The main categories of targeted therapy are currently
small molecules and
monoclonal antibodies. Small molecules Many are
tyrosine-kinase inhibitors. •
Imatinib (Gleevec, also known as STI–571) is approved for
chronic myelogenous leukemia,
gastrointestinal stromal tumor and some other types of cancer. Early clinical trials indicate that imatinib may be effective in treatment of
dermatofibrosarcoma protuberans. •
Gefitinib (Iressa, also known as ZD1839), targets the
epidermal growth factor receptor (EGFR)
tyrosine kinase and is approved in the U.S. for non small cell
lung cancer. •
Erlotinib (marketed as Tarceva). Erlotinib inhibits
epidermal growth factor receptor, and works through a similar mechanism as gefitinib. Erlotinib has been shown to increase survival in metastatic non small cell
lung cancer when used as second line therapy. Because of this finding, erlotinib has replaced gefitinib in this setting. •
Sorafenib (Nexavar) •
Sunitinib (Sutent) •
Dasatinib (Sprycel) •
Lapatinib (Tykerb) •
Nilotinib (Tasigna) •
Bosutinib (Bosulif) •
Ponatinib (Iclusig) •
Asciminib (Scemblix) •
Afatinib (Giotrif) •
Bortezomib (Velcade) is an
apoptosis-inducing
proteasome inhibitor drug that causes cancer cells to undergo cell death by interfering with proteins. It is approved in the U.S. to treat
multiple myeloma that has not responded to other treatments. • The
selective estrogen receptor modulator tamoxifen has been described as the foundation of targeted therapy. •
Janus kinase inhibitors, e.g. FDA approved
tofacitinib •
ALK inhibitors, e.g.
crizotinib •
Bcl-2 inhibitors (e.g. FDA approved
venetoclax,
obatoclax in clinical trials,
navitoclax, and
gossypol. •
PARP inhibitors (e.g. FDA approved
olaparib,
rucaparib,
niraparib and
talazoparib) •
PI3K inhibitors (e.g.
perifosine in a phase III trial) •
Apatinib is a selective
VEGF Receptor 2 inhibitor which has shown encouraging anti-tumor activity in a broad range of malignancies in clinical trials. Apatinib is currently in clinical development for metastatic
gastric carcinoma, metastatic
breast cancer and advanced
hepatocellular carcinoma. •
Zoptarelin doxorubicin (AN-152),
doxorubicin linked to [D-Lys(6)]-
LHRH, Phase II results for ovarian cancer. •
Braf inhibitors (
vemurafenib,
dabrafenib,
LGX818) used to treat metastatic
melanoma that harbors BRAF V600E mutation •
MEK inhibitors (
trametinib,
MEK162) are used in experiments, often in combination with BRAF inhibitors to treat
melanoma •
CDK inhibitors, e.g.
PD-0332991,
LEE011 in clinical trials •
Hsp90 inhibitors, some in clinical trials •
Hedgehog pathway inhibitors (e.g. FDA approved
vismodegib and
sonidegib). •
Salinomycin has demonstrated potency in killing
cancer stem cells in both laboratory-created and naturally occurring breast tumors in mice. •
VAL-083 (dianhydrogalactitol), a “first-in-class” DNA-targeting agent with a unique bi-functional DNA cross-linking mechanism.
NCI-sponsored clinical trials have demonstrated clinical activity against a number of different cancers including
glioblastoma,
ovarian cancer, and
lung cancer. VAL-083 is currently undergoing Phase 2 and Phase 3
clinical trials as a potential treatment for
glioblastoma (GBM) and ovarian cancer. As of July 2017, four different trials of VAL-083 are registered. •
Ibrutinib blocks Bruton's tyrosine kinase (BTK) and is used to treat
mantle cell lymphoma,
chronic lymphocytic leukemia, and
Waldenström's macroglobulinemia.
Small molecule drug conjugates •
Vintafolide is a small molecule drug conjugate consisting of a small molecule targeting the folate receptor. It is currently in clinical trials for platinum-resistant ovarian cancer (PROCEED trial) and a Phase 2b study (TARGET trial) in non-small-cell lung carcinoma (NSCLC).
Serine/threonine kinase inhibitors (small molecules) •
Temsirolimus (Torisel) •
Everolimus (Afinitor) •
Vemurafenib (Zelboraf) •
Trametinib (Mekinist) •
Dabrafenib (Tafinlar)
Monoclonal antibodies Several are in development and a few have been licensed by the FDA and the European Commission. Examples of licensed monoclonal antibodies include: •
Pembrolizumab (Keytruda) binds to PD-1 proteins found on T cells. Pembrolizumab blocks PD-1 and help the immune system kill cancer cells. It is used to treat
melanoma,
Hodgkin's lymphoma,
non-small cell lung carcinoma and several other types of cancer. •
Rituximab targets
CD20 found on B cells. It is used in non Hodgkin
lymphoma •
Trastuzumab targets the
Her2/neu (also known as ErbB2) receptor expressed in some types of
breast cancer •
Alemtuzumab •
Cetuximab target the
epidermal growth factor receptor (
EGFR). It is approved for use in the treatment of metastatic
colorectal cancer and
squamous cell carcinoma of the head and neck. •
Panitumumab also targets the EGFR. It is approved for the use in the treatment of metastatic
colorectal cancer. •
Bevacizumab targets circulating VEGF ligand. It is approved for use in the treatment of
colon cancer,
breast cancer,
non-small cell lung cancer, and is investigational in the treatment of
sarcoma. Its use for the treatment of
brain tumors has been recommended. •
Ipilimumab (Yervoy) •
Brentuximab targets CD30 and is useful in some types of
lymphoma. Many
antibody-drug conjugates (ADCs) are being developed. See also
antibody-directed enzyme prodrug therapy (ADEPT). ==Progress and future==