Targeted Therapy in Treatment of Cancer

Targeted chemotherapy agents affect biochemical factors or cellular pathways that are unique to malignant cells or characteristic of tumors.

These drugs interrupt the ability of the cancer to grow in the body, and ideally they that don’t simultaneously harm healthy tissue the way conventional chemotherapy agents can.  Most new cancer drugs like this.  From 2015 to 2018, the United States Food and Drug Administration approved 43 new medicines for cancer therapy, and 41 of these drugs could be classified as targeted therapy.

The Problem

Conventional chemotherapy drugs are “cytotoxic.”  Cyto means cell. These chemicals kill cells – both cancerous and healthy. Most attack cells during reproduction, by inhibiting cellular division. Because cancer cells tend to multiply faster than healthy cells, the chemotherapy agents kill malignant cells at a greater rate than they kill healthy cells. This differential in killing rates is what makes chemotherapy effective against cancer. However, there are major downsides to this type of approach. First, plenty of healthy cells are killed. Tissues that have rapid cell division tend to do worst. This is why you see the side effects of chemotherapy showing up in areas of the body where rapid cell division happens. The insides of the digestive system are such as place – which is why chemotherapy patients often feel nauseous. The interior of the nasal passages and the follicles on the scalp are affected – which is why common side effects include loss of taste and going bald. And the cells in the bone marrow that make red blood cells are affected – which is why anemia is so common.

The side effects are not just discomforts for the patient. They present real challenges for doctors attempting to manage the cancer. The limiting dose – the highest amount of the chemotherapy drug that can be administered – is often set by the toxicity of the drug to the body.  The “therapeutic ratio” of conventional cancer drugs is narrow.  Indeed, when designing combination regimens of more than one chemotherapy drug, a major factor is selection of drugs with different organ-limiting toxicities.

The Targeted Therapy Answer

Scientists long dreamed of a “magic bullet” that would attack cancer and leave the rest of the body unscathed. In the 1990s the research community got excited by research into angiogenesis inhibitors. These chemicals – some of which occurred naturally in the body and some of which were new synthetic compounds – slowed the growth of blood vessels. The idea was that by stopping the growth of capillaries (small blood vessels), these new drugs would stop the growth of tumors. Without a supply of blood, the tumor could not grow to be big enough to cause problems.

While the initial excitement around angiogenesis inhibitors faded to some extent, many cancer drugs designed to work in this manner are in use today.  Bevacizumab and Lenalidomide are among the top selling (total revenue) cancer drugs today and Ramucirumab, Cabozantinib, Sorafenib, and Sunitinib among the tools in the oncologist’s toolbox.

Another major area of investigation is the class of drugs called tyrosine kinase inhibitors or just kinase inhibitors. These work by “competitive ATP inhibition at the catalytic binding site of tyrosine kinase” https://www.ncbi.nlm.nih.gov/pubmed/19689244   They slow or stop the proliferation of malignant cells and disrupt the integrity of tumors.  Growing cancers have disfunctioning tyrosine kinase activity.  The malignant cells cannot clump together as a tumor, and the ability of the cancer to harm the body declines. Over 30 kinase inhibitors have been approved for treatment of cancer, and others are in development.

Subtypes of kinase inhibitors include phosphoinositide 3-kinase inhibitors, BRAF inhibitors, Bruton’s tyrosine kinase, cyclin-dependent kinases, and MEK inhibitors.  Most kinase inhibitors work on tyrosine kinases, but some work on serine/threonine kinases.

Other biochemical inhibitor drugs target histone deacetylases and proteasomes.  The new class of tumor-agnostic drugs also come under the umbrella of targeted therapies.

New Forms of Targeting and Challenges

Drugs that induce apoptosis (cause the cells to kill themselves) are also being developed as a form of targeted therapy, and some researchers are looking for ways to use monoclonal antibodies as delivery mechanisms for toxic payloads.  The specificity of the antibody allows the toxin to be placed exactly where it should be to kill the malignant cells, without harming healthy cells.

Targeted therapy drugs have the downside that the cancer frequently develops resistance.  The mutation may develop a second mutation that somehow bypasses the target metabolic pathway.  A mutation in a downstream protein may be the culprit, too. Oncologists often combine targeted therapies with conventional chemotherapy drugs for this reason.   Targeted therapy medicines can be prescribed by doctors “off label.”  This is not illegal, unethical, or uncommon. Indeed, it is quite common and not as scary as it might sound at first.

Another interesting and promise approach is tumor-agnostic chemotherapy.  The word agnostic refers to the place of the tumor in the body.  It is also called tissue-agnostic chemotherapy. Cancer treatment has traditionally focused on the type of cancer, as defined partly by where the tumor started.  Tumor-agnostic chemotherapy is not agnostic regarding the biochemistry of the tumor, however.  Indeed, the tumor’s genes or other chemical features are what drives the treatment decision. But the tumors are classified by these molecular characteristics.  A particular sarcoma tumor might have the same genetic mutation as a kidney cancer tumor. These tumors might be amenable to a treatment that is classified as tumor-agnostic.  The first tumor-agnostic therapies, Larotrectinib and Pembrolizumab, were approved by the FDA in 2017 and 2018, and researchers are looking at others.

In the Clinic

An increasing number of cancer cases are being tested for possible application of targeted therapy.

Treatment guidelines published by the National Comprehensive Cancer Network for non–small-cell lung cancer call for the doctor to identify the genetic signature of the cancer before proceeding with a treatment plan. 

Mutated HER2 genes are implicated (or at least part of) some breast cancer cases and specific chemotherapy regimens are used for those breast cancer cases and less so for other breast cancer cases.  However, some lung cancer cases also have HER2 mutations and there is an idea in the oncology community that similar regimens can be used on those cases.

In the Pipeline

Reportedly, over 200 targeted therapy agents are fairly advanced in the development pipeline, according to a 2019 report.

Companion Diagnostics

For some medicines (and a few targeted therapies for cancer are among them), the FDA requires companion diagnostics be used in conjunction with the therapy.  The diagnostic is included on the label.  More on companion diagnostics.

Why don’t we have more targeted therapies?

Challenges to developing new targeted therapies include identification of molecular pathway targets.  Scientists look for differences between malignant cells and normal ones. The differences are usually DNA mutations and protein levels, but not all differences provide useful targets.   A typical cancer cell has multiple genetic mutations, but only a few driver mutations cause the cancer, and it is hard to identify which ones are drivers.

And even if you can find a good target, it is not always straightforward to come up with a drug that affects the target.  Sometimes drugs are found effective against targets in laboratory glassware. When the drugs are tried in animals or humans, it turns out the target turns out to be less important than originally thought.  This is a common reason so many targeted therapy medicines wash out in clinical trials.

Theranostics for cancer.