Targeted Cancer Therapies – Current Status and Future Prospects

Kaushik Bharati, PhD

In the field of anticancer therapy, a number of strategies for improving the therapeutic efficacy of anticancer agents have emerged over the past several decades. These strategies essentially involve strategies for targeted anticancer drug delivery.

Several new classes of targeted anticancer therapies have recently been introduced for routine clinical use. While conventional chemotherapy targets all dividing cells, these molecules target specifically the cancer cells. These include monoclonal antibodies, the small molecule tyrosine kinase inhibitors and nanoparticles.

Monoclonal antibodies

Different types of monoclonal antibodies (mAb) are used in cancer therapy by conjugating them to various types of anticancer drugs. These conjugated drugs are denoted by the suffix –mab (indicating that they are conjugated to a monoclonal antibody). Naked mAbs are the most common for treating cancer. Some naked mAbs boost a person’s immune response against cancer cells by attaching to them and acting as a marker for the body’s immune system to destroy them. An example is alemtuzumab (Campath®), which is used to treat some patients with chronic lymphocytic leukemia (CLL). Other naked mAbs work mainly by attaching to and blocking antigens that are important signals for cancer cells (or other cells that help cancer cells grow or spread). For example, trastuzumab (Herceptin®) is an antibody against the HER2 protein, expressed in large amounts in breast cancer.

Monoclonal antibodies, conjugated to a chemotherapeutic agent or a radioactive molecule, targets these agents directly to the cancer cells, thereby dramatically reducing collateral damage to normal cells that would otherwise have occurred if chemotherapy was used alone. Chemolabeled mAbs have powerful chemotherapeutic agents attached to them. A chemolabeled antibody approved by the US-FDA is brentuximab vedotin (Adcetris®), used to treat Hodgkin’s lymphoma and anaplastic large cell lymphoma that is resistant to other treatments. Likewise, radiolabeled mAbs have small radioactive molecules attached to them. Ibritumomab tiuxetan (Zevalin®) is an example of a radiolabeled mAb that delivers radioactivity directly to cancerous B cells and can be used to treat some types of non-Hodgkin’s lymphoma.

Bispecific mAbs are hybrid in nature i.e. they are made up of parts of two different mAbs that can attach to two different proteins at the same time. An example is blinatumomab (Blincyto®), which is used to treat some types of acute lymphocytic leukemia (ALL).

Monoclonal antibodies are given intravenously and can sometimes cause local side-effects like an allergic reaction. Systemic effects include fever, weakness, headache and hypotension, as well as GI symptoms like nausea, vomiting, and diarrhea. However, compared with chemotherapy, mAbs tend to have fewer serious side-effects. Till date, the US-FDA has approved 21 mAbs against cancer. There is one mAb (Necitumumab) for non-small cell lung cancer that is still under review.

Small molecules

The small molecules block the signal transduction pathways of malignant cells. Among the most common small molecules are the tyrosine kinase inhibitors that inhibit kinases that phosphorylate key proteins to activate signal transduction pathways. A classic example is imatinib (Gleevec®) that is used to treat chronic myeloid leukemia (CML). Small molecules are administered orally, and block a number of different tyrosine kinases. Another class of these molecules include the inhibitors of mammalian target of rapamycin (mTOR). Two examples of this class include everolimus for the treatment of pancreatic neuroendocrine tumor, and temsirolimus for renal cell carcinoma. These molecules bind to an intracellular protein (FKBP-12). This complex then blocks the activity of mTOR kinase which inhibits angiogenesis and tumor cell growth, proliferation and survival.

Nanoparticles

An anticancer drug could be actively targeted to its desired location by covalently attaching it to a polymer along with a homing moiety, attached to the same polymeric carrier. These are called nanoparticles. They are spherical microscopic structures, the size of which falls in the nanometer range (10-9 meter or 0.000000001 m!); hence called nanoparticles. Nanoparticles of polymer-drug conjugates have several advantages over the corresponding parent drug, including fewer side effects, enhanced therapeutic efficacy, ease of drug administration, and improved patient compliance. An example of a nanoparticle of synthetic polymer-drug conjugate is poly glutamic acid-paclitaxel (PG-TXL). Others include poly-glutaraldehyde (PGL), poly-lactide-co-glycolide (PLG) and poly-alkylcyanoacrylate (PACA) nanoparticles for delivery of the anticancer drug 5-fluorouracil. Abraxane® is the first US-FDA approved drug to use albumin-paclitaxel nanoparticles to improve the therapeutic and safety properties of the anticancer agent.

The Future

The foregoing discussion highlights some of the modern strategies to improve the clinical action of anticancer drugs. It is expected that many more targeted therapies will come into routine clinical use in the near future. Monoclonal antibodies will be engineered to increase their immune effects. A future direction for small molecule tyrosine kinase inhibitors will be to combine them to overcome treatment resistance. Importantly, more novel delivery systems for anticancer drugs are on the horizon, and will greatly augment the clinician’s arsenal in the ongoing fight against cancer.