSmithKline |
| PSMA vaccine | PSMA | Prostate cancer | Phase I | Perogenics |
| Theratope | Sialyl Tn | Breast and non-small cell lung cancer | Phase II/III | Biomira |
There are two classes of cancer vaccine, prophylactic and therapeutic. Prophylactic cancer vaccine is used to prevent occurrence of cancer. There are a number of pathogens which are known to cause cancers and these pathogens include human papilloma virus, hepatitis virus, Epstein-Bar virus, human T-cell leukaemia virus, helicobactor pylori, and human immunodeficiency virus etc. Cervical cancer vaccines, Cervarix and Gardasil, are prophylactic vaccine. Human papillomavirus (HPV) is the causative agent of cervical cancer. Cervarix and Gardasil are used to generate immune response and prevent the HPV infection, thus prevent development of cervical cancer. These two vaccines are based on virus-like particle (VLP) technology. The VLP is a structurally identical, non-infectious form of the virus.
Therapeutic cancer vaccine is used for treatment after cancer is developed. Majority of the cancer vaccines under development are therapeutic. So far, there are three therapeutic cancer vaccines reached market in limited countries. They are Avax Technologies' M-Vax, Corixa's Melacine, and IntraCel's OncoVax. M-Vax consists of autologous melanoma cells conjugated to a highly immunogenic hapten, dinitrophenyl, which makes the cancer cells more easily recognized by the immune system. Melacine contains lysed (broken) cells from two human melanoma cell lines combined with adjuvant, including monophosphoryl lipid A (MPL) and mycobacterial cell wall skeleton, both of which activate the human immune system in the context of vaccination. OncoVax is made of autologous colon cancer cells. However, these three therapeutic vaccines have performed poorly, and have only been marketed in limited geographic territories. M-Vax was marketed in Australia in 2000 and launched in Switzerland in October 2005, but was withdrawn from Australia in September 2002. Melancine was marketed in Canada in 2001, but was discontinued in Canada in July 2005, and is thus no longer marketed in any territory worldwide. OncoVax was marketed in Germany, Holland, and Switzerland in 2003. The reasons for the vaccine's failure of achieving commercial success may include: complex and expensive manufacturing procedure, lack of reimbursement status, lack of confidence in the vaccine, and extremely disappointing sales.
A number of cancer vaccine are made of whole tumor cells. The whole cell vaccine may stimulate a stronger immune response than other immunotherapy approaches that use cell fragments, peptides or antigens alone. These whole cancer cells have been irradiated to prevent replication, but they continue to produce antigens and stimulate the immune system for a period of days to weeks after they have been injected into a patient. In contrast, cell fragments, peptides and antigens are more likely to rapidly degrade in the body, which minimizes their ability to stimulate the immune system against cancer.
The whole cells also expose the immune system to multiple antigens that are associated with a wide range of solid tumors. These antigens appear in unpredictable patterns and concentrations among different people and within an individual's cancer as it evolves over time. The presentation of numerous antigens, termed polyvalence, is an important element in eliciting a therapeutic immune response in most patients and reducing a tumor cell's ability to escape the immune response. For example, Canvaxin contains at least 38 antigens that may be associated with tumor and may induce immune responses against tumor. However, Canvaxin was found no evidence of overall survival benefit for stage III melanoma compared to placebo. GVAX are comprised of tumor cells that have been irradiated and genetically modified to secrete granulocyte macrophage-clony stimulation factor (GM-CSF), an immune stimulating hormone, which activates the immune system to recognize and destroy the cancer cells.
A number of vaccines are based on the tumor associated antigens. BLP25 is synthetic MUC1 peptide vaccine, a liposomal vaccine specifically designed to generate a cellular immune response to the tumor associated antigen mucin MUC1. Theratope contains a synthetic form of a cancer-associated carbohydrate antigen, Sialyl Tn (STn). However, the phase III results indicated that the drug failed to improve survival. GMK incorporates an immune stimulant or adjuvant and the GM2 ganglioside, a cancer antigen present in approximately 95% of melanoma cells. MyVax Personalized Immunotherapy combines a protein derived from the patient's own tumor with an immunologic carrier protein keyhole limpet hemocyanin (KLH) and is administered with GM-CSF as an adjuvant.
Allovectin-7 is a DNA plasmid/lipid complex containing the DNA sequences encoding HLA-B7 and ? microglobulin, which together form a Major Histocompatibility Complex, or MHC, Class I antigen. This type of antigen can trigger a potent immune response against cancer cells. Allovectin-7 is injected directly into tumors, and is designed to make malignant cells more visible to the immune system. The treatment may trigger an immune response against tumor cells, both locally and systemically, by enabling the immune system to recognize tumor cells.
Avicine, a therapeutic cancer vaccine, is a synthetic peptide formulation designed to elicit an anti-human chorionic gonadotropin (hCG) immune response targeting hCG-producing cancer cells. This peptide is composed of carboxy terminal 37 amino acids (CTP-37) of the beta-subunit of hCG that has been conjugated to diphtheria toxoid. It is effective in stimulating an immune response to hCG that does not cross-react with related glycoprotein hormones. hCG is a biochemical marker of malignancy associated with all the major types of cancer. The expression of hCG has been shown to correlate with tumor aggressiveness, i.e., the greater the hCG expression, the more aggressive the tumor. The antibody can be used to neutralize hCG, reduce level of hCG, and thus, inhibit tumor growth.
Cell cycle is a series of events making exact replicas of all their genetic material and resulting in two daughter cells with one complete copy of the entire genome. Both normal cell and tumor cell go through a growth cycle or cell cycle. However, normal cell and neoplastic cell differ in the number of cells that are in the various stages of cell cycle. It is thus possible to identify the tumor cell specific step during the cell cycle and inhibit the tumor cell growth, but spare the normal cells.
| Product | Target | Indication | Clinical Status | Manufacturer |
|---|---|---|---|---|
| AP23573 | mTOR | Various tumors | Phase I/II | Ariad pharmaceuticals |
| MKC-1 | Miotosis | metastatic breast cancer | Phase II | EntreMed |
| Torisel (Temsirolimus, CCI-779) | G1 to S phase transition | Kidney cancer | Market | Wyeth |
Torisel, Temsirolimus, an ester of the immunosuppressive agent sirolimus (Rapamune), is a novel mammalian target of rapamycin (mTOR) kinase inhibitor. It binds with high affinity to the immunophilin FKBP, and this complex inhibits mTOR kinase activity, which leads to G1 to S phase cell cycle arrest. Temsirolimus has demonstrated significant inhibitory effects on tumor growth in both in vitro and in vivo models. It is an agent that is being developed to delay the time to tumor progression/recurrence and/or improve survival.
AP23573is a potent mTOR inhibitor that starves cancer cells and shrinks tumors by regulating the response of tumor cells to nutrients and growth factors and by controlling tumor blood supply and angiogenesis through effects on vascular endothelial growth factor in tumor and endothelial cells.
MKC-1 is an orally-active, small molecule, cell cycle inhibitor with a unique mechanism of action. Specifically, MKC-1 arrests cellular mitosis by inhibiting a novel intracellular target important in cellular trafficking that has been shown to be involved in cell division.
Heat shock proteins (HSP) are cytoplasmic proteins and they function in various intra-cellular processes. They play an important role in protein-protein interactions, including folding and assisting in establishing of proper protein conformation, and prevention of inappropriate protein aggregation. HSP is so named because these proteins were first found in cells that were exposed to high temperatures. HSPs are classified into a series of families, such as HSP60, 70, and 96, based on their molecular mass in kilodaltons. They act like 'chaperones,' making sure that the cell's proteins are in the right shape and in the right place at the right time. HSPs are also believed to play a role in the presentation of pieces of proteins (or peptides) on the cell surface to help the immune system recognize diseased cells. These peptides are called antigens - a term that describes any substance capable of triggering an immune response. HSP technology works by generating HSP-peptide complexes that have been isolated from individual patient's cancer cells. The HSP-peptide contains unique profile of signals or the antigenic fingerprint of the patent's cancer. These unique signals have the capacity to activate the immune system to elicit a powerful anti-tumor response.
| Product | Target | Indication | Clinical Status | Manufacturer |
|---|---|---|---|---|
| KOS-983 | Heat shock protein 90 | Various tumors | Phase I/II | Kosan Biosciences |
| AG-858 | Heat shock protein 70 | Chronic myelonic leukemia | Phase II | Antigenics |
| Oncophage | Heat shock protein 96 | Colorectal cancer, kidney cancer, lymphoma, melanoma, and pancreatic cancer | Phase II/III | Antigenics |
Heat shock protein 90 (HSP90) is a protein chaperone that binds to several sets of signaling proteins, known as "client proteins." These client proteins include a list of cancer-relevant targets such as mutated p53, Bcr-Abl, Raf-1, ErbB2 and other kinases, as well as steroid hormone receptors. Disruption of the HSP90-client protein complexes leads to proteosome-mediated degradation of client proteins. The polyketide geldanamycin, such as 17-AAG, and its analog, KOS983, bind to HSP90 and cause its dissociation from, and consequently, degradation of, the client proteins. Because the HSP90 client proteins are so important in signal transduction and in transcription (processes critical to the growth and survival of cancer cells), KOS983 may serve as chemotherapeutic agents in a number of cancers. These compounds are synergistic with certain other inhibitors of the signal transduction client proteins, as well as several conventional anticancer agents.
Oncophage, HSP 96 peptide complexes (HSPPC)-96, is an investigational personalized vaccine designed to treat cancers. Oncophage is a vaccine made from individual patients' tumor. Patients have surgery to remove part or all of the cancerous tissue, and a portion of this tissue is shipped overnight to the manufacturing facilities. The HSP-peptide complexes are extracted and purified from each sample. The vaccine is shipped frozen back to the hospital for use when the patient has recovered from surgery. Oncophages to renal cell carcinoma and melanoma are under phase III development.
AG858 consists of autologous heat shock protein 70 (HSP70)-peptide complexes purified from the peripheral blood mononuclear cells of chronic myelogenic leukemia (CML) patients. Antigen-presenting cells (APCs) take up HSPs together with the peptides they chaperone, the accompanying peptides are delivered into the antigen-processing pathways, leading to peptide presentation by major histocompatibility complex (MHC) molecules. T cells recognize the antigenic peptides and are specifically activated against cancer cells bearing these peptides.
Hormone is responsible for the growth of certain cancers. Hormone-sensitive cancers can be treated with drugs that prevent hormone production or block the action of the hormone, thus prevent tumor growth.
| Product | Target | Indication | Clinical Status | Manufacturer |
|---|---|---|---|---|
| Acapodene (Toremifene) |
Estrogen receptor | Prostate cancer | Phase III | GTx |
| Arimidex | Aromatase inhibitor | Breast cancer | Market | AstraZeneca |
| Aromasin (Exemestane) |
Antiestrogen | Breast cancer | Market | Pfizer |
| Casodex | Anti-androgen | Prostate cancer | Market | AstraZeneca |
| D-63153 | LHRH antagonist | Prostate cancer | Phase II | AEterna Zentaris |
| Faslodex | Estrogen receptor antagonist | Breast cancer | Market | AstraZeneca |
| Femara | Aromatase inhibitor | Breast cancer | Market | Novartis |
| G17DT (Insegia) |
G-17 | Gastro-esophageal and pancreatic cancers | Phase II/III | Aphton and Aventis |
| GnRH Pharmaccine | GnRH | Pancreatic cancer | Phase II | Aphton |
| Nolvadex (Tamoxifen citrate) | Estrogen antagonist | Breast cancer | Market | AstraZeneca |
| Teverelix | LHRH antagonist | Prostate cancer | Phase I | AEterna Zentaris |
| Zoladex (Goserelin acetate) |
LHRH analogue | Breast and prostate cancers | Market | AstraZeneca |
Two classes of drugs most commonly used as hormonal therapy in breast and prostate cancers include: 1. Luteinizing hormone-releasing hormone (LHRH) analogs. This class of drugs, including D63153, Teverelix, and Zoladex, prevents hormone production. 2. Antiandrogens or antiestrogens. This class of drugs, including Casodex, Faslodex, and Tamoxifen, blocks the actions of hormones. The antiestrogen Tamoxifen is used to prevent estrogen stimulation of breast cancer cells. Tamoxifen binds to the estrogen receptor but the complex is not productive, that is, the complex fails to induce estrogen-responsive genes and RNA synthesis does not ensue. The result is a depletion of estrogen receptors, and the growth-promoting effects of the natural hormone and other growth factors are suppressed.
Arimidex and Femara are aromatase inhibitors and highly potent estrogen suppressor. It acts by interfering with the production of estrogen triggered by aromatase and reduces the total amount of estrogen in the body. As a result, less estrogen can reach breast cancer cells.Hormone-dependent breast cancers contain protein molecules called estrogen receptors. When no estrogen is present, the estrogen receptors remain inactive. When the estrogen receptors are exposed to estrogen, however, they trigger a chain of events that results in tumor cell growth and multiplication. Aromatase enzyme is needed to convert androgen into estrogen, which results in tumor growth. The drugs bind to the aromatase enzyme and block it from converting androgen to estrogen, thereby reducing growth of the tumor. Tumors that contain these estrogen receptors are known as estrogen receptor-positive (ER+) tumors. These are the cancers that can be treated by drugs to deprive them of estrogen. Acapodene is a selective estrogen receptor modulator (SERM).
D17DT (anti-gastrin 17) is a vaccine, containing a portion of the hormone gastrin 17 (G17), and diphtheria toxoid (DT), chemically bound together to form G17DT, neutralizes both G17 and the hormone Gly-G17 to treat relevant cancers. Phase III results showed that the drug had no overall survival benefit in pancreatic cancer compared to placebo and development for pancreatic patient was terminated in May 2005.
GnRH Pharmaccine is a vaccine that neutralizes the GnRH hormone for hormone-failed or hormone-resistant patients with prostate cancer.
Immunomodulatory drugs modify or regulate the functioning of the immune system. They induce, or inhibit immune responses, or enhance activity of immune cells. They affect the immune system through different ways, such as, enhancing the activation of T cells, enhancing the activity of natural killer (NK) cells, enhancing production of interleukin 2 (IL-2), inhibiting tumor necrosis factor-alpha (TNF-a) and interleukin 1-beta (IL-1ß), and stimulating the production of interleukin 10 (IL-10). All these activities lead to enhanced antitumor effects.
| Product | Target | Indication | Clinical Status | Manufacturer |
|---|---|---|---|---|
| Actimid | Immune cells | Prostate cancer | Phase III | Celgene |
| Avonex (Interferon beta-1a) | Immune cells | Glioma | Phase II | BiogenIdec |
| Bacillus Calmette-Guerin (BCG, TheraCys, ImmuCyst) | Immune cells | Bladder cancer | Market | Organon and Aventis |
| Intron A (Interferon alfa-2b) | Immune cells | Various tumors | Market | BiogenIdec |
| Ontak | Immune cells | Persistent or recurrent cutaneous T-cell lymphoma | Market | Ligand |
| Proleukin | Immune cells | Melanoma and kidney cancer | Market | Chiron |
| PEG-Intron | Immune cells | Chronic myelogenous leukemia and melanoma | Phase III | Enzon and Schering-Plough |
| Revlimid | Immune cells | Multiple myeloma and myelodysplatic | Market | Celgene |
| Thalomid and dexmethasone | Immune cells | Multiple myeloma | Market | Celgene |
| Thalomid | Immune cells | Thyroid cancer | Phase III | Celgene |
Bacillus Calmette-Guerin (BCG) is used for superficial early-stage bladder cancer. It promotes proliferation of T lymphocytes and causes local, acute inflammation. The inflammation is characterized by macrophage and leukocyte infiltration into the urinary bladder wall. The immune cells that conglomerate at the infection site cause tumor regression.
Thalomid and its derivatives, Revlimid and Actimid, mediate the production of cytokines and other growth factors that are responsible for growth and survival of tumor cells. They direct the immune system to target cancer cells for destruction by NK cells and cytotoxic T lymphocytes. They also lower levels of the proangiogenenic cytokines vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF).
Interferons are a family of naturally-occurring proteins that are produced by cells of the immune system. The interferon products, Avonex (interferon beta-1a), Intron A (interferon alfa-2b), and PEG-Intron (PEG-alpha interferon) direct the immune system's attack on tumor cells.
Interleukin is a number of naturally occurring immune system proteins. Both Ontak and Proleukin are interleukin-2, which activates specialized defense cells called T cells and natural killer (NK) cells to attack and destroy tumor cells.
Communication among and within cells involves in a series of signaling cascade. In the normal cells, the communication is balanced. The cancerous transformation of a cell often results from an excess of certain antennae-like receptors that reside on the cell membrane and protrude into the cell's interior. Activation of these receptors can initiate a cascade of biochemical signals that effectively tell the cell to proliferate wildly and then promote survival of the resulting tumor. Protein kinases play critical role in the signaling pathways. It is possible to use kinase inhibitor to suppress kinase activity and to control tumor growth.
| Product | Target | Indication | Clinical Status | Manufacturer |
|---|---|---|---|---|
| AMG706 | Multi-kinase | Various tumors | Phase II | Amgen |
| AZD0530 | Src kinase inhibitor | Various tumors | Phase I | AstraZeneca |
| CEP-701 | Tyrosine kinase inhibitor | Prostate cancer | Phase II | Cephalon |
| CEP-7055 | VEGFR tyrosine kinase inhibitor | Various tumors | Phase I | Cephalon |
| Sprycel (Dasatinib, BMS354825) |
Tyrosine kinase inhibitor | Chronic myelonic leukemia | Market | Bristol-Myers Squibb |
| EKB-569 | EGFR tyrosine kinase inhibitor | Colorectal and Pancreatic cancers | Phase II | Wyeth |
| Enzastaurin | PKC-beta | Various tumors | Phase II | Eli Lily |
| Gleevec (Imatinib mesylate) |
Tyrosine kinase inhibitor | Chronic myelonic leukemia | Market | Novartis |
| Iressa | EGFR tyrosine kinase inhibitor | Lung cancer | Market | AstraZeneca |
| MLN518 | FLT-3 receptor tyrosine kinase | Acute myeloid leukemia | Phase I | Millennium |
| MLN8054 | Aurora kinase | Various tumors | Phase I | Millennium |
| Nexavar | RAF kinase | kidney cancer | Market | Bayer and Onyx |
| Nexavar | RAF kinase | Liver cancer | Phase II | Bayer and Onyx |
| Nilotinib (AMN107) |
Bcr-Abl | Chronic myelonic leukemia | Phase III | Novartis |
| Perifosine (KRX-0401) | AKT/protein kinase B | Various tumors | Phase II | Aetera Zentaris and Keryx Biopharmaceuticals |
| PKC412 | Protein kinase C | Acute myelonic leukemia | Phase I | Novartis |
| PTK787 (Vatalanib) |
VEGFR tyrosine kinase inhibitor | Colorectal cancer and mesothelioma | Phase II | Novartis |
| Sutent (SU11248, Sunitinib Malate) |
VEGFR tyrosine kinase inhibitor | GIST and kidney cancers | Market | Pfizer |
| Sutent | VEGFR tyrosine kinase inhibitor | Liver Cancer | Phase II | Pfizer |
| Tykerb (Lapatinib) | ErbB-2 and EGFR dual kinase inhibitors. | Breast cancer | Market | GlaxoSmithKline |
| Tarceva | EGFR tyrosine kinase inhibitor | Non small cell lung cancer | Market | Genentech and OSI |
| VX-680 | Aurora kinase | Virious tumors | Phase II | Vertex |
| ZD6474 | VEGFR tyrosinekinase inhibitor | Various tumors | Phase II | AstraZeneca |
Gleevec (Imatinib mesylate) is the first kinase inhibitor approved for treatment of cancer, chronic myelonic leukemia (CML). In CML, there is a constant signal that tells the body to keep producing abnormal white blood cells. The constant signal is created by three events: first, there is a change in a person's DNA; second, this change forms the Philadelphia (Ph) chromosome (named after the city where it was discovered), third, the Ph chromosome creates an abnormal protein that tells the body to send out the constant signal. Gleevec is a tyrosine kinase inhibitor and works by interfering with the abnormal protein, Bcr-Abl, and blocking it from telling the body to keep making more and more abnormal white blood cells. It is a therapy that affects the molecular cause of CML.
Like Gleevec, Sprycel (Dasatinib, BMS354825) is also a kinase inhibitor. But Sprycel is 300 to 1000 times more potent than Gleevec for inhibition of Bcr-Abl tyrosine kinase. Dasatinib is also an Src inhibitor as well as an Abl inhibitor. It is orally bio-available and can be taken as an oral pill. Nilotinib represents the next generation targeted, oral therapy specifically designed to be the most selective inhibitor of Bcr-Abl.
AZD0350 is an Src kinase inhibitor with capacity of reducing tumor invasion and of preventing tumors from spreading.
EKB-569, Iressa, and Tarceva are kinase inhibitors that target epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor (HER1), which is critical to cell growth in many cancers. EGFR/HER1 is a key component of the HER signaling pathway, which is often involved in the formation and growth of numerous cancers. These kinase inhibitors are designed to inhibit specifically the kinase activity of HER1/EGFR, thereby blocking the signaling pathway with the intent of potentially inhibiting tumor cell growth.
CEP-7055, PTK787, and ZD6474 are vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor. Angiogenesis, the natural process used by the human body to produce blood vessels, occurs as a pathological process in the development of solid tumors. The blood vessels created by this process provide the nutrients and oxygen the tumor needs to grow and spread. The process of angiogenesis is mediated by a number of factors including polypeptide VEGF. As a result, inhibitors of the receptor kinase for VEGF have potential utility in the treatment of solid tumors. ZD6474 also has activity against epidermal growth factor receptor tyrosine kinase.
MLN518 is a small molecule specifically designed to inhibit the fms-like tyrosine kinase-3 (FLT-3) receptor tyrosine kinase in patients with acute myeloid leukemia (AML).
Perifosine is an alkyphosphocholine with structural similarity to phospholipids that are main constituents of cellular membranes. It targets AKT/protein kinase B activity and exerts cytotoxic effect.
PKC412 is a kinase inhibitor that blocks several isoforms of protein kinase C (PKC) and receptors for VEGF, platelet-derived growth factor, and stem cell factor, inhibits vascularization.
Nexavar is an orally active, small molecule agent. It targets the RAF kinase, receptors of vascular endothelial growth factor and platelet-derived growth factor. This novel compound inhibits both tumor cell proliferation and angiogenesis.
VX-680 represents the first drug to stop tumors by targeting enzymes called Aurora kinases.? Aurora kinases play an important role in mitosis, or the process of cell division, which is out of control in cancer patients. Aurora kinases have been identified as overly abundant in certain types of cancer, such as leukemia, colon cancer and breast cancer. MLN8054 is a novel small molecule inhibitor of Aurora kinase(s) and exhibits potent anti-tumor activity against a variety of human tumor xenograft models.
Tykerb, Lipatinib, is an ErbB-1 (EGFR) and ErbB-2 (HER-2/neu) dual kinase inhibitors. These two receptors have been implicated in the growth of various tumor types, and often are associated with a poor prognosis.
Sutent is an oral small molecule drug that inhibits several kinases. These are enzymes needed for cell functions.? The specific enzymes that Sutent inhibits are the vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), Kit (a transmembrane receptor tyrosine kinase), and FLT3 receptor tyrosine kinases. By inhibiting these enzymes these receptors have their function inhibited. The drug has anti-angiogenic effects because VEGF and PDGF are important to many types of tumor to develop new blood supplies that are needed for tumor growth. VEGF and PDGF have been implicated in the growth of melanoma tumors.? It also has direct anti-tumor effects.
Enzastaurin HCl (LY317615, e-HCl), an acyclic bisindolylmaleimide, is a potent inhibitor of Protein Kinase C-beta isozyme. The beta isoform lies in the signal cascade of VEGF and inhibition of this pathway may lead to a block in tumor angiogenesis.
AMG 706 is a potent, oral, multi kinase inhibitor with anti-angiogenic and anti-tumor activity achieved by selectively targeting all known VEGF, PDGF, Kit and Ret receptors.
CEP-701 is a class of small, orally active molecules that are selective inhibitors of tyrosine kinase, thus, antagonizing the "survival" signal elicited by this receptor and inhibiting tumor growth.
Microtubule is a part of cytoskeleton in the eukaryotic cell. Cytoskeleton is critical component of mitotic spindle and is essential for the internal movements occurring in the cytoplasm. When cell divides, the mitotic spindle plays an important role in equally partitioning of DNA into the two daughter cells. The microtubule inhibitor disrupts this process by affecting microtubule function.
| Product | Target | Indication | Clinical Status | Manufacturer |
|---|---|---|---|---|
| Abraxane | Microtubule | Various tumors | Market | Abraxis Biosciences |
| AVE-8062 | Microtubule | Various tumors | Phase I/II | Aventis |
| Ixabepilone | Microtubule | Various tumors P | Market | Bristol-Myers Squibb |
| KOS-862 (Epotholine D) | Microtubule | Breast cancer, colorectal cancer, kidney cancer, melanoma, and non-small cell lung cancer | Phase I/II | Bristol-Myers Squibb and Kosan Biosciences |
| Tasidotin | Tubulin | Various tumors | Phase II | Genzyme |
| MAC-321 | Microtubule | Breast and colorectal cancers | Phase II | Wyeth |
| Navelbine | Microtubule | Breast and non-small cell lung cancers | Phase III | GlaxoSmithKline |
| Taxol | Microtubule | Various tumors | Market | Bristol-Myers Squibb |
| Taxotere | Microtubule | Various tumors | Market | Aventis |
Taxol (paclitaxel) and Taxotere (docetaxel) are both from the same drug family - the taxanes. Taxol is the first member of taxane family used in the cancer treatment. Taxotere is a semi-synthetic product.
Abraxane is formed by nanoparticle albumin-bound technology. Paclitaxel is bound to albumin in nanoparticle to get the insoluble drug into cells without a solvent and make the drug selective for tumor cells, since normal cells are too tightly joined even for nanoparticles, but nanoparticles are able to navigate the "leaky junctions" between malformed tumor cells. Therefore, the drug targets the tumor cells and spares the normal cells.
KOS-862, or Epotholine D, appears to be promising microtubule stabilizing agents with a somewhat different spectrum of activities than the taxanes, including activity in paclitaxel-resistant tumors.
Ixabepilone is a semi-synthetic analog of epothilone B, which is strong promoters of microtubulin polymerization and has tubulin polymerizing activity that is 2-10 times stronger than paclitaxel.
Tasidotin is a novel tubulin-interactive agent. The agent is a synthetic dolastatin analog and has a unique mechanism of action that potentially differs from that of microtubule-stabilizers (taxanes and epothilones) and tubulin inhibitors (vinca alkaloids and other dolastatins). It has been chemically modified to provide improved pharmacological properties and is orally bioavailable with a potentially enhanced therapeutic window over earlier-generation dolastatins.
AVE8062 (AC-7700) is a water-soluble derivative of combretastatin A and is a member of a new class of agents called vascular targeting agents. AVE8062 has an innovative mechanism of action: it inhibits tubulin polymerization in activated endothelial cells, which results in a rapid occlusion of the tumor vasculature, leading to vascular shutdown.
MAC-321 is a taxane analog with demonstrated superior antitumor activities and is believed to exert its anti-tumor cell effects through several mechanisms including tubulin binding, microtubule stabilization, apoptosis, TNF-alpha up-regulation and angiogenesis inhibition.
Oncolytic (cancer-killing) viruses have tropism for tumor cells, selectively infect or replicate in tumor cells, but spare normal cells. Some of these viruses are naturally attenuated viral strains (such as some strains of reovirus or vesiculostomatitis virus) that more effectively infect or replicate in tumor cells. Others are genetically modified (such as herpes simplex virus type 1 or adenovirus) to mediate oncolytic effects.
Compared with traditional therapies, oncolytic viruses have a high therapeutic index with respect to their ability to kill tumor cells. In some instances, the therapeutic index of oncolytic viruses has been found to be as high as 10,000 to 1, i.e., for every 10,000 tumor cells that are killed, only one normal cell is killed. This is significantly higher than the therapeutic index commonly seen with chemotherapy, 6 to 1, and may result in greater efficacy with fewer side effects.
| Product | Target | Indication | Clinical Status | Manufacturer |
|---|---|---|---|---|
| CG0070 | Tumor cells | Recurrent bladder cancer | Phase I | Cell Genesys |
| H101 | P53 pathway defective tumors | Head and neck cancers | Market in China | Shanghai Sunway Biotech |
| Reolysin | Ras activated tumor cells | Prostate cancer and glioma | Phase II | Oncolytics Bitotech |
H101, the oncolytic virus used for head and neck cancer, was approved for use in China. H101 is genetic engineered adenovirus, which selectively replicates in cancer cells and spares normal cells. H101 is a modified version of Onyx-015, lacking E1B-55K and E3 gene functions, and can infect cancer cell, replicate within the cell, and kill the cell through lyses. New viruses released from the lysed cell can infect more caner cells, whereas, H101 does not replicate in normal cell, therefore does not damage the normal cell and causes minimal side-effect.
CG0070, an oncolytic virus with specificity for multiple cancers, is armed with granulocyte macrophage clony stimulation factor (GM-CSF), an immune stimulating hormone. CG0070 can potentially destroy cancer cells through direct cell killing by the virus and through immune-mediated cell killing stimulated by GM-CSF.
Reolysin is a reovirus, named for the Respiratory Enteric Orphan virus. Reovirus is found naturally in sewage and the water supply. The majority of humans have shown evidence of reovirus exposure, but the disease is non-pathogenic, or there are typically no symptoms from infection. The link to its cancer-killing ability was established after it was discovered that the virus grew remarkably well in various cancer cell lines. Reolysin has been demonstrated to replicate specifically in tumor cells bearing an activated Ras pathway. In a tumor cell with an activated Ras pathway, reovirus is able to freely replicate and eventually kill the host tumor cell. As cell death occurs, progeny viruses are then free to infect surrounding cancer cells. This cycle of infection, replication and cell death is repeated until there are no longer any tumor cells carrying an activated Ras pathway.
The proteasome is an enzyme complex found within the cytoplasm of cells. It serves both as a disposal system for damaged cellular proteins and as a mechanism for degrading short-lived regulatory proteins that govern cellular functions such as the cell cycle, cell growth, and differentiation. Because these processes or their dysregulation are crucial steps in tumor formation, the proteasome pathway is a logical target for therapeutic intervention. The following mechanisms are involved in the relevant cancer drug action: (1) impede cancer cell proliferation by preventing the breakdown of certain valuable proteins and transcription factors that are known to hinder cancer cell growth; (2) reduce the survivability of cancer cells by inactivating certain genes and proteins that help cancer cells surviving; (3) cause cancer cell death by producing extreme cellular stress in tumor cells through disruption of cell proliferation.
| Product | Target | Indication | Clinical Status | Manufacturer |
|---|---|---|---|---|
| Velcade | Proteasome | Multiple myeloma | Market | Johnson and Johnson and Millennium |
Velcade is the first proteasome inhibitor drug in market for multiple myeloma treatment.
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Molecule is the smallest particle that can exist in free state. The smallest particle of a substance that retains the chemical and physical properties of the substance and is composed of two or more atoms; a group of like or different atoms held together by chemical forces. Small molecules are a diverse group of natural and synthetic substances that generally have a low molecular weight. They are either isolated from natural sources such as plants, fungi or microbes, or they are synthesized by organic chemistry. Most conventional pharmaceuticals, such as aspirin, penicillin, and chemotherapeutics, are small molecules.
| Product | Target | Indication | Clinical Status | Manufacturer |
|---|---|---|---|---|
| Flavopiridol | Cyclin-dependent kinases | Various tumors | Phase I/II | Aventis |
| MLN944 | Cancer cell DNA | Various tumors | Phase I | Millennium |
| Telcyta | GST P1-1 | Various tumors | Phase II/III | Telik |
| Telintra | Bone marrow | Melodysplastic syndrome | Phase II | Telik |
Small molecules can be kinase inhibitor, antiangiogeneses agent, and others. Most of them are already illustrated in an appropriate class. Those can not be classified and are shown in the Table 12. Small molecule kinase inhibitor is one of most successful anti-cancer drugs. Several drugs, such as, Gleevec, Iressa, Nexavar, Sutent. and Tarceva, are in the market for different cancer indications.
Flavopiridol is a small molecule derivative of the alkaloid rohitukine, which inhibits cyclin-dependent kinases causing a halt to cell cycle. MLN944 (XR5944) is a novel small molecule with DNA activity. The primary mechanism of action of MLN944 likely involves DNA binding and intercalation.
Telcyta (TLK286) is a small molecule activated by glutathione S-transferase P1-1 (GST P1-1), an enzyme present in higher levels in many human cancers than in normal tissues. Activation of Telcyta occurs when GST P1-1 splits Telcyta into two active fragments: a glutathione analog fragment and an active cytotoxic fragment. The cytotoxic fragment reacts with important cell components, including RNA, DNA and proteins, leading to cell death.
Telintra (TLK199), a small molecule bone marrow stimulant, is in a Phase II trial in myelodysplastic syndrome, a form of pre-leukemia.
T cell is another arm of immune system that protects human body from pathogens (antigens). For treatment and prevention of tumors, eliciting a strong cellular or T cell immune response is critical. The cellular response is comprised of activated cytotoxic T lymphocyte (CTL) and helper T lymphocyte (HTL) that are directed toward multiple discrete and specific antigen fragments, known as antigen-specific epitopes. The activated T cells have special molecules similar to antibodies on the surface. These special molecules allow T cells to recognize, react to, and destroy cancer cells. Compare to the antibody technology, limited advancement is achieved in the area of T cell technology. So far, there isn't any marketed anti-cancer product derived from T cell-based technology. However, significant progresses are being made in this field.
One of the most important advancement is the identification of numerous immunogenic tumor antigens that are recognized by autologous T cells. The T cell-defined tumor antigens are potential tumor-rejection antigens that can be targeted by augmenting the antigen-specific immune response in one of two ways: adoptive T-cell therapy or vaccine therapy.
Adoptive T-cell therapy involves the ex vivo isolation and expansion of antigen-specific T-cell clones. These can be infused into patients to augment their immune response. To achieve their goal, the primed CTLs must expand to sufficient numbers, migrate to tumour sites, mature into effector cells and perform their cytolytic functions. Tumors, in turn, exploit several mechanisms to elude or derail immunity. These include the ability to inactivate T cells through mechanisms such as anergy, apoptosis and suppression. Another challenge for cancer T cell immunity is to overcome the tumor's abilities to escape from the immune response.
The ability to genetically engineer primary T cells creates new prospects for the T cell-based cancer therapy. The transduction of T cells with genes that encode antigen receptors enables the recognition of antigens that are either poorly immunogenic or ignored by the immune system. Another important impetus for genetically modifying T cells is to enhance their antitumoral activities. This might be accomplished on different levels, such as by increasing T-cell expansion, offsetting anergizing or pro-apoptotic signals, expanding the range of tumoricidal functions and protecting T cells against the suppressive effects of the tumor microenvironment.
| Product | Target | Indication | Clinical Status | Manufacturer |
|---|---|---|---|---|
| INGN225 | p53 | Various tumors | Phase II | Introgen |
| Lapuleucel-T | HER-2/neu | Various tumors | Phase II | Dendreon |
| MDX-1379 | GP100 | Melanoma | Phase III | Medarex |
| Sipuleucel-T (Provenge) |
prostatic acid phosphatase | Prostate cancer | Phase III | Dendreon |
One example of T cell-based therapy is Dendreon's proprietary Antigen Delivery Cassette technology and dendritic/cancer cell fusion technology. The vaccine is created by fusing the patient's own tumor cells/proteins with powerful, immune-stimulating dendritic cells. The fusion product is then injected back into the patient with the goal of sparking a specific immune response (T-cells) against the cancer. Lapuleucel-T and Sipuleucel-T are generated by this technology. Lapuleucel-T targets HER2/neu positive cancers. HER2/neu is a growth factor receptor, and its overexpression has been associated with a number of cancers including breast, ovarian, colon and lung cancers. The HER2/neu protein is delivered to a patient's antigen presenting cells (APCs), dendritic cells. These APCs activate other cells (including T-cells) of the immune system to seek out and destroy HER2/neu-containing cancer cells. Sipuleucel-T targets the prostate cancer antigen, prostatic acid phosphatase (PAP), which is found in approximately 95% of prostate cancers.
INGN 225 is a personalized therapeutic vaccine consisting of a cancer patient's dendritic cells treated with an adenovector carrying the human p53 gene (Ad-p53). When these modified dendritic cells are returned to the patient's body, they activate the patient's T-cells to seek out and destroy cancer cells.
MDX-1379 is made up of two peptides that are pieces of a bigger melanoma protein (gp100). These peptides bind to HLA-A2 which is then recognized by T cells.
The topoisomerases are essential nuclear enzymes for DNA replication. They control DNA structure by maintaining the correct superhelical state within the cell, as well as by resolving intertwined DNA strands. This requires the formation of transient breaks in DNA. Topoisomerase I generates single-stranded breaks, and topoisomerase II introduces double-stranded breaks.
The topoisomerase inhibitors are termed topoisomerase poisons because they convert their enzyme into a potent cellular toxin by preventing DNA from unwinding and interfering with the cell's replication, leading to cell death. All cells require topoisomerases, but fast-growing cancer cells need more of them. By inhibiting the enzymes, the drugs selectively inflict more damage on cancer cells than on normal cells.
| Product | Target | Indication | Clinical Status | Manufacturer |
|---|---|---|---|---|
| Hycamtin | Topoisomerase I | Small cell lung cancer | Market | GlaxoSmithKline |
| Irinotecan (Campto, Camptosar) | Topoisomerase I | Colorectal cancer | Market | Aventis, Pfizer, and Merck |
| Lucanthone | Topoisomerase II | Brain tumor | Phase II | SuperGen |
| MLN576 | Topoisomerase I and II | Various tumors | Phase I | Millennium |
| Novantrone | Topoisomerase II | Leukemia and prostate cancer | Market | OSI |
| Pegamotecan | Topoisomerase I | Gastroesopheagal cancer | Phase II | Enzon |
| Rubitecan | Topoisomerase I | Prostate cancer | Phase III | SuperGen |
Camptothecins and their derivatives are substrates of topoisomerase I. CT-2106 is a polyglutamate-camptothecin. Linking a camptothecin to polyglutamate polymer renders it water soluble, and studies suggest that it permits up to 400% more drug to be administered without an increase in toxicity.Campto (Irinotecan), a topoisomerase I inhibitor, is a reference treatment for advanced colorectal cancer.
Rubitecan, a topoisomerase I inhibitor, is an analogue of camptothecins. Hycamtin (Topetecan) is a semi-synthetic derivative of camptothecin. Pegamotecan (Prothecan) is a PEG-enhanced version of camptothecin.
Novantrone is a potent inhibitor of topoisomerase II. Lucanthone is a topoisomerase II inhibitor and has marked radiosensitizing activity in advanced brain tumors in humans.
MLN576 (XR11576) is a small molecule with DNA-targeting activity that includes dual inhibition of topoisomerases I and II.