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.  The drugs are designed to inhibit overexpression or underexpression of a molecule or combination of molecules specific to the cancer.  Most targeted therapies involve either (1) antibodies and are hence classified as immunotherapy, or (2) small molecule kinase inhibitors and other signal induction inhibitors.

By inhibiting the presence or expression of growth factors, cytokines/chemokines, receptor/adaptor molecules, and other proteins, these drugs interrupt the ability of the cancer to grow in the body.  Ideally they don’t simultaneously harm healthy tissue the way conventional chemotherapy agents can.

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 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 the 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 medical 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 are among the tools in the oncologist’s toolbox.

Biological therapy (also called biological response modifier therapy) uses materials made from living organisms to produce an anti-cancer effect more targeted than cytotoxic drugs do.  Biotherapies include immunotherapies that work on the immune system (either enhancing it or suppressing it), virus therapy, and adoptive cell therapy.

Another major class of drugs is called kinase inhibitors. Most function inside the body 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 dysfunctioning tyrosine kinase activity. The malignant cells cannot clump together as a tumor, and the ability of the cancer to harm the body declines. The FDA has approved more than 50 kinase inhibitors for treatment of cancer.

There are many families of kinases.  Kinase inhibitor drugs approved for cancer and other diseases target 21 of those families.  There are kinase inhibitors for other diseases, but most small molecule kinase inhibitors approved by the FDA are for cancer.  All monoclonal antibodies approved by the FDA that target kinases are for cancer.

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

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

How targeted are the therapies?  Even at the smallest level, medicines considered targeted therapies aren’t always super specific.  Many of the kinase inhibitors are known to interfere with more than one metabolic pathway and have two or more targets.  See the list here.  Monoclonal antibodies are more precise – most have only one antigen they attach to.  But some, called bispecific antibodies, can bind to more than one antigen.

New Forms of Targeting and Challenges

Drugs that induce apoptosis (cause cells to kill themselves) are also being developed as a form of targeted therapy, and researchers have created conjugates that 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.  Pharmacogenomics is another possible avenue for further precision.

Targeted therapy drugs have the downside that the cancer frequently develops resistance The cancer may develop a second mutation that somehow allows it to grow by bypassing the target metabolic pathway. 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 promising approach is tumor-agnostic chemotherapy.  The word agnostic refers to the place of tumor origination 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 growth, however. Indeed, the tumor’s genes or other biological 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 in (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.  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.

Off-label use

Chemotherapy medicines are often given off-label and targeted therapies are no exception.  How oncologists make the decision to give targeted drugs off-label differs from the decision process for conventional cytotoxic drugs.  Because they are newer, there is less evidence about these drugs in combination therapy and less in-the-field evidence as to their effectiveness and safety.  Because they generally have less severe side effects doctors tend to feel more comfortable employing these drugs.  On the other hand targeted drugs are often quite expensive as the new ones are under patent protection, so insurers balk at paying for off-label use.

In the Pipeline

Over 200 targeted therapy agents are fairly advanced in the development pipeline. Metabolic pathway inhibitors and monoclonal antibodies (immunotherapy) are the hot topics in medicinal chemistry.  A 2021 survey found 253 small molecule kinase inhibitors were in development by pharmaceutical companies.

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?

Bust of Asclepius who was the Greek God of Medicine

Asclepius, Greek God of Medicine

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 malignant growth, 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, the target turns out to be less important than originally thought. 

New drugs have a high failure rate in development and targeted therapies are no exception.  One reason observers have floated is that the developers are going after the wrong target.  An interesting study published in 2019 backs up this idea.  The scientists did a detailed study of cancer drugs that had been approved – which have been shown to be effective at least some times in some patients.  However, the researchers showed that the drugs do not work by affecting their putative targets.  They work but by “off-target” effect. 

Skepticism

Despite the optimism, perceived potential of the targeted approach, and the efforts of the pharmaceutical industry, the large number of new targeted therapies in recent years has not resulted in huge increases in cancer survival rates.  Some scientists are expressing skepticism about the wisdom of following the paths researchers have been going down.  Writing in the Journal of Clinical and Translational Medicine in 2018, two scientists said “the outcomes are very bleak and disappointing“.  They also question the cost-benefit of the targeted therapies compared to older chemotherapy treatment.

Nobody disputes that basic research has shed light on genetic alterations in cancer cells and the  molecular drivers of disease progression, but “historically, our ability to translate cancer research to clinical success has been remarkably low,” in the words of a Nature article.

Theranostics for cancer.

Spanish: Terapia Dirigida para el Tratamiento del Cáncer

Other information:

Nature: Targeted cancer therapy

Current Drug Discovery Technologies

NEJM: Chemotherapy-free Treatment — A New Era in Acute Lymphoblastic Leukemia?